to - Kenes Group

Transcription

to - Kenes Group

Volume 16 Supplement 1 2014
Diabetes
Technology &
ISSN 1520-9156
Therapeutics
Editor-in-Chief
Satish K. Garg, M.D.
Senior Editors
Jay S. Skyler, M.D., M.A.C.P.
Irl B. Hirsch, M.D.
Special ATTD issue
•ATTD 2013 Yearbook
•Abstracts from ATTD 2014
7th International Conference on Advanced Technologies
& Treatments for Diabetes
The Official Journal of
ATTD
Advanced Technology
& Treatments for Diabetes
CONFERENCE
DTT-16nS1.indd 1
www.liebertpub.com/DTT
1/10/14 2:23 PM
Diabetes Technology & Therapeutics
DIABETES TECHNOLOGY & THERAPEUTICS is a peer-reviewed journal providing healthcare
professionals with information on new devices, drugs, delivery systems, and software for managing patients
with diabetes. This leading international journal delivers practical information and comprehensive coverage
of the latest technologies and therapeutics in the field, and each issue highlights new pharmacological and
device developments to optimize patient care.
Information for Manuscript Submission: www.liebertpub.com/dia
Submit manuscripts online: http://mc.manuscriptcentral.com/diabetestechnology
The views, opinions, findings, conclusions, and recommendations set forth in any article in DIABETES
TECHNOLOGY & THERAPEUTICS are solely those of the authors of those articles and do not necessarily
reflect the views, policy or position of the Journal, its Publisher, its editorial staff, or any affiliated Societies
and should not be attributed to any of them.
Reprints: For permission to photocopy 99 copies or less of an article for internal purposes, please request
permission and pay the appropriate fee by contacting the Copyright Clearance Center, Inc.: (978) 750-8400. If
the required number of copies of an article is 100 or more, please contact the Publisher at (914) 740-2100.
Advertising inquiries from North America, Europe and all parts of the world should be addressed to
Advertising Department, Mary Ann Liebert, Inc., 140 Huguenot Street, New Rochelle, NY 10801, or call
(914) 740-2100. Send E-mail inquiries to: [email protected] All advertisements are subject
to approval by the Publisher. The acceptance of advertisements does not constitute an endorsement of the
product or service advertised.
Indexed/Abstracted in: MEDLINE, PubMed, PubMed Central, Current ContentsÒ=Clinical Medicine,
Science Citation Index Expanded, Journal Citation Reports=Science Edition, Prous Science IntegrityÒ,
EMBASE=Excerpta Medica, Scopus, Elsevier BIOBASE-Current Awareness in Biological Sciences
(CABS), EMCare, and CINAHLÒ database.
Subscriptions should be addressed to the Publisher and are payable in advance. Bulk subscriptions are
available upon request from the Publisher. No cancellations/refunds can be honored after publication of a
volume’s first issue. Visit our website (www.liebertpub.com/dia) or contact our Customer Service
Department for current subscription rates and pricing information.
DIABETES TECHNOLOGY & THERAPEUTICS (ISSN: 1520–9156) is owned and published by
Mary Ann Liebert, Inc. Copyright Ó2014 by Mary Ann Liebert, Inc. Printed in the United States
of America. Mailed in Canada under CPC CPM #40026674. Postmaster: Send address changes to
DIABETES TECHNOLOGY & THERAPEUTICS, c/o Subscription Department, Mary Ann Liebert,
Inc., 140 Huguenot Street, New Rochelle, NY 10801-5215.
Mary Ann Liebert, Inc.
140 Huguenot Street
New Rochelle, NY 10801-5215
Telephone: (914) 740-2100
E-mail: [email protected]
Editor-in-Chief
Geremia B. Bolli, MD
Satish K. Garg, MD
Joseph D. Brain, ScD
University of Colorado Denver
Barbara Davis Center for Childhood Diabetes
1775 Aurora Court
Aurora, CO 80045
Telephone: (303) 724-6713/(303) 724-6770
Fax: (303) 724-6784 or 6797
Senior Editors
Jay S. Skyler, MD, MACP
University of Miami
Miller School of Medicine
Miami, FL
Irl B. Hirsch, MD
University of Washington Medical
Center—Roosevelt
Seattle
Associate Editor
Stuart A. Weinzimer, MD
Yale University School of Medicine
New Haven, CT 06520-8064
International Associate Editors
Peter Colman, MD
Royal Melbourne Hospital
Parkville, Victoria, Australia
Hans DeVries, MD, PhD
Academic Medical Center
at the University of Amsterdam
The Netherlands
Linong Ji, MD
Peking University Diabetes Center
Peking, P.R. China
V. Mohan, MD, PhD
Dr. Mohan’s Diabetes Specialities Centre
Madras Diabetes Research Foundation
Chennai, India
Naoko Tajima, MD
Jikei University School of Medicine
Tokyo, Japan
Editorial Board
Aus Alzaid, MD
Riyadh Military Hospital, Saudi Arabia
Stephanie Amiel, MD
Kings College London School of Medicine
London, UK
James H. Anderson, MD
Lilly Research Laboratories
Indianapolis, IN
Mark A. Arnold, PhD
University of Iowa, Iowa City
Muthuswamy Balasubramanyam, PhD
Madras Diabetes Research Foundation
Chennai, India
Katharine Barnard, PhD
University of Southampton
Southampton, UK
Richard N. Bergman, PhD
University of Southern California
Los Angeles
Lawrence Blonde, MD
Ochsner Clinic Foundation
New Orleans, LA
University of Perugia, Perugia, Italy
Harvard School of Public Health, Boston
Robert D. Burk, MD
Albert Einstein College of Medicine
Bronx, NY
John Buse, MD, PhD
University of North Carolina School
of Medicine
George Cembrowski, MD, PhD
University of Alberta
Edmonton, Canada
H. Peter Chase, MD
University of Colorado Denver
Thomas Danne, MD
Diabetes Centre for Children
and Adolescents
Hannover, Germany
Steven Edelman, MD
University of California at San Diego
Robert Gabbay, MD, PhD
Pennsylvania State University
Michael S. German, MD
University of California at
San Francisco
Peter A. Gottlieb, MD
Barbara Davis Center for
Childhood Diabetes
Aurora, CO
David A. Gough, PhD
Richard H. Guy, PhD
University of Bath, England
Lutz Heinemann, PhD
Profil Institut for Metabolic Research
Neuss, Germany
Weiping Jia, MD, PhD
Shanghai Clinical Center for Diabetes
Jeffrey I. Joseph, DO
Thomas Jefferson University
Philadelphia
Shashank R. Joshi, MD
Joshi Clinic, Lilavati & Bhatia Hospital
Mumbai, India
Lois Jovanovic, MD
Sansum Diabetes Research Institute
Santa Barbara, CA
David M. Kendall, MD
Eli Lilly and Company
Indianapolis, IN
Joseph Kost, PhD
Ben-Gurion University of the Negev
Beer-Sheva, Israel
Davida F. Kruger, MSN
Henry Ford Medical Center—New
Center One, Detroit, MI
Robert Langer, ScD
MIT, Cambridge
David Maahs, MD, PhD
Barbara Davis Center for
Childhood Diabetes
Aurora, CO
Louis Monnier, MD
Institute of Clinical Research
Montpellier, France
Alan C. Moses, MD
Novo Nordisk, Princeton, NJ
Sunder Mudaliar, MD
David Owens, MD
Cardiff University, Penarth, UK
Neal R. Pellis, PhD
NASA Johnson Space Center, Houston
Moshe Phillip, MD
Tel-Aviv University
Petah Tikva, Israel
Kimberly H. Porter, PhD
International Medical Press, Atlanta
Gérard Reach, MD
Hôpital Avicenne
Bobigny, France
Eric Renard, MD
Lapeyronie University Hospital
Montpellier, France
Matthew C. Riddle, MD
Oregon Health Science University
Portland
David Rodbard, MD
Biomedical Informatics Consultants LLC
Potomac, MD
Kristina I. Rother, MD
National Institutes of Health, Bethesda
David S. Schade, MD
University of New Mexico, Albuquerque
James Shapiro, MD, PhD
University of Alberta
Edmonton, Canada
Arlene Smaldone, MA, DNSc
Columbia University School of Nursing
New York
Ian Sweet, PhD
University of Washington, Seattle
Kazunori Utsunomiya, MD
Jikei University School of Medicine
Tokyo, Japan
Aaron I. Vinik, MD, PhD
Leonard Strelitz Diabetes Institutes
Norfolk, VA
Robert F. Vogt, Jr., PhD
Centers for Disease Control and Prevention
Atlanta
Darrell M. Wilson, MD
Stanford University, Palo Alto, CA
Howard A. Wolpert, MD
Joslin Diabetes Center, Boston, MA
Paul Z. Zimmet, MD, PhD
International Diabetes Institute
Melbourne
Bernard Zinman, MD
University of Toronto
Ontario, Canada
Statistical Advisor
Philip J. Smith, PhD
Centers for Disease Control and Prevention
Atlanta
Editorial Coordinator
Dawn White
Adult Clinic Administrative Assistant
Barbara Davis Center for Childhood Diabetes
1775 Aurora Court
Aurora, CO 80045
Telephone: (303) 724-6770
Fax: (303) 724-6784
Volume 16
Supplement 1
February 2014
ATTD 2013 Yearbook
Advanced Technologies & Treatments for Diabetes
Edited by Moshe Phillip and Tadej Battelino
EDITORIALS
DTT Publishes the ATTD 2013 Yearbook
S-1
Satish K. Garg
Technologies in Diabetes–the Fifth ATTD Yearbook
S-2
Tadej Battelino and Moshe Phillip
ORIGINAL ARTICLES
Self-Monitoring of Blood Glucose—An Overview
S-3
Satish K. Garg and Irl B. Hirsch
Continuous Glucose Monitoring in 2013
S-11
Tadej Battelino and Bruce W. Bode
Insulin Pumps
S-17
John Pickup
Closing the Loop
S-23
Eran Atlas, Andrew Thorne, Kara Lu, Moshe Phillip, and Eyal Dassau
New Insulins and Insulin Therapy
S-34
Thomas Danne and Jan Bolinder
Insulin Pens and New Ways of Insulin Delivery
S-44
Lutz Heinemann
Using Health Information Technology to Prevent and Treat Diabetes
S-56
Neal Kaufman
Technology and Pregnancy
S-68
Adrian Cotarelo, Homaira T. Zaman, Lois Jovanovič, and Moshe Hod
Metabolic Surgery Is No Longer Just Bariatric Surgery
S-78
E. Charles Moore and Walter J. Pories
Immune Intervention for Type 1 Diabetes, 2012–2013
S-85
Jay S. Skyler
(continued )
Physical Activity and Exercise
S-92
Michael Riddell, Sophie Pollack, Homadis Shojaei, Joshua Kalish, and Howard Zisser
Diabetes Technology and Therapy in the Pediatric Age Group
S-100
Shlomit Shalitin and H. Peter Chase
Diabetes Technology and the Human Factor
S-110
Alon Liberman, Bruce Buckingham, and Moshe Phillip
Newer Therapies for Diabetes Management
S-119
Satish K. Garg and Viral N. Shah
Abstracts from ATTD 2014
7th International Conference on Advanced
Technologies & Treatments for Diabetes
Vienna, Austria, February 5–8, 2014
ATTD 2014 Oral Presentations
A-1
ATTD 2014 Poster Presentations
A-34
ATTD 2014 Read By Title
A-147
ATTD 2014 Late Breaking Abstracts
A-153
ATTD 2014 Abstract Author Index
A-163
Instructions for Authors can be found at the back of the issue or on our website at www.liebertpub.com/DTT
DIABETES TECHNOLOGY & THERAPEUTICS
Volume 16, Supplement 1, 2014
ª Mary Ann Liebert, Inc.
DOI: 10.1089/dia.2014.1499
EDITORIAL
DTT Publishes the ATTD 2013 Yearbook
Satish K. Garg , MD
O
nce again, it gives me great pleasure to publish the
prestigious Advanced Technologies & Treatments for
Diabetes (ATTD) 2013 Yearbook as a special supplement to
Diabetes Technology & Therapeutics (DTT). This Fifth Edition
of the Yearbook covers the leading topics and controversies in
the field of diabetes and is authored by key international
opinion leaders in their area of expertise. Each chapter presents a concise summary of the most important articles on that
topic published from July 2012 to June 2013, with insightful
and invaluable expert commentary. Publishing the Yearbook in
the DTT is vital because it means the articles are searchable on
Medline and Google and will be available in over 170 countries around the globe.
I value the support and hard work by all of the authors
and Moshe Phillip’s and Tadei Battelino’s leadership in
bringing out the Yearbook annually.
Beginning in 2014, our relationship with ATTD is expanding—I am pleased to say that DTT has been named the
Official Journal of ATTD. The partnership between ATTD and
DTT is obvious because they represent the leading conference
and journal, respectively, in the field of new technologies and
treatments for diabetes.
We will also be publishing the abstracts from the upcoming
ATTD 2014 meeting—the 7th International Conference on
ATTD to be held in Vienna, Austria, on February 5–8, 2014.
I want to wish you all a happy and prosperous New Year.
Please feel free to send me your comments so that we can
improve and implement changes in the ATTD Yearbook
every year.
University of Colorado Denver and Barbara Davis Center for Childhood Diabetes, Aurora, Colorado.
S-1
—Satish K. Garg, MD
Editor-in-Chief
DOI: 10.1089/dia.2014.1500
EDITORIAL
Technologies in Diabetes–the Fifth ATTD Yearbook
Tadej Battelino, MD1 and Moshe Phillip, MD 2,3
T
he fifth Advanced Technologies and Treatments
for Diabetes (ATTD) yearbook comes to you in its now
already traditional form. Published data reviewed by the
leading experts this year almost suggest that the philosophical stratagem of closed-loop insulin delivery may indeed be close to a product introduced into clinical practice.
Despite the proven clinical benefit of continuous subcutaneous insulin infusion and continuous glucose monitoring,
psychological and behavioral barriers still limit their benefits. When linked together, and at least partially controlled
by an algorithm, its users suddenly become relieved from a
fragment of their daily responsibilities, and it almost looks
like the initial benefit comes at no psychological or behavioral cost. The clinical reader may decide if there is enough
scientific ground for some cautious optimism, and the industry may find reasons for the crucial decision of bringing
a closed-loop insulin delivery system to the market. All of
this is revealed in the broadest frame of 14 chapters covering all that is new and advanced in the ever-expanding
field of diabetes.
The major advantage of ATTD remains its completely open
character without any formal structure that would set limits
or rules. Free flow of creative ideas and friendly exchange of
different opinions provide the background for cooperative
creativity between medical care professionals, scientists, engineers, investors, and managers. The ATTD yearbook touches the base with handpicked data and sets the ground for
plans funded on the best available knowledge.
The ATTD web page and the publisher, Mary Ann
Liebert, Inc., generously provide the electronic text of the
ATTD yearbook free to all. The 11,200 hits and downloads in
the last year speak for itself. The global reach of the ATTD
yearbook fulfills one of the fundamental missions of the
ATTD—free exchange and distribution of knowledge and
clinical experience to each and every member of our diabetes
community.
Finally, it is the dream that creates the future—the ATTD
yearbook through its contributors and associate editors fosters this ongoing dream and provides some fertile soil for
growing it into a reality for our patients.
1
University Children’s Hospital, Lubljana, Slovenia.
Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children’s Medical Center of Israel, Petah
Tikva, Israel.
3
Sackler Faculty of Medicine, Tel Aviv University, Ramal Aviv, Israel.
2
S-2
DOI: 10.1089/dia.2014.1501
ORIGINAL ARTICLE
Self-Monitoring of Blood Glucose—An Overview
Satish K. Garg1 and Irl B. Hirsch 2
Introduction
P
revalence of diabetes is increasing globally. As estimated by the International Diabetes Federation, there will
be more than a billion people with diabetes by the year 2030
(1). Recent data from the United States show that more patients are reaching the target glycosylated hemoglobin
(HbA1c) values without hypoglycemia. This has resulted in a
significantly lower rate of microvascular complications associated with diabetes. Because of new insulin analogs (basal
and prandial insulins), new oral and noninsulin injectables,
self-monitoring of blood glucose (SMBG), and new technologies such as continuous glucose monitor (CGM) and continuous subcutaneous insulin infusion (CSII), diabetes
management has become easier.
SMBG is an effective therapy for the management of diabetes (type 1 diabetes mellitus [T1DM] and type 2 diabetes
mellitus [T2DM]). In T2DM, the use of SMBG clearly results in
early therapeutic changes even in non–insulin-requiring subjects with T2DM. Current and new generations of glucose
meters are meeting the International Organization for Standardization (ISO) benchmark of less than 20% variability (2).
However, all of the manufacturers soon will have to meet the
ISO benchmark of less than 15% variability. A multicenter
analysis including 24,500 patients from 191 centers in Germany
and Australia showed that frequent SMBG is associated with
better metabolic control in patients with T1DM and T2DM (3).
In this chapter, we reviewed articles on SMBG that were
published from July 1, 2012, to June 30, 2013. We found 315
articles/abstracts, of which we are commenting on 13 SMBG
abstracts. We strongly believe that these 13 abstracts represent
the current scenario, usefulness, and recommendations for
SMBG in both T1DM and T2DM.
Possible impacts of new accuracy standards
of self-monitoring of blood glucose
Barbara Davis Center for Diabetes, University of Colorado,
Denver
US Endocrinol 2013; 9: 28–31
Comment
Although SMBG is an integral part of diabetes management, the older SMBG devices were not accurate. However, with strict guidelines and implementation of ISO
requirements, newer SMBG devices are fairly accurate
and improving. This article reviews the accuracy and
standards for glucose meters. However, new ISO standards might pose additional cost burden with which the
companies must comply.
Evidence of a strong association between frequency
of self-monitoring of blood glucose and hemoglobin
A1c levels in T1D Exchange clinic registry participants
Miller KM 1, Beck RW1, Bergenstal RM 2, Goland RS 3,
Haller MJ 4, McGill JB 5, Rodriguez H 6, Simmons JH 7,
Hirsch IB 8 for the T1D Exchange Clinic Network
1
Garg SK 1, Reed K 1, Grey J 1, Westerman A1
1
Self-monitoring of blood glucose (SMBG) was an integral part of the reduction of complication rates in type 1
diabetes during the landmark Diabetes Control and Complications Trial (DCCT). However, the accuracy and standardized reporting of SMBG devices remains a key
concern, with the 2003 version of the ISO 15197 standard
allowing for 5% of readings to fall outside of the acceptable
ranges. A recently revised 2013 version of the ISO 15197
standard includes stricter accuracy benchmarks, with a 36month transition period recommended before compliance
becomes mandatory. These new accuracy standards will
have implications not only for manufacturers of currently
available and future devices but also for the end users, who
may face rising costs and necessary measures to improve
patient error rates associated with SMBG in routine clinical
practice.
Jaeb Center for Health Research, Tampa, FL; 2International Diabetes Center/Park Nicollet, Minneapolis, MN; 3Naomi Berrie
Diabetes Center, Columbia University, New York City, NY;
4
University of Florida, Gainesville, FL; 5Washington University,
St. Louis, MO; 6University of South Florida, Tampa, FL;
1
Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver Health Sciences Center, Aurora, CO.
University of Washington Medical Center, Seattle, WA.
2
S-3
S-4
7
Vanderbilt University Medical Center, Nashville, TN; and
University of Washington Medical Center, Seattle, WA
8
Diabetes Care 2013; 36: 2009–14
Objective
Despite substantial evidence of the benefit of frequent selfmonitoring of blood glucose (SMBG) in type 1 diabetes,
certain insurers limit the number of test strips that they will
provide. The large database of the T1D Exchange clinic
registry provided an opportunity to evaluate the relationship between the number of SMBG measurements per day
and HbA1c levels across a wide age range of children and
adults.
Research Design and Methods
The analysis included 20,555 participants in the T1D Exchange clinic registry with type 1 diabetes ‡ 1 year and not
using a continuous glucose monitor (11,641 aged less than 18
years and 8,914 aged 18 years or older). General linear models
were used to assess the association between the number of
SMBG measurements and HbA1c levels after adjusting for
potential confounding variables.
Results
A higher number of SMBG measurements per day were
associated with non-Hispanic whites, insurance coverage, higher household income, and use of an insulin pump
for insulin delivery ( p < 0.001 for each factor). After
adjusting for these factors, a higher number of SMBG
measurements per day were strongly associated with a
lower HbA1c level (adjusted p < 0.001), with the association
being present in all age groups and in both insulin pump
and injection users.
Conclusions
There is a strong association between higher SMBG frequency and lower HbA1c levels. It is important for insurers to
consider that reducing restrictions on the number of test strips
provided per month may lead to improved glycemic control
for some patients with type 1 diabetes.
Comment
This multicenter study, funded originally by the Helmsley Trust Foundation through Jaeb Center, involving
more than 67 leading diabetes centers in the United States
enrolled more than 20 thousand patients with T1DM. The
data have been presented at national and international
scientific meetings. This real-life, large database clearly
shows the role of SMBG in improving glucose control in
subjects with T1DM. There was a difference of more than
1.5% in HbA1c between subjects who tested none and
those who tested more than eight times per day. However, this is a self-reported database (reported by patients
or parents or clinical staff). The data were not verified by
any other organizations, including Jaeb Center. At least
for T1DM, it clearly documents the importance of SMBG
in improving glucose control.
GARG AND HIRSCH
Clinical review: consensus recommendations
on measurement of blood glucose and reporting
glycemic control in critically ill adults
Finfer S 1, Wernerman J 2, Preiser JC 3, Cass T 4, Desaive T 5,
Hovorka R 6, Joseph JI 7, Kosiborod M 8, Krinsley J 9,
Mackenzie I 10, Mesotten D 11, Schultz MJ 12, Scott MG 13,
Slingerland R 14, Van den Berghe G 11, Van Herpe T 11,15
1
The George Institute for Global Health and Royal North Shore
Hospital, University of Sydney, St. Leonards, Sydney, Australia;
2
Department of Anesthesiology & Intensive Care Medicine, Karolinska University Hospital, Solna, Sweden; 3Department of Intensive Care, Erasme University Hospital, Brussels, Belgium;
4
Institute of Biomedical Engineering, Imperial College, South
Kensington Campus, London, United Kingdom; 5GIGA—Cardiovascular Sciences, University of Liege, Institute of Physics, Liege,
Belgium; 6Institute of Metabolic Science, University of Cambridge
Metabolic Research Laboratories, Level 4, Institute of Metabolic
Science, Addenbrooke’s Hospital, Cambridge, United Kingdom;
7
Department of Anesthesiology, Jefferson Artificial Pancreas Center & Anesthesiology Program for Translational Research, Jefferson Medical College of Thomas Jefferson University, Philadelphia,
PA; 8Saint-Luke’s Mid America Heart Institute, University of
Missouri–Kansas City, Kansas City, MO; 9Division of Critical
Care, Stamford Hospital and Columbia University College of
Physicians and Surgeons, Stamford, CT; 10Department of Anaesthesia and Intensive Care Medicine, Queen Elizabeth Hospital
Birmingham, Queen Elizabeth Medical Centre, Birmingham,
United Kingdom; 11Department of Intensive Care Medicine, University Hospitals Leuven, Leuven, Belgium; 12Department of Intensive Care Medicine, Academic Medical Center at the University
of Amsterdam, Amsterdam, The Netherlands; 13Division of Laboratory and Genomic Medicine, Department of Pathology and
Immunology, Washington University School of Medicine, St.
Louis, MO; 14Isala Klinieken, Department of Clinical Chemistry,
JW Zwolle, The Netherlands; and 15Department of Electrical Engineering (ESAT-SCD), Katholieke Universiteit Leuven, Leuven,
Belgium
Crit Care 2013; 17: 229
The management reporting and assessment of glycemic
control lacks standardization. The use of different methods to
measure the blood glucose concentration and to report the
performance of insulin treatment yields major disparities and
complicates the interpretation and comparison of clinical trials. We convened a meeting of 16 experts plus invited observers from the industry to discuss and, where possible,
reach consensus on the most appropriate methods to measure
and monitor blood glucose in critically ill patients and on how
glycemic control should be assessed and reported. Where
consensus could not be reached, recommendations on further
research and data needed to reach consensus in the future
were presented. Recognizing their clear conflict of interest,
industry observers played no role in developing the consensus or recommendations from the meeting. Consensus recommendations were agreed upon for the measurement and
reporting of glycemic control in clinical trials and for the
measurement of blood glucose in clinical practice. Recommendations covered the following areas: How should we
measure and report glucose control when intermittent blood
glucose measurements are used? What are the appropriate
SELF-MONITORING OF BLOOD GLUCOSE—AN OVERVIEW
performance standards for intermittent blood glucose monitors in the ICU? Continuous or automated intermittent glucose monitoring—methods and technology: can we use
the same measures for assessment of glucose control with
continuous and intermittent monitoring? What is acceptable
performance for continuous glucose monitoring systems? If
implemented, these recommendations have the potential to
minimize the discrepancies in the conduct and reporting of
clinical trials and to improve glucose control in clinical practice.
Furthermore, to be fit for use, glucose meters and continuous
monitoring systems must match their performance to fit the
needs of patients and clinicians in the intensive care setting.
Comment
This is an excellent review on the consensus of SMBG and
CGM in diabetes management. It further includes recommendations for inpatient diabetes management. This
report is an attempt to standardize recommendations of
frequency of SMBG in subjects with diabetes.
S-5
active control (AC) with four-point glycemic profiles performed at baseline and at 6 and 12 months. Two primary end
points were tested in hierarchical order: HbA1c change at 12
months and percentage of patients on target for being at risk
for low and high blood glucose index.
Results
Intent-to-treat analysis showed greater HbA1c reductions over 12 months in ISM ( - 0.39%) than in AC patients
( - 0.27%), with a between-group difference of - 0.12% (95%
confidence interval, - 0.210 to - 0.024; p = 0.013). In the perprotocol analysis, the between-group difference was - 0.21%
( - 0.331 to - 0.089; p = 0.0007). More ISM than AC patients
achieved clinically meaningful reductions in HbA1c ( > 0.3,
> 0.4, or > 0.5%) at study end ( p < 0.025). The proportion of
patients reaching/maintaining the risk target at month 12
were similar in ISM (74.6%) and AC (70.1%) patients
( p = 0.131). At visits 2, 3, and 4, diabetes medications were
changed more often in ISM than in AC patients ( p < 0.001).
Conclusions
Intensive structured self-monitoring of blood glucose
and glycemic control in noninsulin-treated type 2
diabetes: the PRISMA randomized trial
Bosi E 1,2, Scavini M 1,2, Ceriello A 3, Cucinotta D 4, Tiengo A 5,
Marino R 6, Bonizzoni E 7, Giorgino F 8 on behalf of the PRISMA
Study Group
The use of structured SMBG improves glycemic control and
provides guidance in prescribing diabetes medications in
patients with relatively well-controlled non–insulin-treated
type 2 diabetes.
Comment
1
Diabetes Research Institute, San Raffaele Hospital and Scientific
Institute, Milan, Italy; 2San Raffaele Vita-Salute University,
Milan, Italy; 3Institut d’Investigacions Biomèdiques August Pi
Sunyer and Centro de Investigacion Biomedica en Red de Diabetes
y Enfermedades Metabolicas Asociadis, Barcelona, Spain; 4Department of Internal Medicine, Policlinico Universitario Gaetano
Martino, Messina, Italy; 5Division of Metabolic Diseases, Department of Clinical and Experimental Medicine, University of
Padova, Padova, Italy; 6Medical Affairs, Roche Diagnostics,
Monza, Italy; 7Section of Medical Statistics and Biometry G.A.
Maccacaro, Department of Occupational Health Clinica del Lavoro
L. Devoto, School of Medicine, University of Milan, Milan, Italy;
and 8Section of Internal Medicine, Endocrinology, Andrology, and
Metabolic Diseases, Department of Emergency and Organ
Transplantation, University of Bari School of Medicine, Bari, Italy
Diabetes Care 2013 Jun 4: [Epub ahead of print]; DOI: 10.2337/dc130092
Objective
We aimed to evaluate the added value of intensive selfmonitoring of blood glucose (SMBG), structured in timing and
frequency, in non–insulin-treated patients with type 2 diabetes.
The 12-month randomized clinical trial enrolled 1,024 patients with non–insulin-treated type 2 diabetes (median
baseline HbA1c, 7.3% [interquartile range, 6.9–7.8%]) at 39
diabetes clinics in Italy. After standardized education, 501
patients were randomized to intensive structured monitoring
(ISM) with four-point glycemic profiles (fasting, preprandial,
2-hour postprandial, and postabsorptive measurements)
performed 3 days/week; 523 patients were randomized to
The PRISMA study is a randomized controlled trial of
structured SMBG in non–insulin-treated subjects with
T2DM—a controversial topic. The results clearly show
that the appropriate use of SMBG results in guidance for
prescribing diabetes therapies. As expected, it also resulted in improvement in glucose control. The study
highlights the need for reviewing the SMBG data by the
providers and the patients so that necessary modifications in therapy can be made.
Frequency of blood glucose testing in well-educated
patients with diabetes mellitus type 1: how often
is enough?
Minder AE1, Albrecht D1, Schäfer J 2,3, Zulewski H1
1
Division of Endocrinology Diabetes and Metabolism, 2Basel Institute for Clinical Epidemiology and Biostatistics, and 3Clinical
Trial Unit, University Hospital Basel, Basel, Switzerland
Diabetes Res Clin Pract 2013 May 29: [Epub ahead of print]; DOI:
10.1016/j.diabres.2012.12.024
Aims
Self-monitored blood glucose (SMBG) and knowledge of
insulin requirements are pivotal for good metabolic control in
patients with diabetes mellitus type 1. However, the SMBG
frequency needed for optimal glycemic control especially in
well-educated patients is unclear.
Methods
In patients with type 1 diabetes treated with flexible intensified insulin therapy, we evaluated HbA1c values and the
S-6
directly preceding computerized SMBG frequencies over a 12month period. To estimate the association between HbA1c and
SMBG frequency, we fitted a piece-wise linear spline model
with a change in slope at four SMBGs per day, which is the
recommended minimal SMBG frequency at our institution.
GARG AND HIRSCH
sulin, and highlights strategies for improving the effectiveness
of SMBG-based treatment interventions in this population.
Comment
The above two studies further highlight the importance
of SMBG in T1DM and T2DM. In the first study, at least
four SMBG measurements a day resulted in better glucose control in T1DM, and the results are similar to those
in T1DM Exchange clinic data presented in the second
abstract of this chapter.
Results
A total of 150 patients were available for analysis, with a
median baseline HbA1c of 7.1% (interquartile range 6.6–7.8). In
the multivariable analysis (adjusted for sex and psychological
problems), each additional SMBG measurement was associated
with an estimated difference in HbA1c of - 0.19% (95% confidence interval - 0.42, 0.05) for £ 4 SMBGs per day and of - 0.02%
(95% confidence interval - 0.10, 0.06) for > 4 SMBGs per day.
Conclusions
Good diabetes control can be achieved in routine diabetes
care with flexible intensified insulin therapy based on continuing patients’ education and with a minimum of four
SMBGs per day.
2-year follow-up to STeP trial shows sustainability
of structured self-monitoring of blood glucose
utilization: results from the STeP practice logistics
and usability survey (STeP PLUS)
Friedman K1, Noyes J 1, Parkin CG 2
1
Roche Diagnostics, Indianapolis, IN; and 2CGParkin Communications, Inc., Boulder City, NV
Diabetes Technol Ther 2013; 15: 344–47
Value and utility of self-monitoring of blood
glucose in non–insulin-treated patients
with type 2 diabetes mellitus
Blevins T
Texas Diabetes and Endocrinology, Austin, TX
Postgrad Med 2013; 125: 191–204
Self-monitoring of blood glucose (SMBG) levels provides
important information regarding glycemic control for patients with diabetes and is recommended by European and
American diabetes organizations as an essential adjunct to
periodic glycated hemoglobin (HbA1c) level monitoring. The
benefits of SMBG in improving glycemic control in patients
with type 1 diabetes and those with type 2 diabetes mellitus
(T2DM) who are being treated with insulin are well recognized.
In contrast, the potential role of SMBG in patients with T2DM
not treated with insulin remains controversial, which may lead
to underutilization of SMBG in this population. Structured
SMBG, introduced as part of a treatment intervention, has been
associated with modest but significant improvements in
HbA1c levels in patients with T2DM who are not taking insulin
as part of their management plan. Patient-obtained readings
provide valuable real-time feedback on glucose responses to
meals and exercise and provide the patient with guidance on
the day-to-day management of their diabetes. Studies have
shown that when patients perform self-monitoring as part of
their treatment interventions, support through appropriate
educational initiatives is critical to ensure that patients understand the rationale for SMBG. Patients should be trained in
correct testing techniques and data recording for SMBG, as well
as target blood glucose and goal HbA1c levels so that they will
know when their SMBG readings are out of range.
Technology has a potential role in facilitating SMBG-based
interventions by improving patient–physician communication and optimizing glycemic control through the use of remote data uploading, data analysis tools, and, perhaps, even
text messaging. This review outlines the benefits of SMBG in
the management of patients with T2DM not treated with in-
We report findings from a follow-up survey of clinicians from
the STeP study that assessed their attitudes toward and current use of the Accu-Chek 360 View tool (Roche Diagnostics,
Indianapolis, IN) approximately 2 years after the study was
completed. The Accu-Chek 360 View tool enables patients to
record/plot a seven-point self-monitoring of blood glucose
(SMBG) profile (fasting, preprandial/2-hour postprandial at
each of the three meals and at bedtime) on 3 consecutive days,
document meal sizes and energy levels, and comment on their
SMBG experiences. Our findings showed that the majority of
these physicians continue to use the tool with their patients,
citing enhanced patient understanding and engagement,
better discussions with patients regarding the impact of lifestyle behaviors, improved clinical outcomes, and better
practice efficiencies as significant benefits of the tool.
Comment
Last year, the STeP study showed better glycemic control
(in a randomized controlled trial) with structured SMBG
in T2DM. The randomization in this clinical trial was
cluster randomization in which clinics were randomized,
not the individual patients. The 2-year follow-up reported in this abstract shows the majority of the providers continue to use the tools with their patients and
improve clinical outcomes.
Early management of type 2 diabetes based on an
SMBG strategy: the way to diabetes regression—the
St. Carlos study: a 3-year, prospective, randomized,
clinic-based, interventional study with parallel groups
Garcı́a de la Torre N 1, Durán A1, Del Valle L 1, Fuentes M 2,
Barca I 3, Martı́n P1, Montañez C1, Perez-Ferre N 1, Abad R1,
Sanz F 1, Galindo M 1, Rubio MA 1, Calle-Pascual AL 1
1
Endocrinology and Nutrition Department, Hospital Clinico San
Carlos-IdISSC, Professor Martin Lagos s/n, Madrid, Spain; 2Preventive Medicine Department, Hospital Clı́nico San Carlos-
IdISSC, Madrid, Spain; and 3Rehabilitation Service, Hospital
Clı́nico San Carlos-IdISSC, Madrid, Spain
Acta Diabetol 2013 Mar 27: [Epub ahead of print]; DOI: 10.1007/
s00592-013-0467-9
S-7
1
Düsseldorf Catholic Hospital Group, West-German Centre of
Diabetes and Health, Düsseldorf, Germany; and 2Clinical Center of
Endocrinology, Medical University, Sofia, Bulgaria
Aims
Background
The aims are to define the regression rate in newly diagnosed type 2 diabetes after lifestyle intervention and pharmacological therapy based on a self-monitoring of blood
glucose (SMBG) strategy in routine practice as compared to
standard HbA1c-based treatment and to assess whether a
supervised exercise program has additional effects.
Effects of lifestyle change on blood glucose levels can be
observed by self-monitoring of blood glucose (SMBG) in type
2 diabetes mellitus (T2DM) patients. We analyzed whether
the SMBG-structured lifestyle intervention program ROSSOin-praxi-international can improve glucometabolic control in
the short- and the long-term.
Methods
Subjects and Methods
The St. Carlos study is a 3-year, prospective, randomized,
clinic-based, interventional study with three parallel groups.
One hundred ninety-five patients were randomized to the
SMBG intervention group [I group (n = 130): Ia, SMBG
(n = 65); Ib, SMBG + supervised exercise (n = 65)] and to the
HbA1c control group (C group) (n = 65). The primary outcome
was to estimate the regression rate of type 2 diabetes (HbA1c
< 6% on metformin treatment).
One hundred twenty-four SMBG-naı̈ve ambulatory non–
insulin-treated T2DM patients were randomly assigned to an
SMBG group (n = 63) and a control group (n = 61). Both groups
received a 12-week structured lifestyle guidance manual. The
SMBG group additionally got a blood glucose meter with 150
test strips and was instructed to measure blood glucose regularly as well as during life events. Glucometabolic parameters were assessed at baseline, after 12 weeks, and after 1.5
years.
Results
After 3 years of follow-up, diabetes regression was
achieved by 56 patients, 6 (9.2%) from the C group, 21 (32.3%)
from the Ia group, and 29 (44.6%) from the Ib group. The risk
ratio (95% confidence interval) for diabetes regression in the
intervention group (Ia + Ib) was 4.5 (2.1–9), p < 0.001, and remained after stratification by sex, age, and body mass index.
This difference was associated with healthier changes in lifestyle and greater weight loss. The risk ratio for a weight loss
> 4 kg was 3.6 (1.8–7), p < 0.001.
Conclusion
This study shows that the use of SMBG in an educational
program effectively increases the regression rate in newly
diagnosed type 2 diabetic patients after 3 years of follow-up.
These data suggest that SMBG-based programs should be
extended to primary care settings where diabetic patients are
usually attended.
Results
During the 12 weeks of intervention, the SMBG group
significantly improved glycated hemoglobin (HbA1c) levels
(from 7.4 – 1.6% to 6.9 – 1.1% [p < 0.001]) and weight
( - 0.9 – 1.9 kg [p < 0.05]), whereas HbA1c reduction (from
7.5 – 1.0% to 7.3 – 1.0%) and weight loss ( - 0.6 – 2.4 kg) were
not significant in the control group. Of the 124 patients, 122
completed the 1.5-year follow-up. In the control group,
HbA1c increased again, reaching baseline values (7.5 – 0.7%).
In the SMBG group, HbA1c remained stable (6.9 – 0.9%
[p = 0.0003 for trend]), and weight ( - 1.6 – 3.0 kg vs. baseline
[p = 0.0003 for trend]) improved further. Eighty-seven percent
of participants in the SMBG group continued to perform
SMBG. Those who measured their blood glucose more than
three times per week (n = 24) demonstrated an overall reduction in HbA1c of 1.0% ( p = 0.006 vs. three times or fewer per
week) after 1.5 years.
Conclusions
Comment
This study clearly shows that, in non–insulin-treated
subjects with T2DM who are newly diagnosed, SMBG use
results in increased regression rate for T2DM with 3-year
follow-up. The HbA1c only gives us a snapshot of overall
glucose control for the previous 3 months. However,
frequent SMBG use results in behavioral change (by the
patient) and allows the providers to implement necessary
therapeutic changes early in the course of the disease.
ROSSO-in-praxi-international: long-term effects
of self-monitoring of blood glucose on glucometabolic
control in patients with type 2 diabetes mellitus
not treated with insulin
Kempf K 1, Tankova T 2, Martin S1
Integration of SMBG into basic therapy of T2DM for
monitoring the effect of lifestyle changes improves glucometabolic control and has long-term effects.
Comment
The ROSSO study done in Germany highlights the effectiveness of SMBG in T2DM patients on lifestyle modifications. This was a randomized trial where half of the
patients received a glucose meter along with 150 test
strips and they were instructed to check blood glucose
regularly as well as event-driven monitoring, whereas
the control group did not receive the SMBG. The authors
conclude that integration of SMBG into basic T2DM
management, which includes lifestyle changes, improves
glucometabolic control.
S-8
GARG AND HIRSCH
Glucose control in diabetes: the impact of racial
differences on monitoring and outcomes
Diabetes Metab Res Rev 2013; 29: 77–84
Campbell JA1, Walker RJ1,2, Smalls BL1, Egede LE1–3
Background
1
Center for Health Disparities Research, Medical University of
South Carolina, Charleston, SC; 2Center for Disease Prevention
and Health Interventions for Diverse Populations, Charleston VA
REAP, Ralph H. Johnson VA Medical Center, Charleston, SC;
and 3Division of General Internal Medicine and Geriatrics, Department of Medicine, Medical University of South Carolina,
Charleston, SC
Endocrine 2012; 42: 471–82
Type 2 diabetes is the seventh leading cause of death in the
United States and is projected to increase in prevalence globally. Minorities are disproportionately affected by diabetes and
data suggest that clinical outcomes consistently fall below
American Diabetes Association recommendations. The purpose of this systematic review was to examine ethnic differences in self-monitoring and outcomes in adults with type 2
diabetes. Medline was searched for articles published between
January 1990 and January 2012 by means of a reproducible
strategy. Inclusion criteria incorporated the following: (a)
published in English; (b) targeted African Americans, Hispanic,
or Asian adults, ages 18 + years with type 2 diabetes; (c) crosssectional, cohort, or intervention study; and (d) measured
change in glycemic control, blood pressure, lipids, or quality of
life by race. Twenty-two articles met the inclusion criteria and
were reviewed. Overall, significant racial differences and barriers were found in published studies in diabetes management
as it pertains to self-monitoring and outcomes. African Americans tend to consistently exhibit worse outcomes and control
when compared to other minority populations and non-Hispanic whites. In conclusion, significant racial differences and
barriers exist in diabetes management as it pertains to selfmonitoring and outcomes when compared to non-Hispanic
whites. Explanatory and intervention studies are needed to
determine the mechanisms and mediators of these differences
and strategies to reduce these disparities. In addition, more
research is needed to investigate the impact of racial differences
in self-monitoring and outcomes on quality of life.
Comment
We conducted a clinical research study to determine the
effect of self-monitoring of blood glucose (SMBG) on glycemic
control and the value of a putatively less painful blood sampling technique on SMBG in oral hypoglycemic agent-treated
type 2 diabetes patients; SMBG has not been broadly applied
in non–insulin-treated patients in Japan.
Methods
One hundred thirty-seven subjects were recruited for the
24-week, prospective comparison study and randomized into
three groups: 46, no SMBG group; 46, fingertip group; and 45,
palm group. The primary endpoint was change in HbA(1c).
The secondary endpoints were SMBG compliance, dropout
rate, treatment changes, and patient’s and physician’s satisfaction.
Results
Six subjects in the fingertip group (13.2%) and one subject
in the palm group (2.2%) were dropped because of pain.
A(1C) level of all subjects at 24-week was decreased more in
the fingertip ( - 0.23%) and palm ( - 0.16%) groups than that in
the no SMBG group ( + 0.31%) ( p < 0.05). SMBG compliance
was higher in the fingertip group (2.17 times/day) than that in
the palm group (1.65 times/day) ( p < 0.05). A(1C) level of
treatment-unchanged subjects was decreased more in the
fingertip ( - 0.25%) and palm ( - 0.21%) groups than that in the
no SMBG group ( + 0.30%) ( p < 0.05). SMBG compliance was
higher in the fingertip group (2.24 times/day) than that in the
palm group (1.65 times/day) ( p < 0.05). Patient’s questionnaire showed that 84.1% of the fingertip group and 90.2% of
the palm group were satisfied with SMBG. Physician’s satisfaction was higher in the palm group (94.0%) than that in the
fingertip group (80.0%) ( p < 0.05).
Conclusion
SMBG is beneficial for glycemic control, and palm blood
sampling is a useful procedure for oral hypoglycemic agenttreated type 2 diabetes.
Even in the 21st century we are still talking about racial
differences in glucose monitoring, especially in African
Americans, whose frequency of SMBG is significantly
lower. Proper action is mandated to remove these barriers for effective SMBG use in the minority population.
Comment
Although this is a relatively small study, it again suggests
that there are alternative sites one could measure blood
glucose. Although it is unlikely that accuracy would be
different with palm glucose readings, more studies
should be considered as this might make glucose testing
more practical for some patients.
Self-monitoring of blood glucose (SMBG) improves
glycemic control in oral hypoglycemic agent
(OHA)-treated type 2 diabetes
Harashima S1, Fukushima T 1, Sasaki M 1, Nishi Y 1, Fujimoto S1,
Ogura M 1, Yamane S1, Tanaka D1, Harada N 1, Hamasaki A1,
Nagashima K 1, Nakahigashi Y 1, Seino Y 2, Inagaki N 1
1
Department of Diabetes and Clinical Nutrition, Graduate School
of Medicine, Kyoto University, Kyoto, Japan; and 2Department of
Diabetes and Clinical Nutrition, Kansai Electric Power Hospital,
Osaka, Japan
Is there a suitable point-of-care glucose meter for
tight glycemic control? Evaluation of one home-use
and four hospital-use meters in an intensive care unit
Gijzen K 1, Moolenaar DL 2, Weusten JJ 3, Pluim HJ 2,
Demir AY 1
1
2
Department of Clinical Chemistry and Hematology and
Intensive Care Unit, Meander Medical Center, Amersfoort, The
Netherlands; and 3DSM Resolve, Process Analysis & Statistics,
Geleen, The Netherlands
Clin Chem Lab Med 2012; 50: 1985–92
Background
Implementation of tight glycemic control (TGC) and
avoidance of hypoglycemia in intensive care unit (ICU) patients require frequent analysis of blood glucose. This can be
achieved by accurate point-of-care (POC) hospital-use glucose meters. In this study, one home-use and four different
hospital-use POC glucose meters were evaluated in critically
ill ICU patients.
Methods
All patients (n = 80) requiring TGC were included in this
study. For each patient, three to six glucose measurements
(n = 390) were performed. Blood glucose was determined by
four hospital-use POC glucose meters, Roche Accu-Check
Inform II System, HemoCue Glu201DM, Nova StatStrip, and
Abbott Precision Xceed Pro, and one home-use POC glucose
meter, Menarini GlucoCard Memory PC. The criteria described in ISO 15197, Dutch TNO quality guideline, and in
NACB/ADA-2011 were applied in the comparisons.
Results
According to ISO 15197, the percentages of the measured
values that fulfilled the criterion were 99.5% by Roche, 95.1%
by HemoCue, 91.0% by Nova, 96.6% by Abbott, and 63.3% by
Menarini. According to the TNO quality guideline, these
percentages were 96.1%, 91.0%, 81.8%, 94.2%, and 47.7%, respectively. Application of the NACB/ADA guideline resulted
in percentages of 95.6%, 89.2%, 77.9%, 93.4%, and 45.4%, respectively.
Conclusions
When ISO 15197 was applied, Roche, HemoCue, and Abbott fulfilled the criterion in this patient population, whereas
Nova and Menarini did not. However, when TNO quality
guideline and NACB/ADA 2011 guideline were applied, only
Roche fulfilled the criteria.
Performance variability of seven commonly
used self-monitoring of blood glucose systems:
clinical considerations for patients and providers
Brazg RL 1, Klaff LJ 1, Parkin CG 2
1
Rainier Clinical Research Center, Renton, WA; and 2CGParkin
Communications Inc., Boulder City, NV
S-9
manufacturer’s reference procedure at glucose concentrations
< 100 mg/dL and within – 15% for values ‡ 100 mg/dL. We
evaluated seven marketed systems against the current and
proposed ISO criteria (criterion A).
Method
Capillary blood samples were collected from 100 subjects
and tested on seven systems: Accu-Chek Aviva Plus, Advocate Redi-Code, Element, Embrace, Prodigy Voice, TRUEbalance, and WaveSense Presto. Results were compared with
manufacturer’s documented reference system, YSI, or perchloric acid hexokinase; three different strip lots from each
system were tested on each subject, in duplicate.
Results
Compared against current ISO criteria ( ‡ 95% within – 15 mg/dL for values < 75 mg/dL and – 20% for values
‡ 75 mg/dL) the Accu-Chek Aviva Plus, Element, and WaveSense Presto systems met accuracy criteria. However, only
the Accu-Chek Aviva Plus met the proposed ISO criteria
(criterion A) in all three lots. The other six systems failed to
meet the criteria in at least two of the three lots, showing lotto-lot variability, high/low bias, and variations because of
hematocrit.
Conclusions
Inaccurate SMBG readings can potentially adversely impact clinical decision making and outcomes. Clinicians can
reduce controllable variables by prescribing accurate SMBG
systems. Adherence to the proposed ISO criteria should enhance patient safety by improving the accuracy of SMBG
systems.
Comment
These two studies point out that strip quality is not equal
between brands of meters. In the first study, which assessed four inpatient meters used for intravenous insulin
infusions in the ICU (and one outpatient meter), only
accuracy was generally poor depending on which criteria
of accuracy was used. With the most rigorous quality
guidelines, only one meter met the standard. Is it any
wonder we have so much hypoglycemia in the ICU? In
the second study, results for mostly ‘‘off-shore’’ meters
showed unacceptable results for accuracy, despite the
fact that these meters will become widely used in the
United States as a result of the government’s ‘‘competitive bidding’’ law. The impact on potential catastrophic
outcomes is of obvious concern.
J Diabetes Sci Technol 2013; 7: 144–52
Conclusions
Background
Blood glucose data are frequently used in clinical decision making; thus, it is critical that self-monitoring of blood
glucose (SMBG) systems consistently provide accurate results. Concerns about SMBG accuracy have prompted the
development of newly proposed International Organization for Standardization (ISO) standards: ‡ 95% of individual
glucose results shall fall within – 15 mg/dL of the results of the
As we are now well into our third decade of SMBG, some of
our questions have been noted for many years, while others
are new. In the case of the former, the use of SMBG by non–
insulin-requiring patients continues to be controversial, partly
because it is next to impossible to design a study that replicates all practice patterns and philosophies of care. It is curious how bias works. If a study is designed by a payer who has
a financial incentive to minimize any impact of SMBG, the
S-10
results of the study are usually negative. The opposite of
course is the rule when the sponsor has a potential for financial gain. Certainly, in a practice situation where one has
no more than 3–5 minutes to review the diabetes, it is not
surprising that SMBG is discouraged and patients do not find
it helpful since they rarely are able to review the data with
their provider. When time is available to review the information with the provider, SMBG can be extremely important.
One topic that is not controversial, and emphasized by the
Miller study, is the importance of SMBG in type 1 diabetes
(T1DM). Hopefully, payers and governments will not be
questioning this technology for this population until CGM or
some other better strategies for glucose determination are
available.
Although cost has always been an issue, there is a related
issue that, although not new, has become more obvious.
While blood glucose meter accuracy is in itself not a controversial topic, it appears that, at least at the end of 2013, in the
United States poor accuracy is acceptable if costs can be reduced. While this situation is much more complex and is
certainly not isolated to the United States, one can only hope
GARG AND HIRSCH
that all payers will appreciate the importance of accuracy so
that inappropriate treatment decisions are not made. When
we review SMBG in 2014, hopefully this problem will be
improved.
Author Disclosure Statement
No competing financial interests exist.
References
1. Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030.
Diabetes Care 2004; 27: 1047–53.
2. Garg SK, Reed K, Grey J, Westerman A. Possible impacts of
new accuracy standards of self-monitoring of blood glucose.
US Endocrinology 2013; 9: 28–31.
3. Schütt M, Kern W, Krause U, et al. DPV Initiative: Is the
frequency of self-monitoring of blood glucose releated to
long-term metabolic control? Multicenter analysis including
24,500 patients from 191 centers in Germany and Austria. Exp
Clin Endocrinol Diabetes 2006; 114: 384–88.
DOI: 10.1089/dia.2014.1502
ORIGINAL ARTICLE
Continuous Glucose Monitoring in 2013
Tadej Battelino1 and Bruce W. Bode 2
Introduction
Methods
C
Thirty-one autoantibody-negative children with IH underwent a baseline assessment and were followed up for 23.8
months (range, 6–48 months). At the end of the follow-up, the
receiver operating characteristic (ROC) areas under the curve
(AUCs) of glucose data from 17 children who developed diabetes (group A; n = 17) and 14 children who did not develop
diabetes (group B; n = 14) were compared.
ontinuous glucose monitoring (CGM) in the pediatric population with type 1 diabetes (T1D) was
somewhat infamously described as ‘‘satisfaction without
success’’ (1); success with CGM is strongly related to its
use, and children and adolescents in some countries seem
to be particularly reluctant to use CGM devices regularly
as the behavioral changes these devices force on them
may not be desirable. However, the SWITCH randomized clinical trial clearly demonstrated that CGM can be
as successful in adolescents as in adults with T1D. Despite this fact, the reimbursement for CGM in Europe is
still far from universal (2) but growing steadily as data
on its benefits accumulate. The use of retrospective
(professional) CGM has expanded far beyond its initial
indications. Also, type 2 diabetes (T2D) is becoming an
important focus for both retrospective and real-time
CGM. Finally, an important study demonstrated that the
home use of threshold insulin suspend based on sensoraugmented insulin pump therapy in T1D can reduce and
prevent hypoglycemia.
Prognostic accuracy of continuous glucose
monitoring in the prediction of diabetes mellitus
in children with incidental hyperglycemia:
receiver operating characteristic analysis
Brancato D, Saura G, Fleres M, Ferrara L, Scorsone A,
Aiello V, Noto AD, Spano L, Provenzano V
Department of Internal Medicine and Diabetology, Regional Reference Center for Diabetology and Insulin Pumps, Hospital of
Partinico, Palermo, Italy
Results
Two-hour glucose of oral glucose tolerance test (OGTT)
was significantly associated with the development of diabetes
(0.813; 95% confidence interval [CI] 0.621–0.954; glucose at 2
hours: 135 mg/dL [108–141] vs. 83.5 mg/dL [74.5–109.7] group
A vs. group B, p < 0.01) as was the AUC of glucose at OGTT
(0.832; 95% CI 0.611–0.950). CGM glucose peak (0.803; 95% CI
0.621–0.923; 160 mg/dL [139.5–178.5] vs. 135 mg/dL [120.5–
144], group A vs. group B, p < 0.01), percentage of CGM glucose
measurements inside the range 70–125 mg/dL (0.866; 95% CI
0.695–0.961), and percentage of CGM measurements
‡ 126 mg/dL (0.889; 95% CI 0.724–0.973; 13% [9.5–37.5] vs. 3%
[1–4.5], group A vs. group B, p < 0.01) showed significant prognostic performance (ROC AUCs, p < 0.0001). A 2-hour OGTT
plasma glucose cut-off of 135 mg % provided sensitivity = 35.3%,
specificity = 100%, positive predictive value (PPV) = 100%, and
negative predictive value (NPV) = 44%. A CGM glucose cut-off
> 156 mg % and a CGM% above 126 mg/dL cut-off > 42%
provided sensitivity = 64.7%, specificity = 100%, PPV = 100%,
and NPV = 70%. The combination of CGM markers with each
other or with the OGTT markers yielded higher ROC AUCs
(ranging from 0.828 to 0.945). Interestingly, fasting blood glucose
(FBG) and basal and glucagon-stimulated c-peptide were not
different between the two groups. HbA1c was within the normal
range in both groups.
Aims
Conclusions
To evaluate the feasibility of CGM use in prediction of diabetes in children with incidental hyperglycemia (IH) and
negative diabetes-related autoantibodies.
CGM can be used for predicting the development of diabetes in children with IH and negative diabetes-related
autoantibodies.
1
Medical Faculty, UMC–University Children’s Hospital, University of Ljubljana, Slovenia.
Atlanta Diabetes Associates, Atlanta, GA.
2
S-11
S-12
BATTELINO AND BODE
Comment
commonly reported by mothers regularly checking their
babies during sleep. In order to increase the reliability of
CGM devices, an algorithm that would detect pressureinduced factitious hypoglycemia during sleep would be
of substantial importance and would bring direct clinical
benefit. Factitious IH, also rarely observed in this study,
has currently no clear physiological explanation. The
detection of factitious IH is of particular importance for
closed-loop insulin delivery systems, as more insulin is
erroneously delivered to the patient possibly resulting in
severe hypoglycemia.
This retrospective study on a limited group of children
with IH (3) is interesting although it can only be considered as a pilot. HLA risk alleles are not determined, intravenous glucose tolerance test is not performed, and
follow-up of diabetes-related antibodies is suboptimal.
However, IH is a common finding in pediatrics, and less
invasive and less costly investigations like CGM would
certainly be of considerable benefit. Therefore, the use of
CGM could be included in some large ongoing follow-up
and intervention studies in pediatric populations at risk
for developing T1D, where a more robust calculation of
its predictive value would be possible.
Susceptibility of interstitial continuous glucose
monitor performance to sleeping position
Mensh BD 1, Wisniewski NA 2,3, Neil BM 1, Burnett DR 1
1
Theranova, LLC, San Francisco, CA; 2Medical Device Consultancy, San Francisco, CA; and 3Profusa Inc., San Francisco, CA
Aims
To evaluate the impact of different sleeping positions on the
performance of CGM sensors in T1D.
Methods
Healthy volunteers were inserted with commercially
available sensors for 4 days in the abdominal subcutaneous
tissue (four sensors per person, two per side). Sleep was
video-recorded and nocturnal sleeping position determined
from recordings. Sleeping positions were correlated to CGM
sensor readings.
Results
The median glucose concentration of the four sensor
readings was characteristically 70–110 mg/dL during sleep.
Individual sensors intermittently recorded irregular glucose
readings ( >25 mg/dL away from median) that were strongly
correlated with sleeping positions where subjects were lying
on the sensors. Most of these irregular sleep-position-related
CGM readings were abrupt decreases in reported glucose
values, supposedly because of local blood and/or interstitial
fluid flow disturbances caused by tissue compression. Rarely,
abrupt elevations in CGM glucose readings were observed.
Conclusions
Interstitial fluid and local blood flow disturbances may be
associated with sleep-position-related abrupt decreases in
CGM-recorded glucose values.
The use and efficacy of continuous glucose monitoring
in type 1 diabetes treated with insulin pump therapy:
a randomized controlled trial
Battelino T 1, Conget I 2, Olsen B 3, Schütz-Fuhrmann I 4,
Hommel E 5, Hoogma R 6, Schierloh U 7, Sulli N 8, Bolinder J 9;
SWITCH Study Group
1
Faculty of Medicine, UMC–University Children’s Hospital,
University of Ljubljana, Slovenia; 2Diabetes Unit, ICMDM Hospital Clı́nici Universitari, Barcelona, Spain; 3Glostrup Hospital,
Glostrup, Denmark; 4Hospital Hietzing, Vienna, Austria; 5Steno
Diabetes Center, Gentofte, Denmark; 6Groene Hart Ziekenhuis,
Gouda, The Netherlands; 7Clinique Pediatrique, Centre Hospitalier
de Luxembourg, Luxembourg; 8Clinica Pediatrica, Servizio Diabetologia, Policlinico Umberto I, Rome, Italy; and 9Department of
Medicine, Karolinska University Hospital Huddinge, Karolinska
Institute, Stockholm, Sweden
Diabetologia 2012; 55: 3155–62
Aims
To evaluate the efficacy of adding CGM to existing continuous subcutaneous insulin infusion (CSII) therapy without
the impact of diabetes-related education and patient–caregiver contact time in T1D.
Methods
To control for known confounding factors, a randomized
crossover design was used. Children (6–18 years) and adults
(19–70 years) on CSII with HbA1c between 7.5% and 9.5%
were separately electronically randomized to either a SensorOn or Sensor-Off arm for 6 months. Participants were crossed
over to the other arm for 6 months after a 4-month washout
period. The primary outcome was the difference in HbA1c
levels between arms after 6 months. Secondary endpoints
were mean 24-hour glucose and 24-hour AUC values, and
changes in the time spent in hypoglycemia <70 mg/dL
(< 3.9 mmol/L), IH >180 mg/dL ( >10 mmol/L), and euglycemia 70–180 mg/dL (3.9–10 mmol/L).
Results
Comment
This study (4) confirms several anecdotal reports of
nocturnal sleep-position-related abrupt decreases in
CGM sensor glucose values. Factitious hypoglycemia
caused by pressure on the sensor insertion site is
A total of 185 individuals were screened and 153 (52%
male) randomized after the run-in period. The overall mean
HbA1c level was 8.04 in the Sensor-On arm and 8.47% in
the Sensor-Off arm after 6 months (difference - 0.43%; 95%
CI - 0.32%, - 0.55%; p < 0.001). The mean difference in children and adolescents was - 0.46% (95% CI - 0.26%, - 0.66%;
CONTINUOUS GLUCOSE MONITORING IN 2013
p < 0.001) and - 0.41% (95% CI - 0.28%, - 0.53%; p < 0.001) in
adults. Mean overall sensor use was 80% (median 84%) of the
required time (mean 81% over the final 4 weeks); in the pediatric group it was 73% (median 78%) (mean 74% over the
final 4 weeks); in the adult group it was 86% (median 89%) of
the required time (mean 87% over the final 4 weeks). Time
spent < 70 mg/dL ( < 3.9 mmol/L) was significantly shorter
during the Sensor-On period compared with the Sensor-Off
period (19 vs. 31 min/day, respectively; p = 0.009). Glycemic
variability assessed by 24-hour standard deviation (SD) of
glucose concentration was also significantly lower in the
Sensor-On arm. The number of daily boluses, temporary basal
rates, and manual insulin suspends was significantly higher
in the Sensor-On arm. Four severe hypoglycemic events occurred in the Sensor-On arm vs. two in the Sensor-Off arm
( p = 0.40).
Conclusions
The addition of CGM to CSII therapy resulted in an improvement in HbA1c with a concomitant decrease in time
spent in hypoglycemia in both pediatric and adult participants with T1D. More frequent self-adjustments of insulin
therapy were observed in the intervention arm.
S-13
Methods
Data were from the first 12 weeks of a 52-week, prospective, randomized trial comparing RT-CGM (n = 50) with selfmonitoring of blood glucose (n = 50). RT-CGM was used in 8
of the first 12 weeks. HbA1c was collected at baseline and
quarterly. This analysis included 45 participants who wore
the RT-CGM for ‡ 4 weeks. Analyses examined the RT-CGM
data for common response patterns using a novel approach. It
then used multilevel models for longitudinal data, regression,
and nonparametric methods to compare the patterns of A1C,
mean glucose, glycemic variability, and views per day of the
RT-CGM device.
Results
There were five patterns identified. For four patterns, mean
glucose was lower than expected as of the first RT-CGM cycle
of use given participants’ baseline HbA1c. They were named
favorable responses but with high and variable glucose (n = 7);
tight control (n = 14); worsening glycemia (n = 6); and incremental improvement (n = 11). The fifth had no response (n = 7).
A1C, mean glucose, glycemic variability, and views per day
differed across patterns at baseline and longitudinally.
Conclusions
Comment
The SWITCH study (5) provides a unique evidence of
CGM efficacy because of its crossover design eliminating
the most common confounding factors of this treatment
modality: the amount of diabetes-related education and
patient–caregiver contact. Contrary to the Juvenile Diabetes Research Foundation ( JDRF) sensor study (6), the
significant reduction in HbA1c is similar in children and
adolescents as compared to adults, with a high sensor use
also at the end of the study. Moreover, the significant
reduction in HbA1c is accompanied with a reduction of
time spent in hypoglycemia, corroborating the results of
a previous study on a well-controlled population of adolescents and adults with T1D (7). Interestingly, the use
of the sensor was accompanied with significantly more
active insulin dose adjustments, indicating a behavioral
modification.
Heterogeneity of responses to real-time continuous
glucose monitoring (RT-CGM) in patients with type 2
diabetes and its implications for application
Fonda SJ 1, Salkind SJ 1, Walker MS1, Chellappa M 1, Ehrhardt
N 2, Vigersky RA 1
1
Walter Reed National Military Medical Center, Bethesda, MD;
and 2Department of Endocrinology, Ft. Belvoir Community Hospital, Ft. Belvoir, VA
Diabetes Care 2013; 36: 786–92
Aims
To characterize glucose response patterns of people who
wore a real-time continuous glucose monitor (RT-CGM) as an
intervention to improve glycemic control. Participants had
T2D, were not taking prandial insulin, and interpreted the RTCGM data independently.
The patterns identified suggest that targeting people with
higher starting HbA1cs, using RT-CGM short term (e.g., 2
weeks) and monitoring for worsening glycemia that might be
the result of burnout, may be the best approach to using RTCGM in people with T2D not taking prandial insulin.
Comment
The use of RT-CGM in T2D patients not taking prandial
insulin has shown to be effective in improving glycemic
control as measured by HbA1c in the majority of subjects
(8). Specific behaviors that led to improvement in glycemic control were not measured in this study, but patients who looked at the RT-CGM tracings frequently
clearly improved their glycemic control. Targeting people with higher A1Cs as well as using the device in shortterm periods and monitoring for worsening glycemic
control while wearing RT-CGM may improve outcomes
using RT-CGM in this population.
Influence of glycemic variability on HbA1c level
in elderly male patients with type 2 diabetes
Fang FS, Li ZB, Li CL, Tian H, Li J, Cheng XL
Department of Geriatric Endocrinology, Chinese PLA General
Hospital, Beijing, China
Intern Med 2012; 51: 3109–13
Aims
To investigate the influence of glycemic variability on the
HbA1c level in elderly male patients with T2D.
Methods
The 24-hour glucose profiles were obtained using a CGM
system in 291 elderly male patients with T2D who were
S-14
hospitalized. The relationship between the glycemic variability and HbA1c level was assessed in these patients.
Results
The mean amplitude of glycemic excursions (MAGE)
in patients with HbA1c ‡ 7.0% was significantly higher
than that in patients with HbA1c < 7.0% (4.33 – 1.67 vs. 3.48 –
1.46 mmol/L, p < 0.001). A simple (Pearson’s) correlation
analysis indicated that the MAGE was significantly correlated
with the HbA1c (r = 0.229, p < 0.001). Compared with the
lowest quartile, the highest quartile of the MAGE was associated with a significantly increased risk of having a HbA1c
‡ 7.0% after multiple adjustments ( p < 0.001).
Conclusions
The glycemic variability had a significant influence on the
HbA1c level in elderly male patients with T2DM. The present
data suggest that patients with higher glycemic variability
might have higher HbA1c levels.
Comment
Prior studies have shown that mean glucose but not
glycemic variability had a significant influence on HbA1c
levels. Most of these studies had not used CGM to measure glycemic variability. In this inpatient cohort of 291
elderly males, MAGE as determined by CGM correlated
with HbA1c levels where plasma glucose and other
clinical factors did not correlate with HbA1c levels (9).
Future studies using CGM to determine MAGE are needed to verify this finding.
Continuous glucose monitoring and cognitive
performance in type 2 diabetes
Pearce KL 1–3, Noakes M 2, Wilson C 1,4, Clifton PM 1,5
1
Commonwealth Scientific and Industrial Research Organization,
Human Nutrition, Adelaide, South Australia, Australia; 2School of
Pharmacy and Medical Sciences, University of South Australia,
South Australia, Australia; 3Department of Physiology, University
of Adelaide, South Australia, Australia; 4Flinders Centre for
Cancer Prevention and Control, Flinders University, Adelaide,
South Australia, Australia; and 5Baker IDI, Adelaide, South
Australia, Australia
Aims
T2D is associated with reductions in cognitive function that
are associated with HbA1c levels, but there is no information
on whether cognition is related to postmeal glucose spikes.
The authors explored the relationship of cognition to glucose
levels measured by a CGM system (CGMS) both before and
after a weight-loss diet.
Methods
Forty-four subjects with T2D (59.0 – 6.2 years old; body
mass index, 32.8 - 4.2 kg/m2; HbA1c, 6.9 –1.0%) completed an
8-week energy-restricted (approximately 6–7 MJ, 30% deficit)
diet. Cognitive functioning (short-term memory, working
BATTELINO AND BODE
memory, speed of processing [inspection time], psychomotor
speed, and executive function) was assessed during four
practice sessions, baseline, and week 8. Parallel glucose levels
were attained using the CGMS in 27 subjects. Outcomes were
assessed by FBG, postprandial peak glucose (Gmax), time
spent >12 mmol/L (T >12), and 24-hour area under the glucose curve (AUC24).
Results
Despite a fall in FBG of 0.65 mmol/L after 8 weeks, digits
backward results correlated with FBG at both week 0 and week
8 (r = - 0.43, p < 0.01 and r = - 0.32, p < 0.01, respectively).
Digits forward results correlated with FBG (r = - 0.39,
p < 0.01), Gmax (r = - 0.46, p < 0.05), and AUC24 (r = - 0.50,
p < 0.01) at week 0 and FBG (r = - 0.59, p < 0.001), Gmax
(r = 0.37, p = 0.01), AUC24 (r = - 0.41, p < 0.01), and percentage weight loss (r = 0.31, p < 0.01) at week 8. Cognitive function was not altered by weight loss, gender, baseline lipid
levels, or premorbid intelligence levels (National Adult
Reading Test).
Conclusions
FBG, Gmax, and AUC24 were related to cognitive function,
and an energy-restricted diet for 8 weeks did not alter this
relationship.
Comment
This small study (10) of relatively well-controlled 44 type
2 DM subjects showed that FBG, postprandial peak glucose, and total glucose exposure correlated with cognitive function, but intervention with a weight loss diet did
not affect cognitive function in spite an improvement
in glycemic control and other glycemic parameters
measured by CGM. These results corroborate previous
findings in a cohort of elderly patients with T2D (11).
Limitations of this study were that these patients were
well controlled with a mean A1C of 6.8%. Future research
should look at an intervention in a poorly controlled
group of type 2 patients to see if they may show an improvement in cognitive function.
Relationship between fluctuations in glucose levels
measured by continuous glucose monitoring and vascular
endothelial dysfunction in type 2 diabetes mellitus
Torimoto K, Okada Y, Mori H, Tanaka Y
First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushyushi, Japan
Cardiovasc Diabetol 2013; 12: 1
Aims
Fluctuations in blood glucose levels cause endothelial
dysfunction and play a critical role in onset and/or progression of atherosclerosis. This group hypothesized that fluctuation in blood glucose levels correlate with vascular
endothelial dysfunction and that this relationship can be assessed using CGM.
CONTINUOUS GLUCOSE MONITORING IN 2013
S-15
Methods
Methods
Fluctuations in blood glucose levels were measured over 24
hours by masked CGM on admission day 2 in 57 patients with
T2D. The reactive hyperemia index (RHI), an index of vascular endothelial function, was measured using peripheral
arterial tonometry (EndoPAT) on admission day 3.
Patients aged 16–70 years with T1D for >2 years, HbA1c of
5.8–10.0%, and on insulin-pump therapy for more than 6
months were recruited. Those with more than one episode of
severe hypoglycemia (resulting in coma or seizures or requiring medical assistance) were excluded. Patients who wore
sensors >80% of the time and had at least two nocturnal hypoglycemic events during the 2 weeks run-in phase were eligible for randomization to receive either sensor-augmented
insulin-pump therapy with the threshold-suspend feature
(threshold-suspend group, threshold 70–90 ng/dL/3.9–5 mM/)
or standard sensor-augmented insulin-pump therapy (control
group) for 3 months. The primary efficacy end point was the
AUC for nocturnal hypoglycemic events, and the primary
safety end point was the change in HbA1c during the study.
Results
RHI correlated with SD (r = - 0.504; p < 0.001), the MAGE
(r = - 0.571; p < 0.001), mean postprandial glucose excursion
(r = - 0.411; p = 0.001), and percentage of time ‡ 200 mg/dL
(r = - 0.292; p = 0.028). In 12 patients with hypoglycemia,
RHI also correlated with the percentage of time at hypoglycemia (r = - 0.589; p = 0.044). RHI did not correlate with
HbA1c or fasting plasma glucose levels. Furthermore, RHI
did not correlate with low-density lipoprotein cholesterol,
high-density lipoprotein cholesterol, and triglyceride levels or
with systolic and diastolic blood pressures. Finally, multivariate analysis identified MAGE as the only significant
determinant of RHI.
Conclusion
Fluctuations in blood glucose levels play a significant role
in vascular endothelial dysfunction in T2D.
Comment
Fluctuations in blood glucose levels measured by CGM,
specifically MAGE, correlate to vascular endothelial
dysfunction in T2D (12). No measures of oxidative stress
were measured in this study; thus, the direct cause of this
vascular endothelial dysfunction by variability of glucose
was not determined. However, glucose variability influences endothelial function even in nondiabetic subjects
(13). Further prospective studies on prevention and
minimization of variability of glucose are needed to see if
such intervention can lower markers of oxidative stress
and future cardiovascular events.
Threshold-based insulin-pump interruption
for reduction of hypoglycemia
Bergenstal RM 1, Klonoff DC 2, Garg SK 3, Bode BW 4,
Meredith M 5, Slover RH 5, Ahmann AJ 6, Welsh JB 7,
Lee SW 7, Kaufman FR 7; ASPIRE In-Home Study Group
1
International Diabetes Center, Park Nicollet, MN; 2The Diabetes
Research Institute, Mills–Peninsula Health Services, San Mateo,
CA; 3Barbara Davis Center for Childhood Diabetes, University
of Colorado, Denver, CO; 4Atlanta Diabetes Associates, Atlanta,
GA; 5Department of Medicine, University of Wisconsin, Madison,
WI; 6Harold Schnitzer Diabetes Health Center, Oregon Health
and Science University, Portland, OR; and 7Medtronic, Northridge, CA
N Engl J Med 2013; 369: 224–32
Aims
To evaluate sensor-augmented insulin-pump therapy with
and without the threshold-suspend function in T1D patients
with nocturnal hypoglycemia.
Results
The mean ( – SD) AUC for nocturnal hypoglycemic events
in the threshold suspend group was 37.5% less than that of the
control group (980 – 1200 mg/dL · min vs. 1568 – 1995 mg/
dL · min) ( p < 0.001). HbA1c did not change significantly in
either group, and the between-group difference was 0.05%
(CI - 0.05 to 0.15). The rate of nighttime hypoglycemic events
was reduced by 31.8% (1.5 – 1.0 vs. 2.2 – 1.3 per patient-week,
p < 0.001). The mean per-patient number of automatic nighttime pump suspensions was 0.77, with a median duration of
11.9 minutes (mean, 39.4); 43.1% lasted for less than 5 minutes;
and 19.6% for 2 hours. A total of 111 of 121 patients group had
at least one nocturnal threshold-suspend event lasting for
2 hours with the mean sensor glucose value at the end of it of
92.6 – 40.7 mg/dL (5.1 – 2.6 mM). No difference was observed
in scores on the Hypoglycemia Fear Survey and the EQ-5D
between groups. No severe hypoglycemic events occurred in
the threshold-suspend group and 0.13 per patient-year in the
control group. No diabetic ketoacidosis (DKA) was recorded.
Conclusion
The addition of automatic threshold pump suspension over
a 3-month period can reduce the number and severity of hypoglycemic episodes at night without any apparent loss in
overall glucose control.
Comment
The success of the threshold insulin suspend in the
ASPIRE in-home study (14) has importance beyond
its considerable formal achievements: a commercially
available automated system connecting CGM with insulin delivery brought clinical benefit to patients during
home use. Recently, a full closed-loop insulin delivery
system, the MD-Logic artificial pancreas, lessened nocturnal hypoglycemia and improved metabolic parameters in the first randomized controlled trial in home
settings (15). As automated actions of these systems
do not need the involvement of the patients, the major
barriers of diabetes-related technology—adherence and
compliance—seem to be circumvented. It would therefore seem logical to pursue the path to a commercial artificial pancreas using subcutaneous glucose sensing and
insulin delivery with maximal speed.
S-16
BATTELINO AND BODE
Conclusion
CGM is now an established treatment modality for diabetes
with expanding indications, helping improve the well-being
of patients and proficiency of their caregivers in various
challenging situations, including sports and prolong fasting
(16). CGM use in T2D seems to be particularly successful in
both retrospective and real-time use. New technical improvements such as combined insulin set with a continuous
sensor (17), enhancement of the alarm function at home (18),
and improved sensor accuracy and performance (19) will also
improve the acceptability of this treatment modality in all age
groups. However, as psychosocial barriers vary between individual users (20), the use of CGM may finally be most efficient within a closed-loop system.
7.
8.
9.
10.
T.B. institution received research grant support, with receipt
of travel and accommodation expenses in some cases, from
Abbott, Medtronic, Novo Nordisk, GluSense, and Diamyd. He
received honoraria for participating on the speaker’s bureau of
Eli Lilly, Novo Nordisk, Bayer, Medtronic, and consulting fees as
a member of scientific advisory boards from Bayer, Life Scan, Eli
Lily, Sanofi-Aventis, and Medtronic. B.B. has stock ownership in
Aseko (formerly Glytec). He is a consultant for Halozyme,
Janssen, Medtronic, Novo Nordisk, Sanofi, Tandem, and
Valeritas. He is on the speaker’s bureau for Bristol Myers
Squib/Amylin, DexCom, GSK, Insulet, Janssen, Lilly, Medtronic, Merck, Novo Nordisk, Sanofi, and Valeritas. He has
grant and research support received by employer (Atlanta
Diabetes Associates) from Abbott, Biodel, Bristol Myers
Squib/Amylin, DexCom, GSK, Halozyme, Janssen, Lilly/
Boehringer Ingelheim, Macrogenics, MannKind, Medtronic,
NIH, Novo Nordisk, Sanofi, and Valeritas.
11.
12.
13.
14.
15.
References
1. Weinzimer SA. Continuous glucose monitoring in young
children: Satisfaction without success? Diabetes Technol Ther
2012; 14: 753–55.
2. Heinemann L, Franc S, Phillip M, Battelino T, AmpudiaBlasco FJ, Bolinder J, Diem P, Pickup J, Hans Devries J. Reimbursement for continuous glucose monitoring: A European view. J Diabetes Sci Technol 2012; 6: 1498–502.
3. Brancato D, Saura G, Fleres M, Ferrara L, Scorsone A, Aiello
V, Noto AD, Spano L, Provenzano V. Prognostic accuracy of
continuous glucose monitoring in the prediction of diabetes
mellitus in children with incidental hyperglycemia: Receiver
operating characteristic analysis. Diabetes Technol Ther 2013;
15: 580–85.
4. Mensh BD, Wisniewski NA, Neil BM, Burnett DR. Susceptibility of interstitial continuous glucose monitor performance to sleeping position. J Diabetes Sci Technol 2013; 7:
863–70.
5. Battelino T, Conget I, Olsen B, Schütz-Fuhrmann I, Hommel
E, Hoogma R, Schierloh U, Sulli N, Bolinder J; SWITCH
Study Group. The use and efficacy of continuous glucose
monitoring in type 1 diabetes treated with insulin pump
therapy: A randomised controlled trial. Diabetologia 2012; 55:
3155–62.
6. Juvenile Diabetes Research Foundation Continuous Glucose
Monitoring Study Group. Effectiveness of continuous glucose monitoring in a clinical care environment: Evidence
16.
17.
18.
19.
20.
from the Juvenile Diabetes Research Foundation continuous
glucose monitoring ( JDRF-CGM) trial. Diabetes Care 2010; 33:
17–22.
Battelino T, Phillip M, Bratina N, Nimri R, Oskarsson P, Bolinder J. Effect of continuous glucose monitoring on hypoglycemia in type 1 diabetes. Diabetes Care 2011; 34: 795–800.
Fonda SJ, Salkind SJ, Walker MS, Chellappa M, Ehrhardt N,
Vigersky RA. Heterogeneity of responses to real-time continuous glucose monitoring (RT-CGM) in patients with type
2 diabetes and its implications for application. Diabetes Care
2013; 36: 786–92.
Fang FS, Li ZB, Li CL, Tian H, Li J, Cheng XL. Influence of
glycemic variability on the HbA1c level in elderly male patients with type 2 diabetes. Intern Med 2012; 51: 3109–13.
Pearce KL, Noakes M, Wilson C, Clifton PM. Continuous
glucose monitoring and cognitive performance in type 2
diabetes. Diabetes Technol Ther 2012; 14: 1126–33.
Rizzo MR, Marfella R, Barbieri M, Boccardi V, Vestini F,
Lettieri B, Canonico S, Paolisso G. Relationships between daily
acute glucose fluctuations and cognitive performance among
aged type 2 diabetic patients. Diabetes Care 2010; 33: 2169–74.
Torimoto K, Okada Y, Mori H, Tanaka Y. Relationship between fluctuations in glucose levels measured by continuous
glucose monitoring and vascular endothelial dysfunction in
type 2 diabetes mellitus. Cardiovasc Diabetol 2013; 12: 1.
Buscemi S, Re A, Batsis JA, Arnone M, Mattina A, Cerasola
G, Verga S. Glycaemic variability using continuous glucose
monitoring and endothelial function in the metabolic syndrome and in type 2 diabetes. Diabet Med 2010; 27: 872–78.
Bergenstal RM, Klonoff DC, Garg SK, Bode BW, Meredith
M, Slover RH, Ahmann AJ, Welsh JB, Lee SW, Kaufman FR;
ASPIRE In-Home Study Group. Threshold-based insulinpump interruption for reduction of hypoglycemia. N Engl J
Med 2013; 369: 224–32.
Nimri R, Muller I, Atlas E, Miller S, Kordonouri O, Bratina
N, Tsioli C, Stefanija MA, Danne T, Battelino T, Phillip M.
Night glucose control with MD-Logic artificial pancreas in
home setting: A single blind, randomized crossover trialinterim analysis. Pediatr Diabetes 2013; Aug 15. [Epub ahead
of print]; DOI: 10.1111/pedi.12071.
Khalil AB, Beshyah SA, Abu Awad SM, Benbarka MM,
Haddad M, Al-Hassan D, Kahwatih M, Nagelkerke N.
Ramadan fasting in diabetes patients on insulin pump
therapy augmented by continuous glucose monitoring: An
observational real-life study. Diabetes Technol Ther 2012; 14:
813–18.
O’Neal DN, Adhya S, Jenkins A, Ward G, Welsh JB, Voskanyan G. Feasibility of adjacent insulin infusion and continuous glucose monitoring via the Medtronic Combo-Set. J
Diabetes Sci Technol 2013; 7: 381–88.
Kaiserman K, Buckingham BA, Prakasam G, Gunville F,
Slover RH, Wang Y, Nguyen X, Welsh JB. Acceptability and
utility of the mySentry remote glucose monitoring system. J
Diabetes Sci Technol 2013; 7: 356–61.
Christiansen M, Bailey T, Watkins E, Liljenquist D, Price D,
Nakamura K, Boock R, Peyser T. A new-generation continuous glucose monitoring system: Improved accuracy and
reliability compared with a previous-generation system.
Diabetes Technol Ther 2013; Jun 18. [Epub ahead of print];
DOI: 10.1089/dia.2013.0077.
Markowitz JT, Pratt K, Aggarwal J, Volkening LK, Laffel
LM. Psychosocial correlates of continuous glucose monitoring use in youth and adults with type 1diabetes and parents
of youth. Diabetes Technol Ther 2012; 14: 523–26.
DOI: 10.1089/dia.2014.1503
ORIGINAL ARTICLE
Insulin Pumps
John Pickup
Introduction
E
ven though continuous subcutaneous insulin infusion
(CSII) has been in clinical use for more than 30 years, there
is surprisingly little documentation of whether the good glycemic control of pump therapy is maintained over the longterm, and whether there are subgroups of pump users who
respond more favorably or retain good control better than
others. We therefore report on three articles that deal with
long-term CSII. The use of CSII in combination with continuous glucose monitoring (CGM), sometimes called sensoraugmented pump (SAP) therapy, has been increasing in
clinical practice over the last year, and we discuss an evaluation of a large group of type 1 diabetic subjects using this
treatment in routine practice. SAP with automatic basal-rate
insulin suspension in the event of hypoglycemia has still not
received regulatory approval in the United States at the time
of writing (approved at proof stage, September 2013), and we
report on an in-home study of the safety and efficacy of this
technology, which is both the first randomized controlled trial
(RCT) of SAP with low-glucose insulin suspend (LGS) and
may be helpful in accelerating the entry of this treatment into
U.S. practice. Looking to the near future, pumps with insulin
suspension based on predicted hypoglycemia are likely to be
available soon, and we report a first evaluation of the potential for such devices. Finally, we discuss several articles concerning hypoglycemia and glycemic variability, their
improvement with CSII, and their inter-relationships.
LONG-TERM INSULIN PUMP THERAPY
Insulin pump—long-term effects of glycemic control:
an observational study at 10 diabetes clinics
in Sweden
Background
There is comparatively little information on the glycemic
effectiveness of CSII over periods of longer than 1–2 years,
particularly when combining results from more than one
center, with their differing uptake of pump therapy. The aim
of this study was to retrospectively survey the glycemic
control achieved in long-term pump patients versus multiple
daily injection (MDI)–treated subjects.
Methods
Adult type 1 diabetic subjects (n = 272) from 10 centers in
Sweden who had been treated by CSII for at least 5.5 years
were studied. A group of patients treated by MDI (n = 2437)
over the same period acted as controls.
Results
At baseline, the pump patients were younger, were more
often female, had shorter duration of diabetes than MDI subjects,
and had worse control (HbA1c 8.4% vs. 8.1%, p < 0.001). HbA1c
improved for both groups at 5 years, but more so for CSII (unadjusted difference from baseline: 0.44% vs. 0.11%, CSII vs.
MDI). Adjusting for differences in baseline HbA1c, there was a
significant difference in change from baseline, favoring CSII over
the years, but this effect lessened as duration of CSII increased:
at 1 year, - 0.42%; 2 years, - 0.43%; and 5 years, - 0.20%.
Conclusions
CSII achieves significantly lower HbA1c levels than MDI,
even in the long-term, but the effect diminishes with time.
Carlsson B-M 1,2, Attvall S 2,3, Clements M 4, Gumpney SR 5,
Pividic A 6, Sternemalm L 3, Lind M 2,7
1
Centre, Visakhapatnam, India; 6Statistika Konsultgruppen,
Gothernburg, Sweden; and 7Department of Medicine, NUHospital Organization, Trollhatan, Sweden
Department of Medicine, SAS-Hospital Organization, Skene, Sweden; 2Insitute of Medicine, University of Gothenburg, Gothenburg,
Sweden; 3Diabetes Section, Sahlgrenska University Hospital,
Gothenburg, Sweden; 4Section of Endocrinology, Children’s Mercy
Hospitals & Clinics, Kansas City, MO; 5Endocrine and Diabetes
A 7-year follow-up, retrospective, international,
multicenter study of insulin pump therapy
in children and adolescents with type 1 diabetes
Mameli C1, Scaramuzza AE 1, Ho J 2, Cardona-Hernandez R3,
Suarez-Ortega L3, Zucotti GV 1
Diabetes Research Group, King’s College, London School of Medicine, Guy’s Hospital, London, United Kingdom.
S-17
S-18
1
PICKUP
Department of Pediatrics, University of Milan, Milan, Italy;
Department of Pediatrics, University of Calgary, Calgary, Canada;
and 3Department of Endocrinology and Diabetes, Hospital Saint
Joan de Deu, Barcelona, Spain
patients and 39 months in the MDI patients (ns). HbA1c was
similar at baseline (8.0% vs. 7.8%).
Acta Diabetol 17 May 2013: [Epub ahead of print]; DOI: 10.1007/
s00592-013-0481-y
In the pump patients, HbA1c was significantly lower than
at baseline at every time point up to 3 years. The peak reduction was at 6 months ( - 0.64% for CSII, - 0.15% for MDI),
but the reduction declined over time. The difference in HbA1c
from baseline for CSII versus MDI was significant to 2 years.
According to blood glucose meter data, the standard deviation (SD) of glucose was decreased at 6 months in the CSII
group but not the MDI group.
2
Background
Studies of CSII lasting longer than about 4 years are limited,
and the aim of this study was therefore to retrospectively
analyze data from a large cohort of pediatric subjects with
type 1 diabetes treated by CSII for 7 years at three centers in
Canada, Italy, and Spain.
Methods
Demographic, clinical, pump usage, and diabetes-control
data from type 1 diabetic subjects treated by CSII were collected by chart review (n = 121; age 5–20 years; mean followup 6.9 [range 5–12 years]).
Results
HbA1c had significantly improved at 1 year, but showed a
trend to worsen slightly during subsequent follow-up. Although
the baseline HbA1c was similar for males and females, only the
males showed significant improvement over the 7 years. Severe
hypoglycemia (SH) decreased during follow-up, though not
significantly (8.2 vs. 1.1 events/100 patient-years). A subgroup of
patients who used advanced pump features (bolus calculator,
different bolus profiles, and temporary basal rates) had a better
HbA1c at the end of follow-up (7.8% vs. 8.5%, p = 0.003).
Conclusions
CSII was safe and effective in the long-term for this group
of pediatric diabetic patients, but the main benefit was seen in
males, and those who use pump features achieved the best
control.
Long-term metabolic effects of continuous subcutaneous
insulin infusion therapy in type 1 diabetes
Cohen ND 1, Hong ES 2, Van Drie C 3, Balkau B 1,4,5, Shaw J 1
1
Baker Heart and Diabetes Institute, Melbourne, Australia;
Cheongju St. Mary’s Hospital, Cheongju, Korea; 3University of
Amsterdam, Amsterdam, The Netherlands; 4INSERM, U1018,
Villejuif, France; and 5University of Paris Sud, Villejuif, France
2
Background
The aim of this study was to determine the long-term effects
of CSII in comparison with MDI, where both groups had
undergone specialized education programs.
Methods
Records were studied from adults with type 1 diabetes who
commenced CSII (n = 126) or an intensive MDI program
(n = 121) between 2000 and 2011. MDI patients attended a
Dose Adjustment for Normal Eating (DAFNE)–style education program. Follow-up was for 48 months in the pump
Results
Conclusions
The HbA1c improvement seen with CSII versus MDI declines over time.
Comment
All three of these studies confirm that CSII achieves good
glycemic control over many years, but the best effect of
pumps on the mean HbA1c level is seen after 6 months to
1 year from pump start and then the improvement gradually declines, for both adult and pediatric/adolescent
groups. We have comparatively little information still on
how the long-term efficacy of pumps varies from one
person to another, though Mameli et al. provide evidence
that young females do worse. Perhaps this is related to the
insulin resistance of puberty (mean age of the cohort was
13.5 years) or other psychosocial problems associated with
adolescence. Others have previously shown that ‘‘brittle
diabetes’’ associated with poor glycemic control and
multiple admissions to the hospital in adolescent females
is not effectively managed by CSII (1), and that teenage
diabetic patients are those most likely to have poor control
on pumps and to discontinue this therapy (2).
Mameli et al. also report that those who tended to use
advanced features of modern pumps such as different
bolus profiles for different meal types, the bolus calculator, and temporary basal rates achieved the best
control. This is interesting because, although the logic
and potential advantages of these features are quite
apparent, trial evidence to support their use in clinical
practice is still very limited.
The reasons why control deteriorates in some patients
on long-term CSII are not known—loss of motivation and
psychological issues, illness, increasing insulin resistance,
and dietary factors might all play a part. Many clinics find
that re-education in pump procedures, together with
remotivation, is helpful in restoring good control in many
patients whose control has been worsening after a period
on CSII, though the number who respond to these
measures has not been well documented.
It is interesting to note that the MDI patients in the
study of Cohen et al. all underwent a DAFNE-style
structured education program. There is ongoing debate
about whether the improvement in control associated
with CSII is attributable to the technology or to the
education and attention linked to pump programs. This
study indicates that, at least for some subjects, additional
benefit can be obtained from pump therapy.
INSULIN PUMPS
S-19
SENSOR-AUGMENTED INSULIN PUMP (SAP) THERAPY
Routine sensor-augmented pump therapy in type 1
diabetes: the INTERPRET Study
Threshold-based insulin-pump therapy interruption
for reduction of hypoglycemia
Nørgaard K 1, Scaramuzza A 2, Bratina N 3, Lalić NM 4,
Jarosz-Chabot P5, Kocsis G 6, Jasinskiene E 7, DeBlock C 8,
Carrette O 9, Castaneda J 10, Cohen O 11
Bergenstal RM 1, Klonoff DC 2, Garg SK 4, Bode BW 5,
Meredith M 6, Slover RH 4, Ahmann AJ 7, Welsh JB 3,
Lee SW 3, Kaufman FR 3
1
International Diabetes Center, Park Nicollet, Minneapolis, MN;
Diabetes Research Institute, Mills-Peninsula Health Services, San
Mateo, CA; 3Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, CO; 4Atlanta Diabetes Associates,
Atlanta, GA; and 5Department of Medicine, University of
Wisconsin, Madison, WI; 6Harold Schnitzer Diabetes Health
Center, Oregon Health and Science University, Portland, OR;
7
Medtronic, Northridge, CA
Hvidovre University Hospital, Hvidovre, Denmark; 2Luigi Sacco
Hospital, Milan, Italy; 3University Medical Center and Children’s
Hospital, Ljubljana, Slovenia; 4Clinic for Endocrinology, University of Belgrade Faculty of Medicine, Belgrade, Serbia; 5Medical
University of Silesia, Katowice, Poland; and 6Péterfy Hospital,
Budapest, Hungary; 7Lithuanian University Hospital of Health
Sciences, Kaunas, Lithuania; 8Antwerp University Hospital,
Antwerp, Belgium; 9Medtronic International Trading, Tolochenaz,
Switzerland; 10Medtronic Bakken Research Center, Maastrict, the
Netherlands; 11Chaim Sheba Medical Center, Tel Hashomer, Israel
N Engl J Med 2013; 369: 224–32
Background
Background
Hypoglycemia remains a major problem in type 1 diabetes, even during insulin pump therapy. SAP therapy
with automatic suspend of the basal rate for up to 2 hours
when a preset hypoglycemic threshold is reached (LGS)
has been available commercially in Europe since 2009, but
trials have been of short duration and have involved
small numbers of subjects. The aim of this study—the ASPIRE In-Home Study—was to investigate the safety and
compare the effect on hypoglycemia of SAP + LGS with SAP
alone in type 1 diabetic patients prone to nocturnal hypoglycemia.
Although the efficacy of SAP in reducing HbA1c without
increasing hypoglycemia has been demonstrated in recent
RCTs, there is a lack of information about the real-life value
of SAP when used in the long-term. This multicenter, observational study aimed to document usage and safety of
SAP and which variables are associated with improvement
in HbA1c.
1
2
Methods
Type 1 diabetic subjects (aged 16–70 years) who had
documented nocturnal hypoglycemia and used a glucose
sensor for at least 80% of the time during a run-in phase
(n = 247) were randomly allocated to SAP + LGS or to SAP
alone for 3 months. The threshold was initially set at
3.9 mmol/L (70 mg/dL). For the test group, LGS was used
from 10 pm to 8 am but was optional at other times.
Results
HbA1c did not change from baseline to study end in either
group. The area under the curve for nocturnal hypoglycemia
was 37.5% less in the SAP + LGS groups versus the SAPalone groups ( p < 0.001). The mean sensor glucose at the start
of nocturnal hypoglycemia was 3.5 mmol/L (62.6 mg/dL),
and 9.0 mmol/L (162.3 mg/dL) 4 hours later. The median
duration of nocturnal suspends was 11.9 minutes; 19.6%
were for 2 hours (mean glucose 4 hours after suspend
9.4 mmol/L [168.8 mg/dL]). Scores for the Hypoglycemia
Fear Survey did not differ between groups. No episodes of
diabetic ketoacidosis (DKA) occurred. Four episodes of SH
occurred in the SAP-alone group, none in the SAP + LGS
group.
Methods
Data from 263 type 1 diabetes patients who switched from
CSII alone to SAP at 27 centers in 15 countries in Europe and
Israel were analyzed over a 12-month period. Subjects were
children, adolescents, and adults.
Results
The main indications for SAP were glycemic instability
(38%), high HbA1c (30%), recurrent hypoglycemia (8%),
and hypoglycemia unawareness (8%). Mean sensor usage
(30%) decreased over time (37–27%). Factors associated
with improvement in HbA1c were baseline HbA1c, older
age, and more frequent sensor use. Diabetes-related hospital admissions and length of stay were less on SAP than
for the 12 months before SAP start. There was no significant change in the frequency of SH, but patients reported
reduced fear of hypoglycemia and increased treatment
satisfaction.
Conclusions
The results on the factors linked to the effectiveness of SAP
in everyday practice—frequency of sensor usage, elevated
baseline HbA1c, and older age of the patients—are consistent
with information from recently published RCTs in volunteers.
Conclusions
Outpatient safety assessment of an in-home predictive
low-glucose suspend system with type 1 diabetes
subjects at elevated risk of nocturnal hypoglycemia
SAP with an LGS feature is safe to use in the home setting
and reduced nocturnal hypoglycemia without increasing
HbA1c.
Buckingham BA 1, Cameron F 2, Calhoun P 3, Maahs DM 4,
Wilson DM 1, Chase P 4, Bequette BW 2, Lum J 3, Sibayan J 3,
Beck RW3, Kollman C3
S-20
Stanford University, Stanford, CA; 2Rensselaer Polytechnic
Institute, Troy, NY; 3Jaeb Center, Tampa, FL; and 4Barbara
Davis Center for Childhood Diabetes, University of Colorado,
Denver, CO
PICKUP
1
Background
Commercially available SAP with LGS is based on suspension of the basal rate when the CGM glucose falls below a
set threshold. This pilot study tests in the home setting a
prototype SAP system where the LGS is activated for up to 2
hours when hypoglycemia is predicted, rather than when the
actual threshold value is reached.
Methods
Subjects with type 1 diabetes (n = 19, aged 18–56 years)
were randomized to 21 nights of study, either 14 with the
LGS prediction on or 7 with the feature off. The pump
communicated with a bedside laptop computer that contained the algorithm for predictive insulin suspend (three
algorithm versions were tested) and the randomization
procedure.
Results
With the final algorithm, LGS occurred on 53% of the nights
and the occurrence of overnight hypoglycemia was reduced
from 30% of nights with SAP alone to 16% using the SAP +
predictive LGS. Mean morning glucose was 8.0 mmol/L
(144 mg/dL) versus 7.4 mmol/L (133 mg/dL) on intervention
versus control nights. Morning blood ketone levels were
>0.6 mmol/L after LGS on only one occasion.
Conclusions
Predictive LGS in the home setting is safe and shows
promise as a technology for substantially reducing nocturnal
hypoglycemia.
Comment
The study of Bergenstal et al. is important RCT evidence
that confirms the safety and efficacy of SAP with LGS,
though the technology has now been in use and shown to
be safe and effective in Europe for about 4 years. Note
that patients with frequent SH (more than one episode in
the previous 6 months) were excluded, so the use of
SAP + LGS in the group that is arguably the most in need
of it was not tested. Indeed, as previously discussed in the
Yearbook, the limited evidence for a reduction in SH with
SAP (as opposed to mild-to-moderate hypoglycemia) is
mostly because of the exclusion in trials of those with
frequent hypoglycemia at baseline. Observational and
RCT evidence for a reduction in SH with SAP, with or
without LGS, has now been reported (3,4) and should be
available in published form soon.
It is clear from both RCTs and now from the large, reallife study of SAP by Nørgaard et al. that the efficacy of
SAP depends on frequent use of the sensor and is best
applied in those with poor glycemic control at baseline.
Note also in this study the interesting fact that hospital
admissions and length of stay were reduced during SAP
therapy—presumably this and the best application of
SAP in those with poor control will be important
determinants in any cost-effectiveness calculations, essential for reimbursement of CGM.
The study of Buckingham et al. on predictive LGS
pumps documents their potential value, and pumps
using this feature are set to become commercially available in the near future. We will need to know how
effective they are at reducing SH in comparison with
current threshold SAP + LGS.
REDUCTION IN BLOOD GLUCOSE VARIABILITY
AND HYPOGLYCEMIA WITH INSULIN
PUMP THERAPY
Glucose variability assessed by low blood glucose
index is predictive of hypoglycemic events in patients
with type 1 diabetes switched to pump therapy
Crenier L, Abou-Elias C, Corvilain B
Department of Endocrinology, ULB-Erasme Hospital, Brussels,
Belgium
Diabetes Care 2013; 36: 2148–53
Background
Mild-to-moderate hypoglycemia is common in type 1 diabetes, may limit efforts to improve control, and may have
adverse psychosocial effects in patients. Little is known about
the factors that predict any reduction in this type of hypoglycemia on switching from MDI to CSII. The aim of this
study was to identify such factors, particularly to test whether
glycemic variability at baseline identifies those who have the
best response to CSII in reducing hypoglycemia.
Methods
Adults with long-standing type 1 diabetes (n = 50) treated
by CSII because of persistent elevated HbA1c or frequent
hypoglycemia on MDI were studied. In addition to HbA1c,
various glycemic variability indices were calculated from
meter-downloaded self-monitored blood glucose profiles at
baseline and after 6 months of CSII.
Results
The patients had high glycemic variability at baseline,
which was reduced by CSII: glucose SD was reduced from
5.0 mmol/L (90.8 mg/dL) on MDI to 4.6 mmol/L (83.5 mg/
dL) on CSII ( p = 0.006). HbA1c reduced from 8.04% to 7.48%
( p = 0.00001). The baseline HbA1c on MDI was independently
correlated with change in HbA1c on switching to CSII. Hypoglycemic events were in general not significantly different
on MDI and CSII. In a multivariate analysis, baseline low
blood glucose index (LBGI) correlated with change in hypoglycemia on switching to CSII, and those patients with the
highest tertile of LBGI on MDI had a significant (23.3%) reduction in hypoglycemic events and a reduction in LBGI
when treated by CSII.
INSULIN PUMPS
Conclusions
Glycemic variability is reduced on CSII versus MDI. Those
patients with the highest glycemic variability as measured by
LBGI had the largest reduction in hypoglycemic events when
switching from MDI to CSII.
Glycaemic variability in paediatric patients with type 1
diabetes on continuous subcutaneous insulin
infusion (CSII) or multiple daily injections (MDI):
a cross-sectional cohort study
Schreiver C 1, Jacoby U 1, Watzer B2, Thomas A 3, Haffner D 1,4,
Fischer D-C 1
1
Department of Paediatrics, University Hospital Rostock, Rostock,
Germany; 2Department of Paediatrics, Philips University,
Marburg, Germany; 3Medtronic GmbH, Meerbusch, Germany;
and 4Department of Paediatrics, Liver and Kidney Disease,
Hannover Medical School, Hannover, Germany
Clin Endocrinol 2013;79:641–7
Background
The aim of this study was to test the hypothesis that
glycemic variability is less in type 1 diabetic children
treated by CSII than in those treated by MDI and to relate variability to markers of oxidative stress and cyclooxygenase activity.
Methods
In a cross-sectional design, 22 patients using CSII (mean
age 12.6 years) and 26 using MDI (mean age 13.1 years) underwent real-time CGM for 3 days in order to assess blood
glucose variability, including by the indices of mean amplitude of glycemic excursions (MAGE) and glucose SD. Two
consecutive 24-hour urine collections were used to measure
F2-isoprostanes and PGF2.
Results
Patients on CSII were of comparable age, sex, body–mass
index, and diabetes duration to those on MDI. MAGE was lower
in CSII versus MDI patients (4.96 vs. 6.50 mmol/L, p < 0.01), as
was SD of glucose levels (2.54 vs. 3.15 mmol/L, p < 0.05). Mean
glucose levels, number of episodes of glucose < 3.9 mmol/L, and
isoprostanes and PGF2 did not differ between groups.
Conclusions
Insulin pump therapy is associated with less glycemic
variability than MDI, even when mean blood glucose levels
are comparable between the therapies.
A population-based study of risk factors for severe
hypoglycemia in a contemporary cohort
of childhood-onset type 1 diabetes
Cooper MN 1,2, O’Connell SM 2, Davis EA1–3, Jones TW 1–3
1
Telethon Institute for Child Health Research, University of
Western Australia, Perth, Australia; 2Department of Endocrinology and Diabetes, Princess Margaret Hospital, Perth,
Australia; and 3School of Paediatrics, University of Western
Australia, Perth, Australia
S-21
Diabetologia 2013;56:2164–70
Background
SH is the single most important barrier to achieving strict
glycemic control in type 1 diabetes. Changes in the epidemiology of SH may have occurred in recent years as a result of
improved therapies such as insulin pump therapy. This study
aimed to investigate the rates and risk factors for SH in a
contemporary cohort of children and adolescents with type 1
diabetes.
Methods
Children and adolescents attending a diabetes clinic in
Perth, Australia, between 2000 and 2011 were studied
(n = 1,770; mean age 8.6 years; range 0–17.8 years). Data on
management, demographics, and complications such as SH
were prospectively recorded.
Results
The proportion of subjects using CSII increased in all age
groups over the years 2000–2011, for example, from about
1% to 30% in those > 12 years of age. SH rates declined over
the years from a peak of 21.8 in 2002 to 5.5 in 2006, and 6.2
events/100 patient-years in 2011. Compared to those on
injection regimens, those aged 12–18 years on CSII were at
reduced risk of SH: incidence risk ratio (IRR) of CSII versus
twice-daily regimen 0.58, IRR of MDI versus twice-daily
regimen 1.45.
Conclusion
SH rates have declined in recent years, and the usage of
pumps and MDI has increased. At least in older children,
reduced SH is more often associated with CSII than with
either MDI or twice-daily insulin regimens.
Comment
High blood glucose variability is important because it is
related to a high frequency of hypoglycemia in type 1
diabetes (5), and it is a source of much frustration for
patients who are trying to manage their diabetes more
effectively. Whether variability is a risk factor for diabetic
macrovascular or microvascular disease is still under
discussion. Two of these studies confirm that blood glucose variability is lower on CSII than on MDI, a fact
recorded in previous studies (6). Crenier et al. show
that those patients with the highest LBGI, a measure of
variability with weighting for hypoglycemia, enjoy the
largest reduction in hypoglycemia on switching to CSII.
This highlights the fact that although some studies may
show no change in hypoglycemia frequency with CSII
versus MDI, as with the whole group in the Crenier report here, the significant and notable effects of pump
therapy in reducing hypoglycemia emerge when a highrisk, hypoglycemia-prone subgroup is treated.
Cooper et al. report some interesting facts on the
contemporary epidemiology of SH, which is declining in
incidence, possibly related to the increasing use of CSII.
This is indicated by SH rates in the oldest children being
S-22
lowest in those on pumps. Recent data from the Type 1
Diabetes Exchange Clinic Registry in the United States
also show that pump users have the lowest SH rates (6).
J.P. has received speaker and/or consultancy fees from
Medtronic, Roche, CeQur, Novo Nordisk, and Eli Lilly.
References
1. Pickup JC, Williams G, Johns P, et al. Clinical features of
brittle diabetic patients unresponsive to optimised subcutaneous insulin therapy (continuous subcutaneous insulin infusion). Diabetes Care 1983; 6: 279–84.
2. Campbell F, Macdonald AL, Gelder C, Reynolds C, Holland
P, Feltblower RG. Embedding CSII therapy in the routine
management of diabetes in children: a clinical audit of this
service in Leeds. Pract Diabetes Int 2009; 26: 24–28.
PICKUP
3. Choudhary P, Ramasamy S, Brackenridge A, Green L, Gallen
P, Pender S, Amiel S, Pickup J. Real-time continuous glucose
monitoring significantly reduces severe hypoglycemia in hypoglycemia-unaware patients with type 1 diabetes. Diabetes
Care. October, 2013 [Epub ahead of print] doi: 10.2337/dc130939.
4. Ly TT, Nicholas JA, Retterath A, Lim EM, Davis EA, Jong YS.
Reduction of severe hypoglycaemia with sensor-augmented
insulin pump therapy and automated insulin suspension
in patients with type 1 diabetes. Diabetes 2013; 62 (Suppl 1):
58A.
5. Pickup JC. Glucose monitoring. In: Oxford Textbook
of Endocrinology and Diabetes, edited by Wass JAH,
Stewart PM. Oxford University Press, Oxford, 2011, pp.
1861–68.
6. Weinstock RS, Xing D, Maahs DM, Michels A, Rickels MR,
Peters AL, et al. Severe hypoglycaemia and diabetic ketoacidosis in adults with type 1 diabetes: results from the T1D
Exchange Clinic Registry. J Clin Endocrinol Metab. [Epub
ahead of print]; DOI: 10.1210/jc.2013–1589.
DOI: 10.1089/dia.2014.1504
ORIGINAL ARTICLE
Closing the Loop
Eran Atlas1, Andrew Thorne 2, Kara Lu 2, Moshe Phillip1,3, and Eyal Dassau 2,4
Introduction
CLINICAL STUDIES
T
Closed-loop insulin therapy improves glycemic
control in children aged >7 years
echnology is taking massive strides and becoming a
greater and greater part of daily life. The field of medicine
provides a multitude of examples of the rapid progression of
new technology. One prime example of this progression is the
pursuit of the artificial pancreas (AP). People living with type
1 diabetes mellitus suffer from the inability to produce or
adjust insulin secretions according to their metabolic needs.
Technological advances such as the constant glucose monitor
and continuous subcutaneous insulin infusion pumps have
aided type 1 patients in controlling glucose levels. However, a
great deal of patient intervention is required to prevent hyperglycemia and hypoglycemia, and this intervention can be
very difficult with a busy and unpredictable lifestyle. The
pursuit of the AP is the pursuit to eliminate patient involvement in blood glucose management. The hope is that in doing
so human error, hypo- and hyperglycemia, and patient stress
will be greatly reduced. Closed-loop AP systems now include
a constant glucose monitor, constant subcutaneous insulin
infusion pump, and an automated control algorithm to communicate between the two. Clinical trials have begun to show
the safety and efficacy of closed-loop systems particularly in
overnight inpatient settings. Research has even begun to
study the ability for the closed-loop algorithms to function in
outpatient environments (1). Challenges now largely revolve
around controlling postprandial glucose levels, as subcutaneous insulin action is significantly slower than that of
ingested glucose. Another key challenge is developing
closed-loop systems that are robust enough to handle real-life
scenarios in outpatient procedures. Once the technology for
the AP has been established, industry may look to integrating the systems into smart phones and other socially discrete
devices (2). Many promising studies are bringing the AP
closer to becoming a reality. Our aim in this chapter is to
present a few of the most exciting and influential studies
published within the previous year on closed-loop systems.
Dauber A 1, Corcia L 2, Safer J 1, Agus MSD 1,3, Einis S 4,
Steil GM 3
1
Division of Endocrinology, 2Department of Medicine, 3Medicine
Critical Care Program, and 4Department of Nursing, Boston
Children’s Hospital, Boston, MA
Background
Attempting to control hyperglycemia in patients with type 1
diabetes mellitus has lead to a significant increase in episodes of
hypoglycemia, resulting in a need for a completely automated
AP to improve glycemic control. There has been little research in
closed-loop insulin therapy for very young children. This demographic of type 1 patients is especially difficult to manage
and vulnerable to episodes of hypoglycemia because of factors
such as unpredictable eating patterns and erratic activity level.
The goal of this study was to assess the possibility of improving
nocturnal glycemic control as well as meal glycemic response
using closed-loop therapy in children less than 7 years old.
Methods
In a randomized controlled crossover trial, 10 subjects aged
<7 years with type 1 diabetes for 6 months treated with insulin
pump therapy were studied. Closed-loop therapy and standard
open-loop therapy were compared from 10:00 P.M. to 12:00 P.M.
on two consecutive days. At night, control was affected with a
proportional-integral component in series with a proportionalderivative component, and at 8:00 A.M., control was transferred
to an algorithm using a proportional integral component in
parallel with a proportional-derivative component. The primary
1
Diabetes Technology Center, Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, Schneider Children’s Medical Center
of Israel, Petah Tikva, Israel.
2
Sansum Diabetes Research Institute, Santa Barbara, CA.
3
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
4
Department of Chemical Engineering and the Institute for Collaborative Biotechnologies, University of California at Santa Barbara,
Santa Barbara, CA.
S-23
S-24
outcome was plasma glucose time in range (110–200 mg/dL)
during the night (10:00 P.M.–8:00 A.M.). Secondary outcomes
included peak postprandial glucose levels, incidence of hypoglycemia, degree of hyperglycemia, and prelunch glucose levels.
Results
Without reaching statistical significance, closed-loop therapy
did trend toward a higher mean nocturnal time within target
range (5.3 vs. 3.2 hours, p50.12). There was no difference in peak
postprandial glucose or number of episodes of hypoglycemia.
There was significant improvement in time spent >300 mg/dL
overnight with closed-loop therapy (0.18 vs. 1.3 hours, p50.035)
and the total area under the curve of glucose >200 mg/dL
( p50.049). Closed-loop therapy returned prelunch blood glucose closer to target (189 vs. 273 mg/dL on open loop, p50.009).
Conclusion
The closed-loop insulin therapy was able to reduce nocturnal hyperglycemia without increasing the incidence of
hypoglycemia. It was also able to establish similar peak
postprandial glucose concentrations and then return the
concentration closer to target before the next meal.
Comment
This study evaluated a proportional-integral-derivative
controller–based AP system in children aged >7 years.
The authors mentioned that management of type 1 diabetes in very young children is especially difficult because of unpredictable eating patterns, erratic activity
level, and increased susceptibility to severe hypoglycemia. However, with the study design performed, this
challenge was not put to the test. Yet, they did test the AP
system in a very insulin-sensitive age group. As noted in
the article, a change to the system aggressiveness was
performed in the middle of the study in order to cope
better with the patient’s insulin sensitivity.
In order to be able to interpret the benefit of the AP
over the basal-bolus strategy, it is recommended that at
least the primary endpoint will be powered. In addition,
in case the study includes several secondary endpoints, it
is recommended to design for these in advance to
support statistical data analysis. The study results are
encouraging, but it is very hard to say that this study
showed any superiority of the AP system over the
conventional therapy.
One other limitation is that during open-loop control,
additional correction insulin boluses were allowed to be
given overnight. As the authors mentioned, this should
have biased the results. Future design should include a
control group as well as blind the study results and
measurement to the patients and in some situations to the
healthcare providers (double blinded) in order to avoid
changes to their treatment behavior.
Clinical evaluation of a personalized artificial pancreas
Dassau E 1–3, Zisser H 1,3, Harvey RA 1,3, Percival MW 1,3,
Grosman B 1–3, Bevier W 3, Atlas E 4, Miller S 4, Nimri R 4,
Jovanovic L 1–3, Doyle FJ 1–3
ATLAS ET AL.
Department of Chemical Engineering and 2Biomolecular Science
& Engineering Program, University of California, Santa Barbara,
CA; 3Sansum Diabetes Research Institute, Santa Barbara, CA; and
4
Jesse Z. and Sara Lea Shafer Institute for Endocrinology and
Diabetes, National Center for Childhood Diabetes, Schneider
Children’s Medical Center of Israel, Petah Tikva, Israel
1
Background
An automated AP system that is able to control blood
glucose concentrations would prevent complications from
hyper- and hypoglycemia as well as improve the quality of life
of those living with type 1 diabetes mellitus. The objective of
this study was to demonstrate the feasibility of a fully automated system that would require no user input.
Methods
Two pilot prospective trials were conducted using a multiparametric formulation of a model predictive control and an
insulin-on-board algorithm. Patient data were collected for 3
consecutive days before initiating the closed-loop trial in order to develop individual models for the controller. The
protocol evaluated the control algorithm for three main
challenges: (a) normalizing glycemia from various initial
glucose levels, (b) maintaining euglycemia, and (c) overcoming an unannounced meal of 30 g carbohydrates.
Results
Initial glucose values ranged from 84 to 251 mg/dL. Blood
glucose was kept in the near-normal range (80–180 mg/dL)
for an average of 70% of the trial time. The low and high blood
glucose indices were 0.34 and 5.1, respectively. Two subjects
repeated the study multiple times with minimal intrasubject
variability.
Conclusion
This short-term study demonstrates the feasibility of controlling glycemia by delivering insulin through a fully automated AP device based on personalized model predictive
control with safety components. The controller demonstrated
the ability to overcome unannounced meal challenges and
hyperglycemia without overdosing insulin because of the
insulin-on-board system.
Comment
This study is unique in that it represents one of the first
fully automated multiparametric model predictive control algorithm with insulin-on-board that does not rely on
user intervention to regulate blood glucose. It provides
promising results in regulating glycemia levels by tailoring the control algorithm to the individual. The key
advantage of the presented AP system relies on the fact
that the control laws were evaluated off-line, thus minimizing online computing power.
One of the main debates over the past years is focused
on whether we can use continuous glucose monitoring
(CGM) results to evaluate the closed-loop system performance or use only reference gold-standard technique. In
CLOSING THE LOOP
this study, the authors reviewed and analyzed both
methods. Yet, not both methods can be used to accurately
estimate the study endpoints and it may be that these
should complement each other. As we move toward
ambulatory studies, more emphasis should be made on
how data are reported and what are the means to
accurately report the clinical results. Unmodified CGM
data should be considered as the primary source for data
analysis at home. A number of modifications and new
directions may be pursued in future studies. Extending the
duration of the trials, particularly after meals, would better
prove the controller’s ability to avoid overdelivering
insulin. As the insulin-on-board safety constraint was
tuned using the subject’s correction factor, future controllers may be tuned on the basis of the correction factor alone.
S-25
57.3% [IQR 25.2%–71.8%] for control, p50.003) and reduced
the number of hypoglycemic events. Eight participants (53%)
had at least one hypoglycemic event (plasma glucose
<3.0 mmol/L) during standard treatment, compared with just
one participant (7%) during closed-loop treatment ( p50.02).
Conclusion
Dual-hormone closed-loop delivery improved glucose
control and reduced the risk of hypoglycemia in 15 participants, as compared with continuous subcutaneous insulin
infusion. The promising results of the study show that such
therapy may prove useful in controlling hypoglycemia, particularly during the night.
Comment
The use of glucagon within an AP system has been debated in recent years. This is the first randomized controlled study that compares the dual-hormone AP to
standard of care. The presented system relied on glucagon just for a rescue and not as part of the treatment. This
is evident from the fact that insulin dosing was similar
between arms and the system suspended insulin for
about 40 minutes before advising glucagon, which occurred on a glucose level of 4.9 mmol/L (4.2–6.0). These
results are of interest—mainly that patients maintained
tight glucose control with almost no hypoglycemia during closed-loop compared to the control arm. Additional
studies with more patients at different age groups as well
as additional challenges are needed before the full benefit
of the bi-hormonal system could be appreciated. Current
obstacles in the development of a bi-hormonal AP are the
need for a dual-chamber pump/delivery system and a
stable formulation of glucagon. Recent developments
and publications on the latter show promising results
that may encourage pump manufacturers to produce a
dual-chamber pump or delivery system. Yet, this study
shows great potential for the use of glucagon for safety
mitigation in future AP devices.
Glucose-responsive insulin and glucagon delivery
(dual-hormone artificial pancreas) in adults with type 1
diabetes: a randomized crossover controlled trial
Haidar A 1,2, Legault L 3, Dallaire M 1, Alkhateeb A 1, Coriati A 1,
Messier V 1, Cheng P 4,5, Millette M 3, Boulet B 2,
Rabasa-Lhoret R 1,6
1
Institut de Recherches Cliniques de Montréal, Montréal, Quebec,
Canada; 2Centre for Intelligent Machines, McGill University,
Montréal, Quebec, Canada; 3Montréal Children’s Hospital,
Montréal, Quebec, Canada; 4Jaeb Center for Health Research,
Tampa, FL; 5Endocrinology Division, Montréal University
Hospital, Montréal, Quebec, Canada; and 6Nutrition Department,
Université de Montréal, Montréal, Quebec, Canada
CMAJ 2013; 185: 297–305
Background
Hypoglycemia remains the greatest barrier to intensifying
insulin therapy in type 1 diabetic patients. Closed-loop systems
that connect constant glucose monitors and insulin pumps may
help control glucose levels, but cases of hypoglycemia are still
reported with these systems. Dual-hormone therapy systems
using both insulin and glucagon have been proposed, but their
potential benefits to promoting glycemic control are unknown.
The objective of this study is to determine whether dualhormone closed-loop therapy can improve glycemic control
and reduce cases of hypoglycemia in adults with type 1 diabetes
mellitus in comparison to conventional insulin pump therapy.
Nocturnal glucose control with an artificial
pancreas at a diabetes camp
Phillip M 1,2, Battelino T 3, Atlas E 1, Kordonouri O 4,
Bratina N 3, Miller S1, Biester T 4, Stefanija MA 3,
Muller I 1, Nimri R 1, Danne T 4
1
Methods
An open-label, randomized crossover design was used to
compare dual-hormone closed-loop therapy with continuous
subcutaneous insulin delivery in 15 participants. Patients
were admitted to a clinical research facility and received, in
random order, both treatments. Each participant was challenged with a 30-minute exercise, an evening meal, a bedtime
snack, and an overnight stay.
Children’s Medical Center of Israel, Petah Tikva, Israel; 2Sackler
Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Department of Pediatric Endocrinology, Diabetes and Metabolism,
University Medical Center–University Children’s Hospital, and
Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia;
and 4Diabetes Center for Children and Adolescents, Auf der Bult,
Kinder- und Jugendkrankenhaus, Hannover, Germany
N Engl J Med 2013; 368: 824–33
Results
Closed-loop dual-hormone therapy increased time spent in
the target glucose range (median 70.7% [interquartile range
(IQR) 46.1%–88.4%] for closed-loop delivery versus median
Background
Intensive insulin therapy is considered to be the standard
treatment for patients with type 1 diabetes mellitus. Closed-
S-26
ATLAS ET AL.
loop systems have been shown to improve glucose control
and reduce nocturnal hypoglycemia in hospital settings. It is
unclear if these results can be replicated outside of the hospital
setting. The objective of this study is to assess the ability of the
MD-Logic AP system to control nocturnal glucose in adolescent patients in a youth camp setting.
only a single night, and the need to perform frequent
sensor recalibration during the study. Future studies may
look to improve the alerts module in order to reduce the
number of hypoglycemia alerts and increase their specificity, increase the duration of study, broaden patient
diversity, and utilize outpatient procedures to further
demonstrate efficacy in daily life.
Methods
The 56 participants were between 10 and 18 years of age
with at least a 1-year history of type 1 diabetes. During two
consecutive nights, patients were placed on either an AP or a
sensor-augmented insulin pump for one night in random
order. The AP utilized the MD-Logic system, whose algorithm is based upon fuzzy logic theory, a learning algorithm,
an alerts module, and a personalized system setting. The
primary endpoints were the number of hypoglycemic events
(defined as a sensor glucose value of <63 mg/dL [3.5 mmol/L]
for at least 10 consecutive minutes), the time spent with glucose levels below 60 mg/dL (3.3 mmol/L), and the mean
overnight glucose level for individual patients.
Results
Nights when the AP was used yielded significantly fewer
episodes of nocturnal hypoglycemia (7 vs. 22) and significantly shorter periods when glucose levels were below
60 mg/dL ( p50.003 and p50.02, respectively) in comparison
to nights using the sensor-augmented insulin pump. There
was no significant difference in the median overnight glucose
level between patients. Median values for the individual
mean overnight glucose levels were 126.4 mg/dL (IQR, 115.7
to 139.1) with the AP and 140.4 mg/dL (IQR, 105.7 to 167.4)
with the sensor-augmented pump. No serious adverse events
were reported, and at no time did the research team need to
override the decisions of the AP.
Conclusion
The results of the study reveal the efficacy of the MD-Logic
system as well as the reduced risk of hypoglycemia associated
with its use. The improvement in the timing and amount of
insulin provided, together with the presence of an alarm
module, appears to be related to the improvement of glucose
control and reduction in hypoglycemia.
Comment
This research provides excellent follow-up to studies
done as part of the DREAM project (3). Phillip et al. tested
the same MD-Logic AP system on a large cohort under
more realistic conditions as a step toward home use of the
AP. By completing the research in the setting of a diabetes
camp, the study utilizes a transitional phase between
Clinical Research Center (CRC) studies and home evaluation. The challenge to the AP system in this study was
even bigger as it was compared with sensor-augmented
pump treatment and not to just conventional pump
therapy. These studies advanced the AP research and the
awareness of the public, industry, and regulatory bodies
to the benefits of an AP. Limitations of the study include
the high number of hypoglycemia alerts, narrow range of
the patients’ ages, the evaluation of each treatment over
Multivariable adaptive closed-loop control of an artificial
pancreas without meal and activity announcement
Turksoy K 1, Bayrak ES 2, Quinn L 3, Littlejohn E 4, Cinar A 1,2
1
Department of Biomedical Engineering and 2Department of Chemical and Biological Engineering, Illinois Institute of Technology,
Chicago, IL; and 3College of Nursing and 4Biological Sciences
Division, University of Illinois Chicago, Chicago, IL
Background
Numerous modeling strategies have been attempted in
developing closed-loop control for an AP. Popular control
algorithms tend to rely upon meal and activity announcements from the user. Adaptive control techniques provide a
powerful alternative that do not necessitate any meal or
activity announcements.
Methods
Adaptive control systems based on the generalized predictive control framework are developed by extending the
recursive modeling techniques. Physiological signals such as
energy expenditure and galvanic skin response are used
along with glucose measurements to generate a multipleinput–single-output model for predicting future glucose
concentrations used by the controller. Insulin-on-board
(IOB) is also estimated and used in control decisions. The
controllers were tested with clinical studies that include
seven cases with three different patients with type 1 diabetes
for 32 or 60 hours without any meal or activity announcements. During the study, subjects walked on a treadmill
using a ramped up protocol and were given eight meals and
snacks.
Results
The adaptive control system kept glucose concentration
in the normal preprandial and postprandial range (70–
180 mg/dL) without any meal or activity announcements
during the test period. After IOB estimation was added to
the control system, mild hypoglycemic episodes were observed only in one of the four experiments. The gradual
improvement of the results across the seven experiments is
largely because of improvements to the algorithm and
equipment malfunction.
Conclusion
The multivariable adaptive closed-loop controller was able
to operate without meal or activity announcement to yield an
easier to use AP. Better blood glucose regulation is obtained
by using adaptive system identification and a controller that
CLOSING THE LOOP
leverages physiological information. This controller was able
to regulate blood glucose in three patients.
Comment
An effective adaptive control model for the AP would be
incredibly useful in simplifying the lives of patients with
type 1 diabetes mellitus. The utilization of other physiologic variables within an AP system seems logical and
interesting, as it allows the system to be closer to the way
the body decides on insulin delivery and similar to the
way patients reach their conclusion on a day-to-day basis. Although the idea behind the new design could have
great potential, the clinical results of this study are very
preliminary. A fully automated closed-loop system based
on subcutaneous glucose measurements and insulin delivery as presented here may be too much to wish for
without faster insulin or upper bound on the size of
meals. Late postprandial hypoglycemia and large glucose swings were still a challenge as noted by the authors.
As this control system is studied further, it would be
beneficial to obtain greater sample sizes and address the
tendency of hyperglycemia in patients.
S-27
Results
Retrospective testing of the new algorithm on previous
clinical data sets indicated that, for the four cases where the
previous algorithm failed, the mean suspension start time was
30 minutes earlier when using the proposed algorithm compared to the earlier algorithm. In the inpatient studies, the
algorithm prevented hypoglycemia in 73% of subjects. Three
failures were attributed to a positive sensor bias. Suspensioninduced hyperglycemia was not assessed, because hypoglycemia was artificially induced by increasing basal insulin.
Conclusions
The new algorithm functioned well and is flexible enough to
handle variable sensor sample times and sensor dropouts. It also
provides a framework for handling sensor signal attenuations,
which can be challenging, particularly when they occur overnight. Tests in outpatient settings are a focus for future work.
Comment
The unmet need for prevention of hypoglycemia, especially during the nighttime, led to the development of
closed-loop systems and pump shutoff algorithms. Evidence from previous studies, including this one, shows us
that we may need to change our goals into more realistic
ones. As long as the patient is responsible for insulin delivery of the meals, or can intervene during closed-loop
control (as in hybrid system setup), we should aim for
minimizing hypoglycemia rather than preventing it. Even
with glucagon, hypoglycemia cannot be fully prevented.
Therefore, we should look at other benefits the new
technologies can provide us in addition to minimizing
hypoglycemia. In contrast to AP systems, which also aim
at improving the overall glycemic control, pump shutoff
algorithms focus only on hypoglycemia. Furthermore,
these systems still need to prove that they do not cause
rebound hyperglycemia. The main limitation of this study
lies in its design, specifically in the way hypoglycemia
was induced, and that there was neither a control group
nor assessment of potential rebound hyperglycemia.
The Kalman-filter-based predictive pump shutoff algorithm, which was used in this study, is based on glucose
data only. Introducing insulin data into the algorithm may
improve its performance and will allow suspension of the
pump even in cases where glucose is not decreasing.
Inpatient studies of a Kalman-filter-based predictive
pump shutoff algorithm
Cameron F 1, Wilson DM 2, Buckingham BA 2,
Arzumanyan H 3, Clinton P 2, Chase HP 4, Lum J 5,
Maahs DM 4, Calhoun PM 5, Bequette BW 1
1
Department of Chemical and Biological Engineering, Rensselaer
Polytechnic Institute, Troy, NY; 2Department of Pediatric Endocrinology and 3Department of Adult Endocrinology, Stanford
University, Stanford, CA; 4Department of Pediatrics, Barbara
Davis Center for Childhood Diabetes, University of Colorado,
Aurora, CO; and 5Jaeb Center for Health Research, Tampa, FL
Background
Insulin pump shutoff is an important safety feature in
avoiding nocturnal hypoglycemia. Earlier shutoff systems
used a voting algorithm to process the predictions of several
different algorithms and proved capable of preventing 80%
of induced hypoglycemic events. The pump shutoff algorithm presented in the article replaced the voting algorithm
with a single Kalman filter prediction algorithm, reducing
complexity without sacrificing performance. The new algorithm handles variable sampling intervals, sensor signal
dropouts, and safety constraints on allowable pump shutoff
time.
Methods
The Kalman filter algorithm was first tested retrospectively on nocturnal data sets from previous studies. Outcome measurements included time-to-pump suspension in
hypoglycemic cases and number of suspensions in hyperglycemic cases. Sixteen patients were tested in overnight
inpatient trials. Basal insulin was manually increased to induce a decrease in blood glucose and corresponding pump
suspension response.
Effect of pramlintide on prandial glycemic excursions
during closed-loop control in adolescents and young
adults with type 1 diabetes
Weinzimer SA 1, Sherr JL 1, Cengiz E1, Kim G 1, Ruiz JL 1,
Carria L 1, Voskanyan G 2, Roy A 2, Tamborlane WV 1
1
Department of Pediatrics, Yale University School of Medicine,
New Haven, CT; and 2Medtronic Diabetes, Northridge, CA
Diabetes Care 2012; 35: 1994–99
Background
Closed-loop systems release insulin based on sensor output, which picks up on glucose only as it begins to rise. Insulin
S-28
ATLAS ET AL.
action is delayed by the slow absorption rate associated with
subcutaneous infusion. The mismatch between insulin and
glucose availability results in hypoglycemia and postprandial
hyperglycemia. Pramlintide, an analog of human amylin,
slows gastric emptying and may be able to match the rates of
glucose and insulin uptake.
effect. Second, since pramlintide was administered to
patients via manual injection in this study, to preserve the
nature of closed-loop systems, an automated delivery
system for pramlintide should be explored as well. This
may result in a dual hormone system that has its own
complications.
Methods
Eight subjects (4 female, age 15–28 years, A1C 7.5%60.7%)
were studied for 48 hours on a closed loop (CL) insulindelivery system with insulin feedback: 24 hours on CL control
alone (CL) and 24 hours on CL control plus 30 mg premeal
injections of pramlintide (CLP). Target glucose was set at
120 mg/dL. No premeal manual boluses were given. Differences in reference blood glucose excursions, defined as the
incremental glucose rise from premeal to peak, were compared between conditions for each meal.
Results
In the CLP condition, peak blood glucose was delayed by
*1 hour and reduced by an average of 25 mg/dL compared to CL. Pramlintide effects varied by meal type, with
significant reductions at lunch and dinner in association with higher premeal insulin concentrations. Insulin
excursions in CLP were lower in spite of elevated insulin
levels, and no hypoglycemic events occurred under either
condition.
Conclusions
Pramlintide delayed the time to peak postprandial BG and
reduced the magnitude of prandial BG excursions. Beneficial
effects of pramlintide on CL may in part be related to higher
premeal insulin levels at lunch and dinner compared with
breakfast. The delay introduced by pramlintide influences the
closed-loop system to slow insulin release as well, resulting in
elevated insulin and possibly the reduction in glucose peak
magnitude observed.
Comment
The ultimate goal of diabetes caregivers and patients is to
find a solution that could release them from the day-today burden such as carbohydrate counting and mealrelated insulin estimations. Until now, several prototypes
of fully automated AP systems were proposed. However,
because of the limitations imposed by subcutaneous insulin delivery, most of them experienced postprandial
hyperglycemia.
Weinzimer and colleagues approach the insulin delay
issue from a physiological point of view, as opposed to an
engineering perspective. The initial results are encouraging and suggest that the use of adjacent therapy may be
one way to overcome large unannounced meals. The use
of pramlintide as part of the closed-loop system as an
agent that will help to minimize postprandial hyperglycemia for unannounced meals is a novel one; however,
more studies are needed with different meal compositions to better understand the effect on closed-loop
systems. The control algorithm would benefit from a
modification that could account for the delayed meal
The use of an automated, portable glucose control
system for overnight glucose control in adolescents
and young adults with type 1 diabetes
O’Grady MJ 1,2, Retterath AJ 2, Keenan DB 3, Kurtz N 3,
Cantwell M 3, Spital G 3, Kremliovsky MN 3, Roy A 3,
Davis EA 1,2,4, Jones TW 1,2,4, Ly TT 1,2,4
1
Department of Endocrinology and Diabetes, Princess Margaret
Hospital for Children, Perth, Western Australia, Australia;
2
Telethon Institute for Child Health Research, Centre for Child
Health Research, The University of Western Australia, Perth,
Western Australia, Australia; 3Medtronic Minimed, Northridge,
CA; and 4School of Paediatrics and Child Health, The University of
Western Australia, Perth, Western Australia, Australia
Diabetes Care 2012; 35: 2182–87
Background
A constant risk of intensive insulin therapy in patients with
type 1 diabetes mellitus is hypoglycemia. The pursuit of an AP
is not novel, yet many studies have required manual input of
constant glucose monitor data or manual adjustment of insulin by physicians, or control algorithms have been housed
on cumbersome devices. The goal of this study is to develop a
safe, efficacious, closed-loop AP that is portable and allows
for remote monitoring.
Methods
This study was designed to determine the safety and
efficacy of the Medtronic Portable Glucose Control System
(PGCS). This system consists of two constant glucose monitors, a control algorithm based upon proportional-integralderivative, a Blackberry Storm smartphone, a Bluetooth
radiofrequency translator, and a Medtronic Paradigm Veo
insulin pump. The primary endpoint was euglycemia during
overnight closed-loop control. Eight participants were between 12 and 25 years of age, diagnosed with type 1 diabetes
mellitus for over a year, with an HbA1c less than 8.5%, and on
insulin pump therapy for more than 6 months. Subjects underwent a week of baseline open-loop assessment before
participating in an overnight closed-loop study. During the
course of two consecutive nights, the PGCS was used for
nocturnal closed-loop control, while open-loop control was
used from 0700 to 2100 hours.
Results
Mean plasma glucose during overnight closed-loop control
was 661.7 mmol/L. Time spent below 3.9 mmol/L, between
3.9 and 8 mmol/L, and above 8 mmol/L was 7%, 78%, and
15%, respectively. Time spent in the target glucose range was
significantly higher after midnight, and cases of hypoglycemia were significantly higher during the first 3 hours of
CLOSING THE LOOP
closed-loop operation. Investigator intervention was required
on 7 of 16 nights of study.
Conclusion
This study represents the feasibility and safety features
of a portable, automated, closed-loop system for overnight glucose control in adolescents and young adults
with type 1 diabetes mellitus. Monitoring of system operations remotely via wireless network allows for an additional safety feature through physician-supervised home
studies.
S-29
Methods
Twelve adolescents with type 1 diabetes (5 male, mean age
15.0 [SD 1.4] years, HbA1c 7.9% [0.7%], body–mass index 21.4
[2.6] kg/m2) participated in a randomized controlled crossover study. They stayed at a clinical research facility on two
occasions and received, in random order, closed-loop basal
insulin delivery or conventional pump therapy for 36 hours.
Prandial insulin boluses were given before meals but not
snacks. Patients undertook unannounced exercise at a moderate intensity, once in the morning and once in the afternoon.
Primary outcome was percent time during which plasma
glucose was in the target range (71–180 mg/dL).
Comment
Results
Miniaturization and the move toward a portable and
wearable AP is a natural step in the development of the
AP as demonstrated in this article and by other groups
(1). This article presents, for the first time, results from a
feasibility study that involved an AP on a mobile phone,
allowing patients to carry the system during their everyday routine. In the future this new technology will
better facilitate home studies with minimal to no interference in their daily activities. The authors also present
an automatic fault detection mechanism as a safety layer
that can send an alert in cases of sensor or insulin delivery
failures. The ability of the system to automatically detect
faults in the sensor and in the insulin pump is an important safety mechanism in a future product. Two sensors in two different insertion sites were used before and
may be useful but is not practical in real life. In addition,
the choice of the authors to suspend insulin dosing for 2
hours postdetection of a fault is questionable and needs
to be further investigated as this may result in hyperglycemia and even positive ketones. Since it is a feasibility study, the readers should be cautioned regarding
the comparison of closed-loop performed over 2 nights at
a research center to open-loop data collected over 6
nights at home.
Closed-loop delivery increased percentage time in target
(median 84% [IQR 78–88%] vs. 49% [26–79%], p50.02) and
reduced mean plasma glucose levels (128 [19] vs. 165 [55]
mg/dL, p50.02) while also tightening the range (107–161 vs.
85–258 mg/dL). Time in target was 100% on 17 of 24 nights
with closed-loop delivery. Hypoglycemia occurred 10 and 9
times in conventional and closed-loop conditions, respectively. All closed-loop subjects spent ‡ 70% time in target,
while only one-third of conventional therapy subjects had
similar results.
Closed-loop basal insulin delivery over 36 hours
in adolescents with type 1 diabetes:
randomized clinical trial
Elleri D 1,2, Allen JM 1,2, Kumareswaran K 2, Leelarathna L 2,
Nodale M 2, Caldwell K 2, Cheng P 3, Kollman C 3, Haidar A 2,
Murphy HR 2, Wilinska ME 1,2, Acerini CL 1, Dunger DB 1,2,
Hovorka R 1,2
1
Department of Paediatrics, University of Cambridge, Cambridge,
United Kingdom; 2Metabolic Research Laboratories, Institute of
Metabolic Science, Cambridge, United Kingdom; and 3Jaeb Center
for Health Research, Tampa, FL
Background
Previous trials of closed-loop systems have demonstrated
their ability to improve glycemic control, particularly during
sleep. The objective of this study was to assess the response of
closed-loop systems to a 36-hour period with both sleep and
common waking activities.
Conclusions
Twenty-four-hour closed-loop insulin delivery can improve glycemic control in adolescents, but its abilities are
challenged by unannounced exercise and excessive prandial boluses. Work is in progress to target these issues via
small prandial insulin boluses, accounting for insulin levels
when calculating delivery, and adding glucagon rescue
infusions.
Comment
While overnight hypoglycemia has been an important
consideration in the development of closed-loop systems,
this article explores its applications in daily activities as
well. The results of the closed-loop system during
nighttime are repeated compared with other studies
conducted with the same system. This article aims to
show that it can also improve daytime control during
scenarios of meals with preprandial insulin and physical
activities. While closed loop did reach superior glycemic
control during the day, it did not minimize hypoglycemia. It could be that we should aim for different objectives for the AP during daytime when patients are awake
and nighttime when they are asleep. Daytime success
criteria may focus more on hyperglycemia with tolerable
levels in the range 50–70 mg/dL, while during nighttime
we should focus on hypoglycemia minimization without
worsening other glycemic control parameters. Future
discussions in this field are necessary. Increasing automation of the process would be helpful, especially for
populations like adolescents who may have lower compliance and more variability in their daily activities. In
general, it offers an improved quality of life during the
day and night, and the results of this work show that this
is entirely possible.
S-30
ATLAS ET AL.
AP INFRASTRUCTURE AND SYSTEM
ENHANCEMENTS
Comment
As greater trust is given to technology, the safety of that
technology becomes increasingly essential. Multiple layers
of safety systems are key in high-risk devices such as the
AP. The evaluation of the HMS appears promising in
providing such a layer. From previous studies that examined the glucose sensor’s alarms, it is evident that most
patients do not respond to alarms mainly because of their
low reliability. Therefore, we must provide an alarm system that will have higher specificity and sensitivity than
the CGM alarms. This article shows a promising algorithm
but is still susceptible to erroneous CGM errors. Additional
data such as insulin delivery may help in improving alert
specificity. The use of alternative mathematical evaluation
in the HMS system is important in supplementing the
safety features built into the control algorithm. Future
evaluations of the HMS in larger cohorts, in a study design
that allows estimation of the system’s true positive and
false-positive rates as well as with different settings, will
improve the design of the suggested safety layer of the AP.
Design of the health monitoring system for the artificial
pancreas: low-glucose prediction module
Harvey RA 1,2, Dassau E 1–3, Zisser H 1,2, Seborg DE 1,2,
Jovanovic L 1–3, Doyle FJ 1–3
1
Department of Chemical Engineering, University of California–
Santa Barbara, Santa Barbara, CA; 2Sansum Diabetes Research
Institute, Santa Barbara, CA; and 3Biomolecular Science and Engineering Program, University of California–Santa Barbara, Santa
Barbara, CA
Background
Management of type 1 diabetes mellitus through insulin
administration can be dangerous as insulin is toxic at high
doses. The AP device system design requires that multiple safety
layers be built around the control algorithm to ensure the health
of the user and the proper condition of the device. The purpose
of this study was to design and evaluate the health monitoring
system (HMS), a safety system for the AP device system.
Methods
The HMS evaluates the trend of glucose in a mathematically different way from the controller, and thus provides an
extra layer of protection for the user. The HMS was designed
as a modular using a large set of ambulatory data. It was
evaluated in silico by inducing hypoglycemia with a missed
meal [bolus for a 65 g carbohydrate (CHO) meal] and administering rescue CHOs per HMS alerting. The HMS was
validated in-clinic with a real-life challenge of a subject who
overdosed insulin before admission.
Results
The HMS was evaluated for clinical use with a 15-minute
prediction horizon. About 393 days of CGM data from seven
patients was used in a retrospective study. About 93.5% of
episodes were detected with 2.9 false alarms per day. During
in silico evaluation, the HMS reduced the time spent <70 mg/
dL from 15% to 3%. When the HMS was first tested in-clinic,
the subject overdosed *3 U of insulin before her arrival to a
closed-loop session (against protocol). The controller reduced
insulin delivery, and the HMS gave four alerts that were
successfully received via clinical software and text and multimedia messages. Even with insulin reduction and CHO
supplements, hypoglycemia was unavoidable but manageable because of the HMS, confirming that a safety system to
detect adverse events is an essential part of the Artificial
Pancreas Device System (APDS).
Conclusion
The HMS has been evaluated using respective clinical
data and prospective in silico and human clinical trials. Despite the reduction in insulin delivery from the controller,
hypoglycemia was unavoidable. This confirms that a safety
system to detect adverse events is essential in closed-loop
systems.
Real-time improvement of continuous glucose
monitoring accuracy
Facchinetti A 1, Sparacino G 1, Guerra S 1, Luijf YM 2, DeVries
JH 2, Mader JK 3, Ellmerer M 3, Benesch C 4, Heinemann L 4,
Bruttomesso D 5, Avogaro A 5, Cobelli C1
1
Department of Information Engineering, University of Padova,
Padova, Italy; 2Department of Internal Medicine, Academic Medical Centre, Amsterdam, The Netherlands; 3Department of Internal
Medicine, Medical University of Graz, Graz, Austria; 4Profil Institute for Metabolic Research GmbH, Neuss, Germany; and
5
Department of Clinical and Experimental Medicine, University of
Padova, Padova, Italy
Diabetes Care 2013; 36: 793–800
Background
CGM offers a potentially more effective alternative to traditional blood glucose measuring systems by keeping patients
better informed of their blood glucose levels. As the primary
source of data for patients and/or closed-loop systems, CGM
must accurately detect hyper- and hypoglycemia. Three major
confounding factors are noise from sensor measurements, inaccuracy caused by delayed absorption and processing time, and
the need for prealerts to avoid glycemic excursions. The study
proposes and tests a smart CGM (sCGM) system that includes
software modules for denoising, enhancement, and prediction.
Methods
Two studies with 12 type 1 diabetic patients each were
conducted to evaluate the performance of the sCGM. In the
first, patients were fitted with two CGM sensors, one normal
and one smart, and observed over the course of 7 days. In the
second, patients under observation were randomly assigned
to open-loop or closed-loop treatments on the third day for a
24-hour observation period. The outcome metrics used were
smoothness of denoised data, level of clinical danger of inaccurate CGM, time to detect serious glycemic excursion, and
false-positive rate.
CLOSING THE LOOP
Results
The denoising module reduced noise by 57% in both studies. Enhancement of the denoised data deviated less from the
plasma glucose than CGM data (10.3% vs. 15.1%), boosting
accuracy (87.7% vs. 75.1%). With the addition of the prediction
module, sCGM was able to predict glycemic excursions 14
minutes earlier and reduce false alerts (20% vs. 42%).
Conclusions
S-31
identified all three types of failures in the type 1 diabetes mellitus patient datasets, with one spike false-positive.
Conclusion
The method is able to identify system failure with reasonable accuracy in both simulated and real patients. It clearly
demonstrates its potential in improving the safety of type 1
diabetic patients, particularly overnight.
Real-time processing using the modules enhanced CGM
performance significantly. The modular nature of the proposed sCGM opens up opportunities for collaboration and
provides a standardized platform for future modules. The
results demonstrated a promising improvement in CGM
safety, encouraging future patient studies and research into
integrating the sCGM with commercial CGM systems.
Comment
For the past several years, most of the research efforts
were invested in the development of the core control algorithm of the AP. Now that we are close to conducting
home studies, the dream of commercial AP seems closer
than ever. As noted in these two publications by Facchinetti and colleagues, several improvements to the
CGM algorithms and additional safety layers will benefit
the clinical use of the AP and will provide a safer and
more reliable device. Facchinetti et al. combined three
modular stand-alone applications demonstrating the
potential of the sCGM to provide improved signal for
both the AP controller and the standard care. Their success supports their proposed approach, which is a useful
plan that merits further exploration in the future.
Our ability to trust machines to provide the necessary
care is a major concern as technology integrates more
and more within the medical field. Use of safety systems and online/real time monitoring is widely acceptable and should be part of the AP design. The ability to
provide real-time failure detection and diagnosis as
demonstrated by Facchinetti et al. is important to the
field. These two developments should be further investigated and evaluated under prospective clinical studies.
An online failure detection method
of the glucose–insulin pump system: improved
overnight safety of type 1 diabetes subjects
Facchinetti A, Del Favero S, Sparacino G, Cobelli C
Padova, Italy
IEEE Trans Biomed Eng. 2012; 60: 406–16
Background
While closed-loop systems are a promising technology for
smarter insulin therapy, failure of either the continuous subcutaneous insulin infusion (CSII) or CGM systems could result in serious risks for diabetic patients. Facchinetti et al.
propose a method of detecting failure in real time by simultaneously using CGM and CSII data streams and a black-box
model of the glucose–insulin system.
Methods
Based on previously collected CGM and CSII data, an individualized model for the glucose–insulin system is created
and used to generate predictions of future glucose concentrations using CGM and CSII data-streams online. If measured CGM values are inconsistent with model predictions, a
failure alert is generated. The method was tested on 100 virtual patients generated by the UVA/Padova type 1 metabolic
simulator and under three different failure conditions: spike
in the CGM profile, loss of sensor sensitivity, and failure of the
insulin delivery pump. A second test was done on the datasets
of three type 1 diabetes mellitus patients drawn from a larger
database of previous closed- and open-loop trials.
Results
The method successfully generated alerts in all three failure
conditions, with a small number of false-negatives and falsepositives. A false-negative rate of 40% was achieved at small
spikes (7 mg/dL), falling to 3% with spikes of 20–25 mg/dL.
False-positives were reduced by over 66% with increasing spike
size. In the sensitivity loss scenario, an average fall of 15 mg/dL
elicited the correct alert 98% of the time, with 2% misclassified
as spikes. Pump failure was identified within 2 hours at a rate of
86% with an average delay of 63641 min. The method correctly
Assessing performance of closed-loop insulin
delivery systems by continuous glucose monitoring:
drawbacks and way forward
Hovorka R 1,2, Nodale M 1, Haidar A 1, Wilinska ME 1,2
1
Metabolic Research Laboratories, Institute of Metabolic Science,
Cambridge, United Kingdom; and 2Department of Paediatrics,
University of Cambridge, Cambridge, United Kingdom
Background
Closed-loop systems have been tested in inpatient settings,
where reference plasma glucose can be taken to ensure patient
safety and provide data for evaluation. This is not possible in
outpatient studies. CGM offers an alternative method for data
collection, but its reliability is uncertain. Three CGM methods
were tested to determine which, if any, methods are appropriate for outpatient studies.
Methods
The study was a retrospective analysis of three open-label
randomized controlled crossover studies comparing conventional and closed-loop insulin therapies. Thirty-three type 1
diabetes patients, aged 12–65 with at least 1 year since
S-32
diagnosis and 3 months of pump use, were tested in two
overnight sessions. Patients aged 12–18 were tested under an
early evening exercise scenario, while adults (18–65) were
tested under eating-in versus eating-out conditions. Glycemic
control was evaluated by reference plasma glucose and contrasted against unmodified, stochastic, and recalibrated CGM
data. CGM accuracy was defined as the mean absolute relative difference between sensor and plasma glucose levels.
Results
Glucose mean and variability were estimated by unmodified CGM levels with acceptable clinical accuracy. CGM
overestimated time spent in target range (70–145 mg/dL)
during closed-loop nights (CGM vs. plasma glucose median
[interquartile range], 86% [65–97%] vs. 75% [59–91%]; p50.04)
but not during conventional pump therapy (57% [32–72%] vs.
51% [29–68%]; p50.82) providing comparable treatment effect
(mean [SD], 28% [29%] vs. 23% [21%]; p50.11). Stochastic
CGM gave an unbiased estimate of time in target during both
closed-loop (79% [62–86%] vs. 75% [59–91%]; p50.24) and
conventional pump therapy (54% [33–66%] vs. 51% [29–68%];
p50.44), as well as treatment effect (23% [24%] vs. 23% [21%];
p50.96) and time below target. Recalibrated CGM was not
superior to stochastic CGM.
Conclusions
CGM is acceptable to estimate glucose mean and variability,
but without adjustment it may overestimate the benefits of
closed loop. Stochastic CGM provided an unbiased estimate of
time when glucose is in or below target and may be acceptable
for assessment of closed loop in the outpatient setting. Recalibrated CGM has limited applications in the outpatient
setting: though it performed well in closed loop, it overestimated time in target in conventional therapy, despite the
use of highly accurate glucose measurements for calibration.
Comment
One of the biggest arguments the scientific community and
regulatory bodies has is whether it is acceptable to use
continuous glucose sensor to evaluate the safety and efficacy of the AP system. This is mainly because of the lack of
accuracy of CGM compared with the gold-standard reference measurement. Thus, the motto of most groups was
to evaluate the efficacy and safety of the AP using plasma
gold-standard measurements. Eventually, this will not be
available during home studies in which blood glucose is
measured less frequently with a device that has its own
error (sometimes even a higher error than the CGM itself).
On the basis of the above, Hovorka et al. considered
various approaches, looking for the best modification to
the measured CGM data as per the endpoint being
assessed. The idea of introducing the measurement error
into data analysis for time-in-range parameters, as
proposed by the stochastic transformation, seems logical.
Interestingly, this method was used by Phillip et al. and
did not show any difference in the treatment effect of the
AP (compared with control) as was estimated with
unmodified CGM data and after stochastic transformation. More research is required in order to reach the
ATLAS ET AL.
proper evaluation method of the AP system during home
studies. Perhaps one can define limits on sensor accuracy
in order to mark a data set as valid for analysis instead of
modifying the measured CGM values.
Summary
This year brings us ever closer to a fully automated closedloop system. Studies that were conducted at controlled research centers and at diabetic camps this year paved the way
for the ongoing clinical studies conducted at patients’ homes.
Work on control algorithms has improved simplicity, robustness, and accuracy, and recently proposed approaches
incorporate alternative data sources and architecture. Much
progress has been made in patient safety, particularly in addressing overnight and pump-induced hypoglycemia and
system failure, two major sources of concern when using
automated systems. These developments are augmented by
new systems for alerting users and third-party monitors to
emergencies and the addition of dual-hormone therapies to
glycemic control strategies. Some researchers are already
looking beyond to outpatient research and the advancements
in monitoring and data collection technology required for
such endeavors (4). Combined, these efforts shift the AP from
an idea tested in silico and in feasibility studies toward predominantly prospective controlled trials in which the efficacy
and safety of the system is being evaluated against state-ofthe-art treatment.
Yet, some of the challenges that were already presented last
year still need to be addressed. The movement toward human
studies at patients’ homes makes it increasingly important to
find an accurate, day-to-day measure of glucose levels to
protect subjects and accurately evaluate the efficacy of tested
treatments. Addressing these concerns, Kowalski and Dutta
propose a standardization of glucose measurement metrics
for future consideration (5). However, setting the right measures is not enough. Work should also be done to define the
expected accuracy from the glucose sensor and the suitable
statistical measures to be used in these studies. Furthermore,
discussion on the different success criteria for the AP—when
patients are awake and nighttime when they are asleep—
should also be performed. In addition, other algorithms related to automatic fault detection still need to be developed
and tested. This should be a joint effort of academy and insulin pump/CGM industry.
In the meantime, progress is being made on future technologies involving the AP. This includes the development of a
dual-chamber insulin pump to be used with a bi-hormonal
system (with glucagon or with pramlintide). Another such
work is the combined AP and technosphere therapy, which
has made the transition from in silico to inpatient trials to be
discussed in the following years (6).
With existing systems improving and novel approaches
being explored, we are making steady progress toward a reality in which patients can use a fully automated system in
their daily lives.
E.A, A.T., K.L., and E.D. have no competing financial interests. M.P. is a member of advisory boards for AstraZeneca,
CLOSING THE LOOP
Sanofi, Medtronic, and Eli Lilly. He is a consultant to Bristol
Myers-Squibb, AstraZeneca, and Andromeda. He is on the
speaker’s bureau of Johnson and Johnson, Sanofi, Medtronic,
Novo Nordisk, and Roche. He is a shareholder of CGM-3.
References
1. Cobelli C, Renard E, Kovatchev BP, Keith-Hynes P, Ben
Brahim N, Place J, Del Favero S, Breton M, Farret A, Bruttomesso D, Dassau E, Zisser H, Doyle III FJ, Patek SD, Avogaro
A. Pilot studies of wearable outpatient artificial pancreas in
type 1 diabetes. Diabetes Care 2012; 35(9): e65–e67.
2. Murphy HR. 21st century diabetes care: a marriage between
humans and technology. Trends Endocrinol Metab 2013; 24(5):
219–21.
S-33
3. Nimri R, Danne T, Kordonouri O, Atlas E, Bratina N, Biester
T, Avbelj M, Miller S, Muller I, Phillip M, Battelino T. The
‘‘Glucositter’’ overnight automated closed loop system for
type 1 diabetes: a randomized crossover trial. Pediatr Diabetes
2013; 14(3): 159–67.
4. Capozzi D, Lanzola G. A generic telemedicine infrastructure
for monitoring an artificial pancreas trial. Comput Methods
Programs Biomed 2013; 110(3): 343–53.
5. Kowalski AJ, Dutta S. It’s time to move from the A1c to better
metrics for diabetes control. Diabetes Technol Ther 2013; 15(3):
194–96.
6. Lee JJ, Dassau E, Zisser H, Harvey RA, Jovanovic L, Doyle III
FJ. In silico evaluation of an artificial pancreas combining exogenous ultrafast-acting technosphere insulin with zone model
predictive control. J Diabetes Sci Technol 2013; 7(1): 215–26.
DOI: 10.1089/dia.2014.1505
ORIGINAL ARTICLE
New Insulins and Insulin Therapy
Thomas Danne1 and Jan Bolinder 2
Introduction
nsulin degludec (Tresiba) is the first of the new generation of ultra-long-acting insulins that have entered the
market. In January 2013, the European Commission granted
Novo Nordisk marketing authorization for degludec treatment of adult patients with type 1 and type 2 diabetes in
Europe, where the analog will be fully launched during 2013–
2014. Approval has also been obtained in Japan and Mexico.
The U.S. Food and Drug Administration (FDA) issued a
complete response letter in February 2013 that requested additional cardiovascular data from a dedicated cardiovascular
outcomes trial before the review of the new drug application
can be completed.
In a new statement published online in May 2013, the
European Medicines Agency (EMA) has concluded that
insulin-glargine–containing medicines (Lantus, Optisulin,
Sanofi) for diabetes do not show an increased risk of cancer, so
the balance of the medicine’s benefits and risks remains unchanged. In previous years, we have repeatedly commented
on the issue of a potential link between insulin analogs and
cancer. A series of four highly controversial epidemiological
articles in Diabetologia had indicated this link as a possibility
for glargine. In a response in 2011, the FDA updated the information about the safety of insulin glargine. In addition to
the four published observational studies, the FDA had reviewed results from a five-year randomized trial comparing
glargine to neutral protamine Hagedorn (NPH) insulin in
individuals with type 2 diabetes. The results did not support
an increased risk of cancer associated with Lantus in comparison to NPH insulin. In Europe, the Committee for Medicinal Products for Human Use (CHMP) requested that the
Lantus-producer Sanofi provide further data; the company
subsequently carried out further studies and submitted the
results to the CHMP for review. The new data include results
from two cohort studies. The first collected information from
around 175,000 patients in Northern Europe treated with insulin glargine, human insulin, or combined insulin, while the
other obtained data from approximately 140,000 patients in
the United States. Both looked at the occurrence of breast,
I
1
2
colorectal, and prostate cancer with various insulins. Also
included in the review were results from a case–control study
conducted in Canada, France, and the United Kingdom,
comparing 775 patients with diabetes who had breast cancer
with a control group of patients who had diabetes but did not
have breast cancer, comparing insulin glargine with human
insulin and other types of insulin. ‘‘Based on the assessment of
the population-based studies, the CHMP concluded that
overall the data did not indicate an increased risk of cancer
with insulin glargine,’’ said the EMA. It notes also that ‘‘there
is no known mechanism by which insulin glargine would
cause cancer and that a cancer risk has not been seen in
laboratory studies.’’ Particularly the last remark may raise
some eyebrows as several cell culture models have indicated
potential changes in the mitogenic properties of insulin analogs compared with human insulin, but the relevance of
these observations for the human situation remains questionable. (1)
With regard to short-acting insulins for meal-time insulin
supplementation, the patents will expire in the next few years
for current ‘‘rapid-acting’’ insulins (humalog, aspart, glulisine), which means that those will also become more accessible for many more patients. At the same time, this serves as
an incentive for the pharmaceutical industry to intensify efforts to create an ultra-rapid-acting insulin. A quicker insulin
action would better match the rapid rise in blood sugar that
follows meals (and better mimic the near immediate speed of
the first-phase insulin response in nondiabetic people). A
faster insulin would also be more convenient than current
rapid-acting insulins, which in studies still deliver the best
postprandial glucose control when taken before meals. Newer
ultra-rapid-acting insulins could also be associated with less
hypoglycemia (and thus potentially less weight gain). If these
new insulins can drop blood glucose more quickly, patients
would be less likely to stack insulin and have a lower risk for
delayed hypoglycemia. Finally, development of an ultrarapid-acting insulin may prove to be a critical step forward for
the artificial pancreas, since closed-loop algorithms’ ability to
control glucose tightly is limited by the slow speed of available rapid-acting analogs.
Diabetes-Zentrum für Kinder and Jugendliche, Kinder- und Jugendkrankenhaus AUF DER BULT, Hannover, Germany.
Department of Medicine, Karolinska University Hospital Huddinge, Karolinska Institute, Stockholm, Sweden.
S-34
NEW INSULINS AND INSULIN THERAPY
All in all, this review demonstrates that also in 2013 significant advances in our understanding of new insulins have been
made. As we comment on the recent trials, we are looking
forward to the upcoming results of large clinical trials to identify patients that profit from these developments. However,
even in the more affluent countries, the regulatory approval is
no longer sufficient to secure reimbursement for these new insulins. In 2013, for the first time a newly developed insulin
(Tresiba) was not marketed in Germany in spite of approval by
EMA. The overall German health policy development with new
regulatory processes (called ‘‘AMNOG’’) made it unlikely that
reimbursement was achievable in the current situation, and
thus Novo Nordisk refrained from market introduction.
LONG-ACTING INSULIN ANALOGS:
INSULIN DEGLUDEC—APPROVED FOR TREATMENT
OF TYPE 1 AND TYPE 2 DIABETES IN EUROPE
S-35
less total daily insulin doses than in the insulin glarginetreated patients ( p < 0.01).
Conclusions
Long-term basal insulin supplementation with insulin
degludec in patients with type 1 diabetes required lower insulin doses and reduced the risk for nocturnal hypoglycemia
by 25% as compared with insulin glargine therapy.
Efficacy and safety of insulin degludec in a flexible
dosing regimen vs insulin glargine in patients
with type 1 diabetes (BEGIN: Flex T1):
a 26-week randomized, treat-to-target trial
with a 26-week extension
Mathieu C 1, Hollander P 2, Miranda-Palma B 3, Cooper J 4,
Franek E 5, Russell-Jones D 6, Larsen J 7, Tamer SC 7, Bain SC 8
1
Insulin degludec improves glycaemic control
with lower nocturnal hypoglycaemia risk than insulin
glargine in basal-bolus treatment with mealtime insulin
aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1):
2-year results of a randomized clinical trial
Bode BW 1, Buse JB 2, Fischer M 3, Garg SK 4, Marre M 5,
Merker L 6, Renard E 7, Russell Jones DL 8, Hansen CT 9,
Rana A 9, Heller SR 10, on behalf of the BEGIN Basal-Bolus
Type 1 Investigators
1
UZ Gasthuisberg, KU Leuven, Leuven, Belgium; 2Baylor Endocrine Center, Dallas, TX; 3Miller School of Medicine, University of
Miami, Miami, FL; 4Department of Medicine, Stavanger University Hospital, Stavanger, Norway; 5Central Clinical Hospital
MSWiA and Medical Research Center, Polish Academy of Sciences, Warsaw, Poland; 6Royal Surrey County Hospital and
University of Surrey, Guildford, United Kingdom; 7Novo Nordisk
A/S, Soeborg, Denmark; and 8Institute of Life Sciences, Swansea
University, Swansea, United Kingdom
J Clin Endocrinol Metab 2013; 98: 1154–62
2
Atlanta Diabetes Associates, Atlanta, GA; University of North
Carolina School of Medicine, Chapel Hill, NC; 3Glasgow Royal
Infirmary, Glasgow, United Kingdom; 4Barbara Davis Center of
Childhood Diabetes, Aurora, CO; 5Bichat Claude Bernard Hospital,
Paris, France; 6Diabetes and Nierenzentrum, Dormagen, Germany;
7
Montpellier University Hospital, Montpellier, France; 8Royal Surrey County Hospital, Guilford, United Kingdom; 9Novo Nordisk A/S,
Soeborg, Denmark; and10University of Sheffield, United Kingdom
Diabet Med 2013 May 26: [Epub ahead of print]; DOI: 10/1111/
dme.12243
Background
To compare the efficacy and safety of insulin degludec
versus insulin glargine (both together with meal-time insulin
aspart) in patients with type 1 diabetes over a 2-year period.
Methods
Open-label trial with a 1-year main study followed by a
1-year extension period. Patients were randomized to oncedaily insulin degludec or insulin glargine and titrated to
fasting plasma glucose levels of 3.9–4.9 mmol/L.
Results
The rate of nocturnal confirmed hypoglycemia (plasma
glucose < 3.1 mmol/L or severe episodes necessitating assistance) was 25% lower with insulin degludec than with insulin
glargine ( p = 0.02), whereas rates of overall confirmed hypoglycemia, severe hypoglycemic episodes, and adverse events
were similar between groups. Improvements in glycemic
control (glycated hemoglobin and fasting plasma glucose)
were comparable in the two groups. In the insulin degludectreated patients this was achieved with 12% less basal and 9%
Background
To evaluate the efficacy and safety of insulin degludec once
daily with varying injection timing in patients with type 1
diabetes.
Methods
A 26-week, open-label, treat-to-target, noninferiority trial
comparing forced flexible dosing of once-daily insulin degludec (injections given in fixed schedule with 8–40 hours
between doses) with insulin degludec or insulin glargine
given at a fixed time once daily. Thereafter, in a 26-week extension period, all patients randomized to insulin degludec
were transferred to a free-flexible regimen (dosing of degludec allowed any time of the day) and compared with patients
continuing on insulin glargine therapy.
Results
After the first 26-week period, reductions in mean glycated
hemoglobin were similar in patients using forced flexible dosing of insulin degludec ( - 0.40%) or fixed dosing of insulin
degludec ( - 0.41%) or glargine ( - 0.58%) ( p = NS). The decrease
in fasting plasma glucose was comparable with forced-flexible
degludec and fixed insulin glargine dosing, whereas it was
greater with fixed degludec ( - 2.54 mmol/L) than with forcedflexible degludec injections ( - 1.28 mmol/L) ( p = 0.021). At
week 52, the free-flexible insulin degludec regimen resulted in
similar mean glycated hemoglobin but with a more pronounced lowering of fasting plasma glucose (between-group
difference - 1.07 mmol/L, p = 0.005) as compared with the insulin glargine therapy. Rates of overall confirmed hypoglycemia (plasma glucose < 3.1 mmol/L or severe hypoglycemia)
were comparable at week 26 and at week 52. At 26 weeks,
S-36
nocturnal confirmed hypoglycemia with the forced-flexible
degludec regimen was 37% lower than with fixed degludec
( p = 0.003) and 40% lower than with fixed glargine dosing
( p = 0.001). At 52 weeks, the rate of nocturnal confirmed hypoglycemia was 25% lower with free-flexible insulin degludec
therapy than with insulin glargine.
Conclusions
Insulin degludec therapy in patients with type 1 diabetes
allows variation of the daily administration timing without
compromising glycemic control or safety, as compared with
once-daily, fixed-time insulin degludec or glargine regimens.
This may result in better adherence to basal insulin supplementation by permitting changes in injection time according
to personal needs.
Insulin degludec/insulin aspart administered
once daily at any meal, with insulin aspart at other
meals versus a standard basal-bolus regimen
in patients with type 1 diabetes: a 26-week, phase 3,
randomized, open-label, treat-to-target trial
Hirsch IB 1, Bode B 2, Courreges J-P 3, Dykiel P 4, Franek E 5,
Hermansen K 6, King A 7, Mersebach H 8, Davies M 9
1
University of Washington Medical Center–Roosevelt, Seattle,
WA; 2Atlanta Diabetes Association, Atlanta, GA; 3Diabetology and
Vascular Disease Unit, General Hospital, Narbonne, France;
4
BioStat Degludec, Novo Nordisk A/S, Soeborg, Denmark; 5Department of Internal Diseases, Endocrinology and Diabetology,
CSK MSWiA, and Medical Research Center, Polish Academy of
Science, Warsaw, Poland; 6Department of Endocrinology and
Metabolism MEA, Aarhus University Hospital, Aarhus, Denmark; 7Department of Endocrinology, Diabetes Care Center, Salinas, CA; 8Medical and Science Degludec, Novo Nordisk A/S,
Soeborg, Denmark; and 9Department of Cardiovascular Sciences,
University of Leicester and University Hospitals of Leicester NHS
Trust, Leicester, United Kingdom
Diabetes Care 2012; 35: 2174–81
Background
To evaluate the efficacy and tolerability of a basal-bolus
regimen consisting of a coformulation of insulin degludec and
insulin aspart administered once daily at a main meal together with insulin aspart at the other meals (IDegAsp) in
patients with type 1 diabetes. Comparison was made with a
conventional basal-bolus therapy using insulin detemir and
meal-time insulin aspart (IDet).
Methods
Multinational, parallel-group, open-label, treat-to-target
trial, where 548 adult patients with type 1 diabetes (glycated
hemoglobin 7.0–10.0%; body–mass index £ 35.0 kg/m2) were
randomized 2:1 to IDegAsp or IDet regimens over a 26-week
period. IDegAsp was administered with a meal, and IDet was
given in the evening with the addition of a second, breakfast
dose if required.
Results
Reductions in glycated hemoglobin were similar with
IDegAsp ( - 0.75%) and IDet ( - 0.70%) regimens (estimated
DANNE AND BOLINDER
treatment difference IDegAsp minus IDet 0.05% [95% confidence interval (CI) - 0.18 to 0.08]), confirming noninferiority
for IDegAsp versus IDet. Rates of severe hypoglycemia (0.33
vs. 0.42 episodes/patient-year) and overall confirmed (plasma
glucose < 3.1 mmol/L) hypoglycemia (39.17 vs. 44.34 episodes/patient-year) were comparable between the IDegAsp
and IDet groups. The rate of nocturnal confirmed hypoglycemia was 37% lower with IDegAsp than with IDet (3.71 and
5.72 episodes/patient-year, respectively; p < 0.05). Weight
gain was more pronounced with IDegAsp (2.3 kg) than with
IDet (1.3 kg) ( p < 0.05). Despite achieving similar improvements in glycemic control, the total insulin dose was 13%
lower in the IDegAsp group than in the IDet group
( p < 0.0001). No differences were observed between the two
insulin regimens regarding health-related quality of life,
safety parameters, or adverse events.
Conclusions
A basal-bolus insulin regimen comprised of a once-daily
administration of an insulin degludec/insulin aspart coformulation at a main meal together with insulin aspart at the
other meals improves glycemic control equally well and is
noninferior to a conventional basal-bolus insulin therapy with
once- or twice-daily injections of insulin detemir in combination with meal-time insulin aspart. In comparison with the
IDet therapy, the IDegAsp regimen results in a reduced risk of
nocturnal hypoglycemia and fewer daily insulin injections.
Insulin degludec versus insulin glargine
in insulin-naive patients with type 2 diabetes. A 1-year
randomized, treat-to-target trial (BEGIN Once Long)
Zinman B 1, Philis-Tsimikas A 2, Cariou B 3, Handelsman Y 4,
Rodbard HW 5, Johansen T 6, Endahl L 6, Mathieu C 7, on behalf
of the NN1250-3579 (BEGIN Once Long) trial investigators
1
Samuel Lunenfeld Research Institute, Mount Sinai Hospital,
University of Toronto, Toronto, Ontario, Canada; 2Scripps Whittier Diabetes Institute, La Jolla, CA; 3Clinique d’Endocrinologie,
l’Institute du Thorax, CHU Nantes, France; 4Metabolic Institute of
America, Tarzana, CA; 5Endocrine and Metabolic Consultants,
Rockville, MD; 6Novo Nordisk A/S, Soeborg, Denmark; and 7UZ
Leuven, University of Leuven, Belgium
Diabetes Care 2012; 35: 2464–71
Background
To compare the efficacy and safety of insulin degludec
versus insulin glargine in insulin-naive patients with type 2
diabetes inadequately controlled with oral antidiabetic drugs
(OADs).
Methods
Parallel-group, randomized, open-label, treat-to-target trial.
Adult patients with type 2 diabetes with inadequate glycemic
control (A1C 7–10%) despite treatment with OADs were randomized 3:1 to once-daily basal insulin replacement with insulin degludec or insulin glargine in combination with
metformin over 1 year. Insulin doses were titrated to attain
prebreakfast plasma glucose of 3.9–4.9 mmol/L. Primary
endpoint was validation of noninferiority of degludec versus
glargine therapy in A1C reduction at study end (ITT-analysis).
S-37
Results
Methods
In total, 1,030 patients (mean age 59 years and baseline A1C
8.2%) were randomized to degludec (n = 773) or glargine
(n = 257) therapy. The reduction in A1C was similar in the two
groups (degludec - 1.06%; glargine - 1.19%) with an estimated treatment difference between degludec versus glargine
of 0.09% (95% CI - 0.04 to 0.22), confirming noninferiority.
Total rates of confirmed hypoglycemic episodes (plasma
glucose < 3.1 mmol/L or severe hypoglycemia necessitating
assistance) were comparable between the two groups (degludec 1.52 and glargine 1.85 episodes/patient-year of exposure, respectively). The rate of nocturnal confirmed
hypoglycemia was generally low, but significantly lower with
degludec than with glargine (0.25 and 0.39 episodes/patientyear of exposure, respectively; p = 0.038). The relative proportion of patients achieving A1C below 7% without experiencing
hypoglycemia was similar in the two groups. Mean total insulin doses at the end of the study period were comparable
(degludec 0.59 and glargine 0.60 units/kg body weight, respectively). Relative proportion of adverse events was similar
in both groups.
A 26-week, open-label, treat-to-target trial. Adult patients
with type 2 diabetes either previously insulin-naı̈ve and receiving treatment with OADs (A1C 7–11%) or patients with
ongoing therapy with basal insulin – OADs (A1C 7–10%)
were eligible and randomized to three parallel groups: (a)
once-daily insulin degludec, administered in a varying way
according to a prespecified dosing schedule with 8–40-hour
intervals between each injection (n = 229); (b) once-daily insulin degludec administered at the main evening meal
(n = 230); (c) once-daily insulin glargine given at the same
time each day (n = 230). The primary outcome was noninferiority of flexible degludec dosing to glargine therapy in
terms of A1C reduction at study end.
Conclusions
Insulin degludec and insulin glargine, both administered
in a once-daily basal regimen together with metformin,
provided comparable improvements in long-term glycemic
control in insulin-naive patients with type 2 diabetes, with
lower frequency of nocturnal hypoglycemia with insulin
degludec.
The efficacy and safety of insulin degludec given
in variable once-daily dosing intervals compared
with insulin glargine and insulin degludec dosed
at the same time daily: a 26-week, randomized,
open-label, parallel group, treat-to-target trial
in individuals with type 2 diabetes
Results
After 26 weeks, the reductions in A1C were comparable in
all three study groups (flexible degludec - 1.28%, standardized degludec - 1.07%, and standardized glargine - 1.26%,
respectively). The estimated treatment difference of flexible
degludec to glargine therapy was 0.04% (95% CI - 0.12 to
0.20), demonstrating noninferiority. Rates of overall confirmed hypoglycemic events as well as rates of nocturnal
confirmed hypoglycemia and adverse event profiles were
comparable across the three study groups.
Conclusion
The timing of the once-daily injection of insulin degludec
can be varied substantially from day to day without jeopardizing glycemic control or safety.
Low-volume insulin degludec 200 units/mL once daily
improves glycemic control similar to insulin glargine
with a low risk of hypoglycemia in insulin-naı̈ve
patients with type 2 diabetes: a 26-week, randomized,
controlled, multinational, treat-to-target trial: the BEGIN
LOW VOLUME trial
Meneghini L1, Atkin SL 2, Gough SCL 3, Raz I 4, Blonde L 5,
Shestakova M 6, Bain S 7, Johansen T 8, Begtrup K 8,
Birkeland KI 9, on behalf of the NN1250-3668 (BEGIN FLEX)
trial investigators
Gough SCL 1, Bhargava A 2, Jain R 3, Mersebach H 4,
Rasmussen S 4, Bergenstal RM 5
1
1
University of Miami Miller School of Medicine, Miami, FL;
Michael White Diabetes Centre, Hull York Medical School, Hull,
United Kingdom; 3Oxford Centre for Diabetes, Endocrinology and
Metabolism, and NIHR Oxford Biomedical Research Centre,
Churchill Hospital, Oxford, United Kingdom; 4Diabetes Unit,
Hadassah-Hebrew University Hospital, Jerusalem, Israel; 5Ochsner
Diabetes Research Unit, Department of Endocrinology, Ochsner
Medical Center, New Orleans, LA; 6Endocrinology Research
Center, Moscow, Russian Federation; 7Abertawe Bro Morgannwg
University Health Board, Singleton Hospital, Swansea, United
Kingdom; 8Novo Nordisk A/S, Soeborg, Denmark; and 9Department of Endocrinology, Oslo University Hospital, and Faculty of
Medicine, University of Oslo, Oslo, Norway
2
Background
To investigate the efficacy and safety of varying the time of
administration of insulin degludec in patients with type 2
diabetes.
Oxford Centre for Diabetes, Endocrinology and Metabolism, and
NIHR Oxford Biomedical Research Centre, Oxford, United
Kingdom; 2Iowa Diabetes and Endocrinology Center, Des Moines,
IA; 3Aurora Advanced Healthcare, Milwaukee, WI; 4Novo Nordisk
A/S, Soeborg, Denmark; and 5International Diabetes Center at
Park Nicollet, Minneapolis, MN
Diabetes Care 2013 May 28: [Epub ahead of print]; DOI: 10.2337/
dc12-2329
Background
A more concentrated formulation of insulin degludec
(200 units/mL) has been developed that contains equal units
of insulin in half the volume compared with the standard
100 units/mL formulation. In this study, the efficacy and
safety of once-daily administration of the 200 units/mL formulation of degludec was compared with once-daily insulin
glargine (100 units/mL) in insulin-naı̈ve type 2 diabetes
patients with insufficient glycemic control with oral antidiabetic drugs.
S-38
DANNE AND BOLINDER
Methods
A 26-week, open-label, treat-to-target trial; 457 patients
with type 2 diabetes (mean A1C 8.3%, fasting plasma glucose
9.6 mmol/L, and body mass index 32.4 kg/m2) were randomized to receive once-daily insulin degludec 200 units/mL
or insulin glargine, both in combination with metformin with
or without addition of a dipeptidyl peptidase-4 inhibitor. Insulin dose was initiated with 10 units/day, and titrated
weekly to achieve self-measured fasting plasma glucose
below 5 mmol/L.
Results
At the end of the study period, the reduction in A1C was
almost identical in the two groups ( - 1.3%). The mean decrease in fasting plasma glucose was larger with insulin
degludec 200 units/mL than with insulin glargine ( - 3.7 vs.
- 3.4 mmol/L, respectively; p < 0.02). Rates of overall confirmed hypoglycemic episodes were similar with insulin degludec 200 units/mL and insulin glargine (1.22 vs. 1.42
episodes/patient-year, respectively); this was also the case
with nocturnal confirmed hypoglycemia (0.18 vs. 0.28 events/
patient-year, respectively). The mean daily insulin dose was
11% lower with degludec 200 units/mL than with glargine
( p < 0.05). Therapy with insulin degludec 200 units/mL was
well tolerated, and the adverse event profile was comparable
in the two groups.
Conclusion
In this treat-to-target trial, insulin therapy with degludec
200 units/mL resulted in comparable A1C reductions as
glargine in insulin-naı̈ve patients with type 2 diabetes, with a
low rate of hypoglycemia.
Comments
In the molecular structure of degludec, the amino acid
residue threonine in position B30 of the natural human
insulin has been removed, and a 16-carbon fatty diacid
has been coupled to lysine in position B29 via a glutamic
acid spacer. By so doing, degludec forms soluble multihexamers after subcutaneous administration, which then
slowly dissociate and results in a slow and stable release
of degludec monomers into the circulation. Pharmacodynamic investigations in patients with type 1 and type 2
diabetes (2,3) have indeed shown that the glucoselowering action of degludec is stable and flat, and that it
extends for more than 40 hours with a terminal half-life at
a steady state of approximately 25 hours. After oncedaily administration, a steady state is achieved after
about 3 days, and in patients with type 1 diabetes the
day-to-day variability of the glucose-lowering effect of
degludec at steady-state conditions is four times lower
relative to that with insulin glargine.
In earlier chapters, we have reviewed the first series of
published phase 2 and phase 3 trials, where the efficacy
and safety of insulin degludec had been compared with
insulin glargine in treat-to-target designed studies in
adult patients with type 1 and type 2 diabetes. In short,
the findings of those trials showed reduced rates of
hypoglycemic events—and above all of nocturnal hypoglycemia—at comparable improvements in glycemic
control (i.e., reductions in A1C). The study by Bode
et al., which reports data from an extension period of a
previously published phase 3 trial (4), suggests that the
same apply after long-term (2-year) basal insulin replacement with degludec in type 1 diabetes. Perhaps not
surprisingly, similar findings were observed in a metaanalysis of all phase 3 trials with once-daily degludec
versus glargine and with durations of 26–52 weeks (5). In
the type 1 diabetes population (two trials), the rate of selfreported, nocturnal confirmed episodes of hypoglycemia
was 25% lower with degludec versus glargine, whereas
the overall rate of hypoglycemia was comparable. In
patients with type 2 diabetes (five trials), glargine
therapy resulted in significant reductions in both total
rates of hypoglycemia (17% lower) and nocturnal hypoglycemia (32% lower).
The ultra-long action profile of degludec should also
allow less stringent timing of basal insulin administration
from day to day. Accordingly, the study by Meneghini
and co-workers, who tested this concept in a standardized way in patients with type 2 diabetes, showed that
glycemic control or safety (i.e., risk of hypoglycemia) was
not compromised despite very large dosing intervals
between daily injections. Likewise, applying more flexible once-daily dosing of degludec in patients with type 1
diabetes resulted in similar improvement in glycemic
control and less nocturnal hypoglycemia relative to
insulin glargine administered at the same time every
day, as showed in the study by Mathieu et al.
Another feature of degludec is that it can be mixed
with short-acting insulins without the risk of forming
hybrid hexamers and erratic pharmacokinetics/dynamics. Thus, a premixed insulin degludec/insulin aspart
formulation has been developed (Ryzodeg), consisting
of 70% degludec and 30% aspart. The rationale was to
create an action profile in which the prandial insulin
profile of aspart is superimposed on the ultra-long-acting
profile of degludec. This coformulation has previously
been tested in a short-term, phase 2 trial in patients with
type 2 diabetes and was proven to provide comparable
glycemic control and lower risk of hypoglycemia, as
compared with biphasic NPH/aspart-insulin (6). In the
study by Hirsch and colleagues, similar findings were
observed in patients with type 1 diabetes, where the
premixed degludec/aspart formulation administered before the main meal together with prandial aspart at the other
meals was compared with a basal-bolus regimen consisting
of basal insulin replacement with insulin detemir given once
or twice daily in combination with mealtime aspart. An
obvious advantage with the use of the degludec/aspart
coformulation is that fewer daily injections are needed. On
the other hand, titration of the basal insulin replacement
might prove more difficult, and fine-tuning of the prandial
insulin dose according to variations in meal intake, physical
activity, and so on, is not possible with a premixed insulin.
Notably, in the trial by Hirsch et al., the proportion of
patients achieving the preset targets of glycemic control was
rather low (about ¼ with A1C below 7%).
S-39
PEGYLATED INSULIN LISPRO: RESULTS OF THE
FIRST PHASE 2 CLINICAL TRIALS
Better glycemic control and weight loss with the novel
long-acting basal insulin LY2605541 compared with
insulin glargine in type 1 diabetes
A randomized, controlled study of once-daily
LY2605541, a novel long-acting basal insulin,
versus insulin glargine in basal insulin-treated
patients with type 2 diabetes
Rosenstock J 1, Bergenstal RM 2, Blevins TC 3, Morrow LA 4,
Prince MJ 5, Qu Y 5, Sinha VP 5, Howey DC 5, Jacober SJ 5
Bergenstal RM 1, Rosenstock J 2, Arakaki RF 3, Prince MJ 4,
Qu Y 4, Howey DC 4, Jacober SJ 4
1
International Diabetes Center at Park Nicollet, Minneapolis, MN;
Dallas Diabetes and Endocrine Center at Medical City, Dallas,
TX; 3University of Hawaii at Manoa, Honolulu, HI; and 4Eli Lilly
and Company, Indianapolis, IN
1
Dallas Diabetes and Endocrine Center at Medical City Dallas,
Dallas, TX; 2International Diabetes Center at Park Nicollet,
Minneapolis, MN; 3Texas Diabetes and Endocrinology, Austin,
TX; 4Profil Institute for Clinical Research, Inc., Chula Vista, CA;
and 5Eli Lilly and Company, Indianapolis, IN
2
Diabetes Care 2012; 35; 2140–47
Background
To compare the effect of LY2605541 versus insulin glargine
on fasting blood glucose in patients with type 2 diabetes.
Methods
A 12-week, randomized, open-label, phase 2 trial. Patients
with type 2 diabetes with A1C < 10.5% and ongoing combination therapy with once-daily insulin (glargine or NPH) and
metformin and/or sulphonylurea were eligible. During a
lead-in period, all patients administered their basal insulin
once daily in the morning. Thereafter, patients with glargine
(n = 248) or NPH (n = 95) were randomized 2:1 to therapy with
a daily morning dose of LY2605541 (n = 195) or glargine
(n = 95). Insulin doses were titrated according to standardized
algorithms, to achieve self-measured fasting blood glucose
< 5.6 mmol/L.
Results
At study end, laboratory-measured fasting plasma glucose
was similar in the two groups (LY2605541 6.6 – 0.1 and glargine
6.5 – 0.2 mmol/L, respectively), and there was no difference in
A1C (7.0 – 0.1% vs. 7.2 – 0.1%). Intraday blood glucose variability (standard deviation of self-measurements of blood
glucose) was lower with LY2605541 (1.9 – 0.1 mmol/L) than
with glargine (2.2 – 0.1 mmol/L)( p = 0.031). LY2605541
therapy resulted in weight loss ( - 0.6 – 0.2 kg), whereas
glargine was associated with weight gain (0.3 – 0.2 kg), the
treatment difference being - 0.8 kg ( p = 0.001). The rates of
overall and nocturnal hypoglycemic events were similar in
the two groups. However, when adjusting for baseline
hypoglycemia, nocturnal hypoglycemia was reduced by
48% in LY2605541 patients ( p = 0.021). Adverse events were
comparable across the groups. Alanine aminotransferase
and aspartate aminotransferase levels were significantly
higher with LY2605541 ( p < 0.001), albeit within the normal
range.
Background
To compare effects of LY2605541 and insulin glargine as
basal insulin replacement in a basal-bolus regimen on daily
mean glucose control in patients with type 1 diabetes.
Methods
Randomized, phase 2, open-label, 2 · 2 crossover trial;
137 patients with type 1 diabetes were randomized to oncedaily (pre-breakfast) LY2605541 or glargine plus mealtime insulin for 8 weeks, followed by crossover therapy
for an additional 8-week period. Daily mean glucose was
determined from 8-point profiles of self-monitored
blood glucose. The noninferiority boundary was preset at
10.8 mg/dL.
Results
In comparison with insulin glargine, LY2605541 fulfilled noninferiority and superiority criteria in daily mean
glucose (LY2605541 144.2 mg/dL and glargine 151.7 mg/dL,
respectively); the least squares mean difference being
- 9.9 mg/dL ([90% CI - 14.6 to - 5.2 mg/dL], p < 0.001). Reductions in fasting blood glucose variability and A1C were
greater with LY2605541 than with glargine ( p < 0.001 for
both parameters). Mealtime insulin dose was reduced with
LY2605541 and increased with glargine. LY2605541 was associated with weight loss (on average - 1.2 kg), and glargine
with weight gain (0.7 kg) ( p < 0.001). The rate of overall hypoglycemia was higher with LY2605541 ( p = 0.04), whereas
the rate of nocturnal hypoglycemia was lower ( p = 0.01)
relative to glargine. Total adverse events (including severe
hypoglycemic events) were comparable, but gastrointestinal-linked events were more frequently observed with
LY2605541 (15% vs. 4%, p < 0.001). Mean changes of liver
enzymes (alanine aminotransferase and aspartate aminotransferase), triglycerides, and LDL-cholesterol were higher,
and HDL cholesterol lower with LY2605541 than with glargine ( p < 0.02 for all parameters), although they were all
within normal ranges.
Conclusions
Conclusions
Treatment with LY2605541 and glargine in patients with
type 2 diabetes resulted in comparable glycemic control and
overall hypoglycemia rates, but LY2605541 exhibited lower
intraday glucose variability and reduced nocturnal hypoglycemia and weight loss relative to glargine.
Relative to glargine, replacement of basal insulin with
LY2605541 in patients with type 1 diabetes resulted in
better improvements in glycemic control, increased rate of
overall hypoglycemia, but lower incidence of nocturnal
hypoglycemia, weight loss, and reduced mealtime insulin
doses.
S-40
Comments
LY2605541, developed by Lilly, is a novel long-acting
insulin analog based on the polyethyleneglycol(PEG)ylation principle. It consists of insulin lispro covalently
modified with a 20 kDa PEG-unit attached to lysine at
position B29. The large hydrodynamic size results in delayed insulin absorption from the subcutaneous depot and
reduced renal clearance, and hence prolonged duration of
action. It has also been speculated that the large functional
size of the molecule might influence the tissue distribution,
leading to a more hepatoselective mode of action. As reviewed (7), initial pharmacokinetic/dynamic studies with
LY2605541 indicate a flat action profile with duration of
more than 36 hours and with low variability.
From the first two published phase 2 trials in patients
with type 1 and type 2 diabetes, it seems that basal insulin
supplementation with LY2605541 results in similar or
better glycemic control, lower glucose variability, and
possibly a lower risk of nocturnal hypoglycemia, as
compared with glargine. Moreover, weight loss was a
consistent finding in both trials. With regard to safety, the
underlying cause of the observed elevations in liver
enzymes and triglycerides (albeit within normal levels)
needs to be further explored; while these findings might
be due to a more preferential hepatic action, potential
hepatotoxic effects must be ruled out. Hopefully, additional data from longer-term trials will clarify in greater
detail the benefits and safety aspects of this basal insulin
analog.
INSULIN GLARGINE APPROVED DOWN TO 2 YEARS
OF AGE
A randomized trial comparing the rate
of hypoglycemia—assessed using continuous glucose
monitoring—in 125 preschool children with type
1 diabetes treated with insulin glargine
or NPH insulin (the PRESCHOOL study)
Danne T1, Philotheou A 2, Goldman D 3, Guo X 3, Ping L 3,
Cali A 4, Johnston P 3
1
Kinder- und Jugendkrankenhaus ‘‘AUF DER BULT’’, Hannover,
Germany; 2Diabetes Clinical Trials Unit, UCT Private Academic
Hospital, Cape Town, South Africa; 3Sanofi, Bridgewater, NJ;
4
Sanofi, Paris, France
Pediatr Diabetes 2013 Jun 3: [Epub ahead of print]; DOI: 10.1111/
pedi.12051
Background
Avoidance of hypoglycemia is a key consideration in
treating young children with type 1 diabetes mellitus (T1DM).
The objective of the study was to evaluate hypoglycemia with
insulin glargine versus NPH insulin in young children, using
continuous glucose monitoring (CGM).
Methods
Children aged 1 to < 6 years treated with once-daily glargine versus once- or twice-daily NPH, with bolus insulin lispro/regular human insulin provided to all, were studied in a
DANNE AND BOLINDER
24-week, multicenter, randomized, open-label study. Primary
endpoint was event rate of composite hypoglycemia [symptomatic hypoglycemia, low CGM excursions ( < 3.9 mmol/L),
or low fingerstick blood glucose (FSBG; < 3.9 mmol/L)].
Noninferiority of glargine versus NPH was assessed for the
primary endpoint.
Results
One hundred twenty-five patients (mean age, 4.2 years)
were randomized to treatment (glargine, n = 61; NPH, n = 64).
At baseline, mean HbA1c was 8.0% and 8.2% with glargine
and NPH, respectively. Composite hypoglycemia episodes/
100 patient-years were 1.93 for glargine and 1.69 for NPH;
glargine noninferiority was not met. Events/100 patient-years
of symptomatic hypoglycemia were 0.26 for glargine versus
0.33 for NPH; low CGM excursions 0.75 versus 0.72; and low
FSBG 1.93 versus 1.68. There was a slight difference in
between-group severe/nocturnal/severe nocturnal hypoglycemia and glycemic control. All glargine-treated patients received once-daily injections; on most study days, NPHtreated patients received twice-daily injections.
Conclusions
While glargine noninferiority was not achieved, in young
children with T1DM there was a slight difference in hypoglycemia outcomes and glycemic control between glargine
and NPH. Once-daily glargine may therefore be a feasible
alternative to basal insulin in young populations for whom
administering injections can be problematic.
Comment
PRESCHOOL is the largest prospective study to date
investigating the occurrence of hypoglycemia in children
with type 1 diabetes aged ‡ 1 to < 6 years. The results
appear confusing at first sight as a composite endpoint of
various measures for hypoglycemia was used because of
concerns regarding the statistical power in this difficultto-recruit young population. It is common clinical
knowledge that families introduced to a new insulin
regimen test FSBG more frequently and are less likely to
change the insulin dose. As more patients in the insulin
glargine group had to switch to a new basal insulin
regimen from their pretrial basal insulin, more FSBG was
performed overall in this group. As a result, in the insulin
glargine group, there were a greater number of low FSBG
values, which were not recorded at times of low CGM
excursions or symptomatic hypoglycemia signals, and
thus glargine noninferiority was not achieved. In contrast, CGM monitoring is a more objective means of low
blood glucose detection. It is thus independent of parental choice regarding when to check FSBG instinctively
and may be influenced by other factors such as mealtimes, concern over new insulin regimens, or recent/
upcoming periods of exercise. Investigation of hypoglycemia by CGM showed no significant difference between
regimens in terms of confirmed low CGM. CGM therefore should be the preferred means to study hypoglycemia when CGM also permits an accurate assessment of
daily blood glucose variability.
S-41
Plasma exposure to insulin glargine and its
metabolites M1 and M2 after subcutaneous injection
of therapeutic and supratherapeutic doses of glargine
in subjects with type 1 diabetes
rapidly cleaved into its metabolites, both of which have
lower metabolic and similar mitogenic potencies to
human insulin. This may serve as additional evidence for
the safety of glargine, as the absence of insulin glargine
from the circulation after subcutaneous injection questions the relevance of the in vitro findings of enhanced
IGF-1 binding and mitogenicity.
Bolli GB 1, Hahn AD 2, Schmidt R 2, Eisenblaetter T 2, Dahmen
R 2, Heise T 3, Becker RH 2
1
Department of Internal Medicine, University of Perugia, Perugia,
Italy; 2Sanofi-Aventis, Frankfurt/Main, Germany; 3Profil Institut
für Stoffwechselforschung, Neuss, Germany
Diabetes Care 2012; 35: 2626–30
Objective
In vivo, after subcutaneous injection, insulin glargine
(21(A)-Gly-31(B)-Arg-32(B)-Arg-human insulin) is enzymatically processed into 21(A)-Gly-human insulin (metabolite 1
[M1]). 21(A)-Gly-des-30(B)-Thr-human insulin (metabolite 2
[M2]) is also found. In vitro, glargine exhibits slightly higher
affinity, whereas M1 and M2 exhibit lower affinity for IGF-1
receptor, as well as mitogenic properties, versus human insulin. The aim of the study was to quantitate plasma concentrations of glargine, M1, and M2 after subcutaneous
injection of glargine in male type 1 diabetic subjects.
Methods
Glargine, M1, and M2 were determined in blood samples
obtained from 12, 11, and 11 type 1 diabetic subjects who
received single subcutaneous doses of 0.3, 0.6, or 1.2 units/kg
glargine in a euglycemic clamp study. Glargine, M1, and M2
were extracted using immunoaffinity columns and quantified
by a specific liquid chromatography-tandem mass spectrometry assay. Lower limit of quantification was 0.2 ng/mL
(33 pmol/L) per analyte.
Results
Plasma M1 concentration increased with increasing dose;
geometric mean (percent coefficient of variation) M1-area
under the curve (AUC) between time of dosing and 30 hours
after dosing [AUC (0–30 hours)] was 1,261 (66), 2,867 (35), and
4,693 (22) pmol/h/L at doses of 0.3, 0.6, and 1.2 units/kg,
respectively, and correlated with metabolic effect assessed as
pharmacodynamics-AUC (0–30 hours) of the glucose infusion
rate after glargine administration (r = 0.74; p < 0.01). Glargine
and M2 were detectable in only one-third of subjects and at a
few time points.
Conclusions
After subcutaneous injection of glargine in male subjects
with type 1 diabetes, exposure to glargine is marginal, if any,
even at supratherapeutic doses. Glargine is rapidly and nearly
completely processed to M1 (21(A)-Gly-human insulin),
which mediates the metabolic effect of injected glargine.
THE QUEST FOR ULTRA-FAST MEALTIME
INSULIN ACTION
A T3R3 hexamer of the human insulin variant B28Asp
Palmieri LC 1, Fávero-Retto MP 1,2,3, Lourenço D 4, Lima LM 1,4,5
1
School of Pharmacy, Federal University of Rio de Janeiro, Rio de
Janeiro, RJ, Brazil; 2Brazilian National Cancer Institute (INCA),
20230-014, Rio de Janeiro, RJ, Brazil; 3Brazilian National Institute
of Traumatology and Orthopedics (INTO), Rio de Janeiro, RJ,
Brazil; 4Laboratory for Biotechnology (LaBio-DIPRO), Brazilian
National Institute of Metrology, Quality and Technology–INMETRO, Rio de Janeiro, Brazil; 5National Institute of Science and
Technology for Structural Biology and Bioimaging (INBEB-INCT),
Federal University of Rio de Janeiro, Rio de Janeiro 21941-590, Brazil
Biophys Chem 2013; 173–174: 1–7
Abstract
Insulin shows a complex equilibrium between monomers
and hexamers, involving varying conformers and association
states. We sought to perform a structural characterization of
the fast-acting human insulin variant B28Asp (‘‘aspart’’).
Small-angle X-ray scattering measurements reveal similar
globular behavior in both the aspart and regular human insulin, with an Rg of 19Å and a Dmax of approximately 50Å,
indicating similar mean quaternary assembly distribution.
Crystallographic assays revealed a T3R3 assembly of the aspart insulin formed by the TR dimer in the asymmetric unit,
with all the first 8 residues of the B chain in the R-state
monomer in helical conformation and the participation of its
B3Asn in the stabilization of the hexamer. Our data provide
access to novel structural information on aspart insulin such
as an aspart insulin dimer in solution, the aspart insulin in T
conformation and a pure R-state conformer establishing a
T3R3 assembly, providing further insight on the stepwise
conformational transition and assembly of this fast insulin.
A review of a family of ultra-rapid-acting insulins:
formulation development
Krasner A 1, Pohl R 1, Simms P 1, Pichotta P 1, Hauser R 1,
De Souza E 1
1
Biodel Inc., Danbury, CT
Comment
Abstract
Since M2 levels were also below the level of detection, it
was concluded that M1, and not glargine itself, mediated
the glucodynamic effects. In vivo, insulin glargine is
This review summarizes the clinical development of a
family of ultra-rapid-acting recombinant human insulin
formulations. These formulations use ethylenediaminetetraacetic acid (EDTA) to chelate zinc and thereby destabilize
S-42
insulin hexamers. In addition, insulin monomer surface
charges are chemically masked with citrate to prevent reaggregation. The first phase 1 trials were performed using
BIOD-090, an acidic 25 U/mL insulin formulation, which
contained disodium-EDTA (NaEDTA). When compared with
regular human insulin (RHI) and/or insulin lispro in multiple
phase 1 studies, BIOD-090 consistently showed more rapid
absorption and/or onset of action. A standard meal challenge
study also demonstrated improved postprandial glucose
profiles associated with BIOD-090. However, increased patient exposure in larger phase 3 trials showed that this formulation was associated with an increased incidence of local
injection site reactions, most commonly pain. A next-generation formulation, BIOD-100, contained the same excipients as
a standard insulin concentration of 100 U/mL. BIOD-100
maintained an ultra-rapid action profile and was associated
with modest but significantly improved toleration when
compared with BIOD-090. In order to further improve toleration, the hypothesis that NaEDTA contributed to discomfort
by chelating endogenous calcium was tested by either
substituting calcium-EDTA for NaEDTA or by adding calcium chloride to the NaEDTA formulation. These calcium
formulations essentially eliminated the excess discomfort associated with BIOD-090 but were associated with less optimal
pharmacokinetic profiles in humans. Recent efforts have
succeeded in developing ultra-rapid-acting human insulin
formulations with acceptable injection site toleration by optimizing concentrations of calcium (BIOD-125) and with the
use of magnesium sulfate to mitigate discomfort (BIOD-123).
Similar formulation technology has also been shown to accelerate absorption of insulin analogs in animal models.
Ultra-rapid absorption of recombinant human insulin
induced by zinc chelation and surface charge masking
Pohl R1, Hauser R 1, Li M 1, De Souza E 1, Feldstein R1,
Seibert R 1, Ozhan K 2, Kashyap N 3, Steiner S 4
1
Biodel Inc., Danbury, CT; 2Louisiana State University, Baton
Rouge, Louisiana; 3Pii, Hunt Valley, Maryland; 4Steiner Ventures,
Mt. Kisco, NY
Background
In order to enhance the absorption of insulin following
subcutaneous injection, excipients were selected to hasten the
dissociation rate of insulin hexamers and reduce their tendency to reassociate postinjection. A novel formulation of
recombinant human insulin containing citrate and disodium
ethylenediaminetetraacetic acid (EDTA) has been tested in
clinic and has a very rapid onset of action in patients with
diabetes. In order to understand the basis for the rapid insulin
absorption, in vitro experiments using analytical ultracentrifugation, protein charge assessment, and light scattering have
been performed with this novel human insulin formulation
and compared with a commercially available insulin formulation (RHI).
DANNE AND BOLINDER
mers, dimers, and hexamers in the formulations. Electrical
resistance of the insulin solutions characterized the overall net
surface charge on the insulin complexes in solution.
Results
The results of these experiments demonstrate that the zinc
chelating (disodium EDTA) and charge-masking (citrate) excipients used in the formulation changed the properties of
RHI in solution, making it dissociate more rapidly into
smaller, charge-masked monomer/dimer units, which are
twice as rapidly absorbed following subcutaneous injection
than RHI (Tmax 60 – 43 vs. 120 – 70 min).
Conclusions
The combination of rapid dissociation of insulin hexamers
upon dilution due to the zinc chelating effects of disodium
EDTA followed by the inhibition of insulin monomer/dimer
reassociation due to the charge-masking effects of citrate
provide the basis for the ultra-rapid absorption of this novel
insulin formulation.
Comparative pharmacokinetics and insulin action
for three rapid-acting insulin analogs injected
subcutaneously with and without hyaluronidase
Morrow L 1, Muchmore DB 2, Hompesch M 1, Ludington EA 2,
Vaughn DE 2
1
Profil Institute for Clinical Research, Chula Vista, CA; 2Halozyme
Therapeutics, San Diego, CA
Objective
To compare the pharmacokinetics and glucodynamics of
three rapid-acting insulin analogs (aspart, glulisine, and lispro) injected subcutaneously with or without recombinant
human hyaluronidase (rHuPH20).
This double-blind, six-way, crossover, euglycemic glucose
clamp study was conducted in 14 healthy volunteers. Each
analog was injected subcutaneously (0.15 units/kg) with or
without rHuPH20.
Results
The commercial formulations had comparable insulin timeexposure and time-action profiles as follows: 50% exposure at
123–131 min and 50% total glucose infused at 183–186 min.
With rHuPH20, the analogs had faster yet still comparable
profiles: 50% exposure at 71–79 min and 50% glucose infused
at 127–140 min. The accelerated absorption with rHuPH20 led
to twice the exposure in the first hour and half the exposure
beyond 2 hours, which resulted in 13- to 25-min faster onset
and 40- to 49-min shorter mean duration of insulin action.
Conclusions
Method
Analytical ultracentrifugation and dynamic light scattering
were used to infer the relative distributions of insulin mono-
Coinjection of rHuPH20 with rapid-acting analogs accelerated insulin exposure, producing an ultra-rapid time-action
profile with a faster onset and shorter duration of insulin action.
Comment
Just as last year the current progress on new basal insulins was already on the horizon, this year indicates imminent progress in speeding up the insulin action for
prandial insulin. Although presently no full articles on
clinical studies are available yet, the announcement of
Novo in December 2012 that it will advance FIAsp, an
ultra-rapid-acting version of Novolog (insulin aspart),
directly into phase 3 trials in late 2013 is of particular
interest. The protocols are announced on clinicaltrials
.gov. The phase 3 program, called ‘‘Onset,’’ will include
about 3,000 patients with type 1 or type 2 diabetes. The
timing means that regulatory submission of FIAsp could
occur around late 2014 or early 2015 at the earliest,
meaning approval could come as soon as late 2015 or
early 2016. While Biodel works with human insulin and
Novo with insulin aspart, the principle underlying the
more rapid insulin action is related in both cases to a
quicker appearance of monomers after injection. Biodel
has several different ultra-rapid-acting insulins in development, and data from phase 1 and phase 2 studies
are expected throughout 2013.
In contrast, Halozyme is also attempting to produce
faster-acting insulin by adding an enzyme (rHuPH20)
that would temporarily degrade connective tissue in the
skin, allowing insulin to be absorbed more quickly.
Another approach to subcutaneous injection of rHuPH20
described in the article above will test an injection of
rHuPH20 before inserting an insulin pump infusion set
(‘‘preadministration’’). As mealtime insulin administration leaves a lot to be desired, all of these approaches may
hold a great potential benefit to patients if long-term
effectivity and safety can be established.
T.D. has been a speaker on an advisory panel and has research support from AstraZeneca, Bayer, Bristol-Myers
S-43
Squibb, DexCom, Eli Lilly, GlaxoSmithKline, Johnson &
Johnson, Medtronic, NovoNordisk, Roche, Sanofi, Unomedical, Ypsomed and holds no stocks. J.B. has received
consulting and/or lecture fees from Abbott Diabetes Care,
AstraZeneca, Sanofi-Aventis and Merck Sharp & Dohme.
References
1. http://www.ema.europa.eu/docs/en_GB/document_library/
Medicine_QA/2013/05/WC500143823.pdf, accessed October
2013.
2. Heise T, Hermanski L, Nosek L, Feldman A, Rasmussen S,
Haar H. Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady-state
conditions in type 1 diabetes. Diabetes Obesity Metab 2012; 14:
859–64.
3. Heise T, Nosek L, Böttcher SG, Hastrup H, Haahr H. Ultralong-acting insulin degludec has a flat and stable glucoselowering effect in type 2 diabetes. Diabetes Obesity Metab 2012;
14: 944–50.
4. Heller S, Buse J, Fisher M, Garg S, Marre M, Merker L,
Renard E, Russel-Jones D, Philotheou A, Ocampo Francisco
AM, Pei H, Bode B. Insulin degludec, an ultra-long acting basal insulin, versus insulin glargine in basal-bolus
treatment with mealtime insulin aspart in type 1 diabetes
(BEGIN Basal-Bolus Type 1): a phase 3, randomised, openlabel, treat-to-target non-inferiority trial. Lancet 2012; 379:
1489–97.
5. Ratner RE, Gough SCL, Mathieu C, Del Prato S, Bode B,
Mersebach H, Endahl L, Zinman B. Hypoglycaemia risk with
insulin degludec compared with insulin glargine in type 2
and type 1 diabetes: a pre-planned meta-analysis of phase 3
trials. Diabetes Obesity Metab 2013; 15: 175–84.
6. Niskanen L, Leiter LA, Franek E, Weng J, Damci T,
Muños-Torres M, Donnet J-P, Endahl L, Vang Skjöth,
Vaag A. Comparison of a soluble co-formulation of insulin degludec/aspart vs biphasic insulin aspart 30 in
type 2 diabetes: a randomised trial. Eur J Endocrinol 2012;
167: 287–94.
7. Zinman B. Newer insulin analogs: advances in basal insulin
replacement. Diabetes Obesity Metab 2013; 15 (Suppl. 1): 6–10.
DOI: 10.1089/dia.2014.1506
ORIGINAL ARTICLE
Insulin Pens and New Ways of Insulin Delivery
Lutz Heinemann
Introduction
USAGE OF PENS IN DAILY LIFE
O
Dose accuracy of new versus used Novopen 4
insulin pens
ne has to acknowledge that not too much was published during the last year in this area of research that is
worth being reported—at least when it comes to the results of
clinical trials. However, the number of ‘‘reviews’’ and commentaries about noninvasive insulin delivery appears to be as
high as in the previous years. So, interest in the topic is indeed
there, but the progress made is simply not overwhelming.
Interestingly enough, the number of publications on insulin
pens was also lower than that in the years before. Nevertheless, a number of small biotechnology companies are still
active in developing insulin products that can be administered by other routes than the subcutaneous (SC) route. Even
the big players in the insulin arena are keeping their eyes open
for promising developments, for example, intradermal (ID)
administration or oral insulin.
Insulin Pens
A year ago, in the book chapter summarizing the data
published in 2011/2012, I lamented the lack of studies on
the usage of insulin pens in daily life. Happily enough,
some studies looking into this were published during the
last year. The assumption is that patients use pens according to the instructions of the manufacturer; however,
when you talk with experienced diabetes nurses, they can
tell you numerous stories—not all of them positive—about
the reality of pen usage (the same holds true for all medical
devices). Some patients use pens for years that are designed
for multiple usages but appear to never change the needle
during this period of time. Some interesting publications about needles, ID insulin delivery, and novel approaches for microneedles have been published. It remains
to be seen if such approaches will make their way into
clinical practice.
Another question is: what do we actually know about what
patients want when it comes to the design and handling of
pens? It might very well be that companies know the answers
to such questions but do not publish them, because they regard them as proprietary information.
Yucel H 1, Taks M 2, Menheere P 3, Grouls R 2, Bravenboer B 1
Departments of 1Internal Medicine and 2Clinical Pharmacy,
Catharina Hospital, Eindhoven; and 3Maastricht University, The
Netherlands
Background
The number of studies evaluating dose accuracy in both
new and used insulin injection pens is limited. We hypothesized that the dose accuracy of used insulin pens ( > 1 year) is
less accurate than that of new insulin pens and studied if such
differences influence the treatment. This study compared the
dosing accuracy of 11 new and 11 used Novopen 4 pens.
Methods
Dosing accuracy differences between new and used pens
were studied by weighing the volume of the dosage of 8 and
32 IU; each measurement was repeated 15 times. It was tested
whether the pens complied with the ISO limits of 10% for 8 IU
and 5% for 32 IU.
Results
For the 8 IU dose, the mean delivered dose was 8.04 IU in
new pens and 7.91 IU in used pens; for the 32 IU dose, the mean
delivered dose was 31.90 IU and 31.68 IU. The difference in the
median values between the pens was significant ( p < 0.001).
Three individual doses in the 32 IU dose exceeded the International Organization for Standardization (ISO) range in the
lower range. The difference in mean variation coefficient between the two groups was also significant ( p < 0.001).
Conclusions
There was a significant difference between the accuracy
of new versus used insulin pens. More studies with larger
Science & Co., Düsseldorf, Germany.
S-44
INSULIN PENS AND NEW WAYS OF INSULIN DELIVERY
S-45
sample sizes are necessary to confirm our findings and further
elucidate the relationship between age of insulin pens and
dose accuracy.
storing an in-use pen. For three-quarters of the insulin pens
being used, users did not follow the manufacturer’s instructions for proper administration and storage of insulin pens.
Correct usage scores were higher if initial education was
performed by a pharmacist or nurse.
Comment
Allow me to applaud the authors of this publication for
addressing this important topic. This same significant
difference in dosing accuracy between new pens and
pens used in daily life over a period of time was also
observed in a recent study in Germany. Patients use
such devices for several years, and the dosing accuracy
is usually never evaluated in daily practice by their
treating diabetologist/diabetes nurse. What can we
expect: such pens have to be ‘‘inexpensive’’ in terms of
production costs and are probably used several times a
day under a wide range of environmental conditions
but are supposed to maintain the same precision in
performance over time? Is this honestly realistic? It is of
interest to note that the manufacturer guarantees dose
accuracy for 3 years. Clearly this study should be repeated with both a larger sample size and other pens.
Patients that show up at an outpatient clinic might make
for good candidates for such studies. Another question
that merits attention is: how well do such pens work
when handled by the patients themselves and not by
trained personnel?
Conclusions
These data show that a majority of patients may be ignoring or unaware of key components for consistent insulin
dosing using disposable insulin pens. A better education and
reeducation on correct use of disposable insulin pens are
needed.
Comment
This study also addressed the practice of daily pen usage,
and it shows quite convincingly that many, if not most, of
the patients do not use the pens according to the instructions of the manufacturer under daily circumstances. However, some of the instructions are either not
practical or are cost intensive; for example, using a new
PN for each insulin injection is most often simply not
reimbursed. It remains to be studied if a group of patients
who adhere carefully to instructions differs in any clinically relevant manner from a group that uses its pens
without paying attention to the instructions and as it
deems correctly.
One wonders how well patients are trained in pen
usage and who is performing this training step, which
should take place when patients are switched to insulin
or from using a syringe/vial to a pen. To my knowledge,
this was never evaluated in daily practice. Also, when
patients are switched from one pen to the other, the
differences between these pens need to be adequately
trained. It would be of interest to see data from many
more patients from different settings and countries. It
might very well be that certain differences exist in pen
usage and in quality of this usage according to patient
education strategies in various countries.
Administration technique and storage of disposable
insulin pens reported by patients with diabetes
Mitchell VD 1,2, Porter K 3, Beatty SJ 1
1
Division of Pharmacy Practice and Administration, Ohio State
University College of Pharmacy, Columbus, OH; 2The Department
of Pharmacy, Wexner Medical Center of the Ohio State University,
Columbus, OH; and 3The Center of Biostatistics, The Ohio State
University, Columbus, OH
Diabetes Educ 2012; 38: 651–58
Background
The aim of this study was to evaluate insulin injection
technique and storage of insulin pens as reported by patients
with diabetes. In addition, usage of pens was evaluated, as
well as HbA1c, duration of insulin therapy, and duration of
insulin pen usage.
Methods
A questionnaire was administered to patients at a university-affiliated primary care practice. Patients were 18 years or
older and used a disposable insulin pen for at least 4 weeks.
A correct usage score was calculated for each patient based
on manufacturer recommendations for disposable insulin
pen use.
Results
Sixty-seven patients completed the questionnaire, reporting total use of 94 insulin pens. The three components most
often neglected were priming pen needle (PN), holding for
specific count time before withdrawal of PN from skin, and
NEEDLES
Insulin pen needles: effects of extra-thin wall needle
technology on preference, confidence, and other
patient ratings
Aronson R 1, Gibney MA 2, Oza K2, Bérubé J 2,
Kassler-Taub K 2, Hirsch L 2
1
LMC Diabetes & Endocrinology, Toronto, Ontario, Canada; and
Beckton, Dickinson and Company, Franklin Lakes, NJ
2
Clin Ther 2013; 35: 923–33
Background
PNs are essential for insulin injections using pens. The
properties of these needs affect patients’ injection experience.
The goal of this study was to evaluate the impact of a new
extra-thin wall (XTW) PN versus standard PNs on patient
preference, ease of injection, perceived time to complete the
full dose, thumb button force to deliver the injection, and dose
delivery confidence in patients with diabetes. The patients
S-46
injected insulin with the KwikPen (Eli Lilly), SoloSTAR
(sanofi-aventis), and FlexPen (Novo Nordisk) insulin pens.
Methods
Quantitative testing of the XTW and comparable PNs with
the three insulin pens was performed to evaluate thumb force,
flow rate, and time to deliver medication. Subsequently, a
prospective, randomized, 2-period, open-label, crossover trial
was then conducted in patients with type 1 or type 2 diabetes
mellitus who injected insulin by pen for ‡ 2 months, with at
least one daily dose ‡ 10 U. Patients who used 4–8-mm-long
PNs with 31–32G diameter were randomly assigned to use
their current PN or the same/similar size XTW PN at home
for *1 week and the other PN the second week.
Results
XTW PNs had better performance for each studied PN
characteristic (thumb force, flow, and time to deliver medication) for all pens combined and each individual pen brand
(all, p £ 0.05). Data sets of 198 patients randomized to study
groups (80, SoloSTAR; 77, FlexPen; 59, KwikPen) were evaluable. Nearly all of these patients used a single PN. Patients
rated the XTW PNs (mean [95% CI]) as preferable and it required less thumb force and less time to inject the dose, and
was rated as providing greater confidence in full dose delivery. Results were similar for each of the three pens, those with
impaired hand dexterity, and for all users of 4 mm PNs. Skin
leakage and insulin dripping from the needle tip were rated as
less frequent with the XTW PNs ( p < 0.05).
Conclusions
PNs with thin walls were preferred overall, rated as requiring less time and less thumb force to inject, and providing
greater confidence in completing a full dose compared with
usual PNs in this group of patients with type 1 or type 2
diabetes mellitus.
Comment
The advantage of shorter and thinner PNs is that the pain
associated with insulin administration is reduced; this is
also influenced by the sharpness of the needle tip.
However, if the inner diameter of the needle is reduced
too much, the pressure and time required to press the
insulin formulation through increases too much. By reducing the thickness of the walls of the needle the inner
diameter can be kept high. The development of thinner
and shorter needles is ongoing; however, it appears that
some technical limits have been reached. At least with the
materials currently available—that is, steel—the walls
cannot be made thinner without losing the necessary
stability.
Comparison of the effects of a new 32-gauge · 4-mm
pen needle and a 32-gauge · 6-mm pen needle on
glycemic control, safety, and patient ratings
in Japanese adults with diabetes
Miwa T, Itoh R, Kobayashi T, Tanabe T, Shikuma J,
Takahashi T, Odawara M
HEINEMANN
Department of Diabetes, Endocrinology and Metabolism, Tokyo
Medical University, Tokyo, Japan
Background
A prospective, open-label, controlled crossover study was
performed to evaluate the potential effects of two PNs with
the same diameter but different lengths (4 and 6 mm) and
different needle tip shapes (straight and tapered) on glycemic
control, perceived pain, safety, patients’ ease of use and
preferences, and visual impression.
Methods
Forty-one insulin-treated patients with type 1 or type 2
diabetes were randomized into either Group 1 (4 mm PN in
Study Period 1; 6 mm PN in Study Period 2) or Group 2 (the
order for using the PNs was reversed).
Results
The 4 mm PN provided a comparable glycemic control as
the 6 mm PN, with an equivalent occurrence rate of adverse
events. The 4 mm PN was perceived as less painful and rated
as more favorable than the 6 mm PN according to the survey
results on patients’ ease of use and preferences and on their
visual impressions.
Conclusions
The shorter PN was not only as safe and efficacious as the
6 mm PN, but also perceived as less painful, easier to use, and
more favorable to Japanese adult patients with diabetes.
Comment
In an editorial accompanying this publication, an experienced U.S. clinician commented on the important
progress made in PNs over the last decades and how
much this has improved the convenience of pen usage
(clearly also the case when insulin is administered by
syringe). The term ‘‘convenience’’ is probably not strong
enough to clarify how much the barrier of administering
insulin several times per day can be reduced if administering insulin does not induce significant pain. That no
difference in metabolic control could be observed in this
study with Japanese patients is of no surprise; this study
repeats results obtained in a larger U.S. study with more
obese subjects (mean body mass index [BMI] 31.0 vs.
23.2 kg/m2). The idea that patients prefer the shorter
needle has also been reported before. It is of interest to
note that this study—and the one presented before—
were supported by Becton Dickinson.
One important question is how often patients change
the PN in daily practice. This—beside its diameter and
length—strongly determines how much pain the insulin
injection causes. Clearly, PNs contribute to the cost of pen
insulin therapy, which is more expensive than using a
syringe and a vial. The question is, if the quality of life is
improved (i.e., reduced injection pain) with better needles/insulin pen usage, how much does this contribute to
S-47
an improved metabolic control and thereby reduce costs in
the long run by avoiding the development of diabetesrelated late complications? Studies evaluating such questions would be of great interest.
studied for a number of years now, and it appears as if the
slow but steady progress toward a practically usable
product is taking significant steps in the right direction.
Different time intervals between insulin administration
and meal ingestion as well as different insulin doses (under- and overdosing) were tested, showing the expected
differences in meal-related increases in glycemia. Of interest to note (and worth being studied in more detail) is
the reduction in intra- and intersubject variability with ID
insulin administration. It remains to be shown in larger
clinical studies to what degree the benefits observed in
such clinical–experimental trials translate into improvements in metabolic control under daily life conditions.
Pharmacokinetics and postprandial glycemic excursions following insulin lispro delivered by intradermal
microneedle or subcutaneous infusion
McVey E 1, Hirsch L2, Sutter DE 1, Kapitza C 3, Dellweg S3,
Clair J 3, Rebrin K 4, Judge K1, Pettis RJ 1
1
BD Technologies, Research Triangle Park, NC; 2BD Medical–
Diabetes Care, Franklin Lakes, NJ; 3Profil Institut für Stoffwechselforschung GmbH, Neuss, Germany; and 4BD Medical–Diabetes
Care, Billerica, MA
Background
ID delivery by means of microneedles has been shown to
accelerate insulin absorption. In this study, the pharmacokinetic (PK) and pharmacodynamic (PD) effects of insulin lispro
administered before two daily standardized solid mixed
meals (breakfast and lunch) were studied, using ID or traditional SC delivery.
Methods
Twenty-two patients with type 1 diabetes participated in
an eight-arm full crossover block design. One arm established
each subject’s optimal meal dose. In six additional arms,
the optimal, higher, and lower doses (+ 30%, - 30%) were each
given ID and SC delivery, in random order. The final
arm assessed earlier timing for the ID optimal dose (-12
versus - 2 min).
Faster pharmacokinetics and increased patient
acceptance of intradermal insulin delivery using
a single hollow microneedle in children
and adolescents with type 1 diabetes
Norman JJ 1,2, Brown MR 1, Raviele NA 1, Prausnitz MR 2,
Felner EI 1,2
1
Division of Endocrinology, Department of Pediatrics, Emory
University School of Medicine, Atlanta, GA; and 2School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA
Pediatr Diabetes 2013; 14: 459–65
Background
To improve compliance with insulin therapy and to accelerate
insulin absorption, we tested if ID insulin delivery using a hollow microneedle causes less pain and leads to faster onset and
offset of insulin pharmacokinetics in children and adolescents
with type 1 diabetes compared with an SC insulin infusion.
Methods
Results
The primary end point, postprandial time in range (70–
180 mg/dL), showed no route-based differences with a high
level of overall BG control for both SC and ID delivery.
PK end points showed more rapid ID availability versus SC
across doses and meals (DTmax - 16 min, DT50rising - 7 min,
DT50falling - 30 min, all p < 0.05). Both intra- and intersubject
variability for ID Tmax were lower. ID showed modest, secondary PD differences across doses and meals, generally within
90–120 min postprandially (D12 mg/dL BG at 90 min, D7 mg/
dL BGmax, D7 mg/dL mean BG 0–2 hours, all p < 0.05).
Sixteen patients received insulin lispro by microneedle and
SC administration on separate days. Subjects rated the pain of
insertion and infusion using a visual analog scale.
Results
Microneedle insertion pain was lower compared with insertion of the SC infusion catheter ( p = 0.005). Insulin onset
time was 22 min faster ( p = 0.0004) and offset time was 34 min
faster ( p = 0.017) after hollow microneedle delivery compared
with SC infusion.
Conclusions
Conclusions
This study suggests that ID insulin delivery is superior to
SC delivery in speed of systemic availability and PK consistency and helps to reduce postprandial glycemic excursions.
ID insulin delivery using a single hollow microneedle device resulted in less insertion pain and faster insulin onset and
offset in patients with type 1 diabetes. A reduction in pain
might improve compliance with insulin delivery.
Comment
Comment
This article demonstrated what can be achieved by using
a different compartment when it comes to improving
insulin absorption, thereby reducing postprandial glycemic excursions. ID insulin administration has been
As indicated above, ID insulin administration is a hot
topic as it allows improving insulin pharmacokinetic and
pharmacodynamic properties by simply administrating
it via a different compartment.
S-48
Transdermal insulin application system
with dissolving microneedles
Ito Y, Nakahigashi T, Yoshimoto N, Ueda Y, Hamasaki N,
Takada K
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan
Background
The aim of this study was to test a dissolving microneedle
(DM) application system, where 225–300 insulin-loaded DMs
were formed on a chip. After the heat-sealed sheet is removed,
the system covered with the press-through package layer is
put on the skin. By pressing with the hand, insulin DMs were
inserted into the skin.
HEINEMANN
The development and characteristics of novel microneedle arrays fabricated from hyaluronic acid, and
their application in the transdermal delivery of insulin
Liu S1, Jin MN 1, Quan YS 1,2, Kamiyama F2, Katsumi H 1,
Sakane T 1, Yamamoto A1
1
Department of Biopharmaceutics, Kyoto Pharmaceutical University, Kyoto, Japan; and 2cOSmed Pharmaceutical Co. Ltd,
Kyoto, Japan
J Control Release 2012; 10: 933–41
Background
The aim of this study was to test novel insulin-loaded microneedle arrays (MNs) fabricated from hyaluronic acid
(HA) and characterize their applicability in the transdermal
delivery of insulin.
Methods
Methods
Factors affecting the penetration depth of DM were studied
using applicator in vitro and in vivo experiments. The penetration depth was determined for rat and human skin. Twolayered DM array chips were prepared to obtain complete
absorption of insulin and administered to the rat abdominal
skin. Plasma glucose levels were measured for 6 hours. By
comparing the hypoglycemic effect with that obtained after
SC injection, relative pharmacological availability (RPA) was
determined.
The shape of MNs was observed via scanning electron
microscopy. The characteristics of these MNs, including hygroscopy, stability, drug release profiles, and dissolution
properties, were evaluated from a clinical application point of
view. Transepidermal water loss was measured to investigate
the piercing properties of MNs and the recovery of the skin
barrier after the removal of MNs to confirm their safety. The
transdermal absorption of insulin from MNs was examined
via an in vivo absorption study in diabetic rats.
Results
The penetration depth increased from 21 – 3 to 63 – 2 lm
in proportion to application speed to isolated rat skin, at
0.8–2.2 m/s. Human skin showed similar results in the
penetration depth. The in vivo penetration depth was dependent on the force (0.5–2.5 N) and duration (1–10 min), as
the secondary application force. The penetration depth was
211 – 3 lm with a duration of 3 min in the in vivo rat experiment. DM array chips having an insulin-loaded space of
181 – 4 and 209 – 4 lm were evaluated in the rat. RPA values
of insulin from DMs were 98.1 – 0.8% and 98.1 – 3.1%, respectively.
Conclusions
These results suggest the usefulness of DM for transdermal
delivery of insulin.
Results
The length of MNs was 800 lm with a base diameter of
160 lm and a tip diameter of 40 lm. MNs were found to
maintain their skin piercing abilities for at least 1 hour, even at
a relative humidity of 75%. After storing MNs for a month at
- 40C, 4C, 20C, and 40C, more than 90% of insulin remained in MNs at all temperatures. It was also found that
insulin is rapidly released from MNs via an in vitro release
study. These findings were consistent with the complete dissolution of MNs within 1 hour of application to rat skin in vivo.
MNs possess self-dissolving properties after their dermal
application, and insulin appears to be rapidly released from
these MNs. A continuous hypoglycemic effect was observed
after 0.25 IU of insulin was administered to skin via MNs.
Lower peak plasma insulin levels, but higher plasma insulin
concentrations after 2 hour, were achieved compared with the
SC administration of insulin of the same dose.
Comment
This article does not present clinical data; however, it did
a nice job of showing which interesting options are being
developed to further reduce the burden of insulin therapy (i.e., reducing pain) while using a compartment that
enables more rapid insulin absorption. To become a
consumer product, such interesting developments have
to fulfill a long list of requirements, not the least of which
is production cost. So, we will have to wait and see which
of the attempts (see following publications) to develop
true microneedles will be successful (the ones used in the
study presented before are large compared with the idea
of ‘‘true’’ microneedles).
Conclusions
These findings indicate that the MNs fabricated from HA
are a useful alternative method of delivering insulin via the
skin into the systemic circulation without inducing serious
skin damage. It remains to be studied if HA MNs are an effective and safe method of transdermal insulin delivery in the
clinic.
Comment
This interesting approach is only in the beginning stages
and, although no human data were reported in this
S-49
publication, the introduction of this article provided a
useful review of the pros and cons of such MNs. The data
presented are also impressive, that is, the decreases in
blood glucose levels of rats when these MNs were administered with different insulin loads.
allow for direct clinical experience with the devices. On a
positive note, it is good to see how pens improve from one
generation to the next. This constant evolution of pens over
the last decades has surely helped pave the way for their
usage by most patients in most countries.
EVALUATION OF PENS
Study on the dosing accuracy of commonly used
disposable insulin pens
A randomized, cross-over comparison of preference
between two reusable insulin pen devices
in pen-naı̈ve adults with diabetes
Krzywon M 1, van der Burg T 2, Fuhr U 3,
Schubert-Zsilavecz M 1,4, Abdel-Tawab M 1
Wong M 1, Abdulnabib R2, Careyc MA 3, Fu H 1
2
1
Eli Lilly and Company, Indianapolis, IN; 2Pharmanet i3, Ann
Arbor, MI; and 3Pharmanet i3, Blue Bell, PA
Curr Med Res Opin 2013; 29: 465–73
Background
The ease-of-use attributes of two reusable pen injectors,
HPS (HumaPen Savvio) and HPL (HumaPen Luxura), and the
final preference were evaluated in patients with type 1 or type
2 diabetes.
Methods
This was a 1-day, randomized, two-period crossover, openlabel, simulated-injection study in 203 pen-naı̈ve patients
(mean age 58 years). For evaluation, a 16-item survey (7-point
scale) was used: higher scores reflect greater preference and
equal scores reflect no preference. The primary objective was
final pen preference, with statistical gate-keeping to the ease
of detecting an insufficient remaining dose (IRD) of insulin
upon dose selection.
Results
HPS was chosen by 150 of 203 subjects (74%, 95% confidence interval [CI] = 67%–80%) for final overall pen preference. For the IRD item, HPS was preferred by 94 of 107
subjects with a preference (88%, 80%–93%). In 14 of the remaining 15 survey items, 64% to 88% of subjects with a
preference preferred HPS over HPL. To confirm the results,
subjects with no preference for either pen, which ranged between 95 and 148, were included in a Bayesian analysis.
Conclusions
The majority of pen-naı̈ve subjects preferred HPS over
HPL. Some attributes of both pens were equally acceptable, as
many subjects had no preference.
Comment
This is another one of those publications that give you a
hint as to why such ‘‘studies’’ are not often performed
by an independent institution in a head-to-head manner
against other comparable pens. The authors themselves
also acknowledged some other limitations: this was an injection simulation, an invalidated survey was used, and an
office setting was used for the evaluation, which did not
1
Central Laboratory of German Pharmacists, Eschborn, Germany;
Medical Devices/Quality, Regulatory & Risk Management, Sanofi-Aventis Deutschland GmbH, Frankfurt-am-Main, Germany;
3
Clinical Pharmacology Unit, Department of Pharmacology, University of Cologne, Cologne, Germany; and 4Institute of the
Pharmaceutical Chemistry, J.W. Goethe-University, ZAFES,
Frankfurt am Main, Germany
Background
The advantages of insulin pens have led to the widespread
use of insulin pens, particularly in Europe. In most of the former
studies on the dose accuracy of insulin pens, only a small
number of doses and pens were included. The present study
was directed at the dose accuracy of one specific dose dispensed
repeatedly with the same pen. This is the first study providing
detailed comparative data on the accuracy of repeated dose
delivery with prefilled disposable insulin pens at low, middle,
and high doses dispensed over the entire pen volume.
Methods
Fifteen previously unused insulin pens from two lots of
each pen type (SoloSTAR, FlexPen, Next Generation FlexPen,
and KwikPen) were used to deliver 5 IU (low), 30 IU (middle),
and 60 IU (high) doses, respectively, dispensed four times
from each pen. Actual doses were determined gravimetrically
taking the density of the respective insulin into account and
were evaluated according to the ISO guidelines.
Results
All tested pens met the requirements for accuracy with none
of the single values being outside the range of the ISO recommendations (1 – 1 IU, 30 – 2 IU, and 60 – 3 IU, respectively).
Conclusion
These data demonstrated a consistent and accurate dose
delivery at all dosage levels for all tested pens, with no clinically relevant differences among the products.
Comment
It is good to see that this study (which was sponsored
by one of the large manufacturers) showed no relevant
differences in dose delivery between widely used disposable insulin pens in a head-to-head study over a wide
range of insulin doses. In a sense, this publication ends a
S-50
dispute between manufacturers presenting studies that
their own pens are more accurate than those of their
competitors.
Perceptions of usability and design for prefilled
insulin delivery devices for patients with type 2 diabetes
Heron L 1, Reaney M 2, Hermanns N 3, Abetz L1, Gregg L 4
1
Adelphi Values, Bollington, Cheshire, United Kingdom; 2Eli Lilly,
Windlesham, Surrey, United Kingdom; 3Diabetes Research Institute, Mergentheim, Germany; and 4Adelphi International Research, Bollington, Cheshire, United Kingdom
HEINEMANN
simulation study, three of the most widely used pens
were studied. A relatively small number of insulin-naı̈ve
patients and more experienced users were asked to answer a number of questions. An impressive number of
tables and analyses showed that no pronounced differences exist between the pens studied.
Usability and preference assessment of a new
prefilled insulin pen versus vial and syringe in people
with diabetes, physicians and nurses
Campos C, Lajara R, Deluzio T
Diabetes Spectrum 2013; 26: 16–28
The Institute for Public Health and Education Research, New
Braunfels, TX
Background
Expert Opin Pharmacother 2012; 13: 1837–46
Insulin initiation in patients with type 2 diabetes is often
delayed because of factors such as patients’ resistance to insulin therapy and worries about injections. Such delays affect
glycemic control, have a direct effect on patient encounters,
and may affect medication adherence. Usage of insulin pens
addresses some of these concerns.
Background
In this multicenter, crossover study, the preference and
usability of a prefilled insulin pen (FlexTouch, FT) versus vial
and syringe (V&S) was assessed.
Methods
Methods
Initially, semi-structured qualitative interviews were conducted to identify the most important features of insulin delivery devices for prandial use from the perspective of
patients (n = 8) and healthcare professionals (HCPs; n = 10). In
the second step, a 26-item questionnaire was developed. Patients (n = 33 insulin naive, n = 78 pen users) and HCPs
(n = 151) were asked to indicate the most important features to
them in insulin pens. Patients then simulated injection using
three different pens (SoloSTAR, KwikPen, and FlexPen) and
ranked them based on the same features.
Results
The most important features included knowing that the
entire dose has been injected, ease of reading the dose correctly, and ease of correcting if the dose is over-dialed.
KwikPen and SoloSTAR scored higher (paired t test, p < 0.05)
in the simulation study than FlexPen on ‘‘knowing if you have
injected the entire dose’’ (mean score out of 10: KwikPen, 8.9;
SoloSTAR, 8.6; and FlexPen, 8.4). No other significant differences among the pens were noted in usability or design, and
the mean ranking (from 1 to 3) of the pens was similar
(KwikPen, 2.0; FlexPen, 2.1; and SoloSTAR, 1.9).
Patients with type 1 or type 2 diabetes (n = 60), and physicians (n = 30) and nurses (n = 30) with experience of diabetes
management, performed test injections with FT and V&S. They
answered written questions on ease of use and preference. The
primary end point was preference for FT versus V&S.
Results
More respondents preferred using FT (88%) to V&S (5%;
p < 0.001; the remainder chose ‘‘no preference’’), found FT (91%)
easier to use than V&S (6%; p < 0.001), and would recommend
FT (91%) over V&S (3%; p < 0.001). FT received better ratings
than V&S for ease of use, holding the device stable when injecting, depressing the push-button/plunger, and reading the
dose scale (all p < 0.001). Ratings for confidence in correct insulin delivery were also better with FT (both p < 0.001).
Conclusions
FT was preferred to V&S for insulin delivery in this comparative analysis. Usage of this pen may improve the experience of insulin injection compared with V&S for a wide
range of patients.
Comment
Conclusions
HCPs can choose the most appropriate pen for patients by
knowing which pens offer features that might help with earlier insulin initiation, greater patient adherence, and better
clinical outcomes.
Comment
This publication—in an unusual journal for this topic—
focused on relevant features of prefilled disposable pens
from the perspective of patients and physicians. In this
This study was sponsored by the manufacturer of the
FlexTouch. It is important to keep in mind that the pen
uses a 32G extra-thin-wall needle with a length of 5 mm,
whereas standard 30G needles were used with the syringes. It is interesting to note that many patients regard
it as an advantage that using a syringe makes it easier to
see that the full insulin dose is truly administered. One
wonders how the outcome of this evaluation might have
changed if another modern pen would have been used as
comparator or as a third study arm. Without it, it appears
as if the comparison was somewhat unfair.
S-51
Accuracy and preference assessment of prefilled
insulin pen versus vial and syringe with diabetes
patients, caregivers, and healthcare professionals
Comment
Just as with the previous article, the results of this study
are not surprising. Thus, in view of the lack of a good
comparator, the last sentence of the abstract can be interpreted as marketing.
Pfützner A1,2, Bailey T 3, Campos C 4, Kahn D 1, Ambers E1,
Niemeyer M 5, Guerrero G6, Klonoff D 7, Nayberg I 7
1
ICRD Institute, San Jose, CA; 2IKFE, Mainz, Germany; 3AMCR
Institute Inc., Escondido, CA; 4The Institute for Public Health and
Education Research, New Braunfels, TX; 5Novo Nordisk NS, Søborg, Denmark; 6Novo Nordisk Inc., Princeton, NJ; and 7Mills
Peninsula Health Services, San Mateo, CA
Curr Med Res Opin 2013; 29: 475–81
Comparison of patient preference for two insulin
injection pen devices in relation to patient dexterity skills
Pfützner A1, Schipper C1, Niemeyer M 2, Qvist M 2, Löffler A1,
Forst T 1, Musholt PB 1
1
Background
The aim of this study was to investigate the dosing accuracy of the prefilled FlexTouch insulin pen (FT) in comparison to conventional vial and syringe (V&S) when used by
patients (Pts), caregivers (CG), and healthcare professionals
(HCPs).
Methods
One hundred twenty subjects participated in this study
(40 patients with diabetes, age 61 – 11 years, 20 caregivers
[parents and other relatives], 20 physicians, and 40 nurses/
Certified Diabetes Educators [CDE]). The participants were
introduced to the devices in randomized order and were
asked to perform injections of 5, 25, 43, and 79 IU doses
into laboratory tubes. Dosing accuracy was analyzed by
weighing the tubes on a pharmaceutical balance and calculating the mean absolute deviation ( MAD) from the intended doses. After completing a device assessment
questionnaire, patient perception questionnaire (PPQ), with
questions regarding device design and performance, the
procedure was repeated with the other pen, and the patients
were finally asked to complete a device preference questionnaire (DPQ).
IKFE–Institute for Clinical Research and Development, Mainz,
Germany; and 2Novo Nordisk AB, Søborg, Denmark
Background
A number of patients with diabetes have impaired dexterity independent from the existence of diabetic neuropathy.
In this study the impact of dexterity impairment on patient
preference for two insulin pens (InnoLet and FlexTouch) was
evaluated.
Methods
Ninety patients [54 male/36 female; age 62 – 8 years; disease duration 18 – 11 years; HbA1c 7.2 – 1.0%] were included
in this study. They were stratified into four different groups
based on the results of a dexterity test ( Jebsen–Taylor Hand
Function Test) and assessment of visual impairment: 15 patients with type 1 (group A) and 30 with type 2 (group B)
patients with impaired dexterity, 30 type 1/type 2 patients
with visual impairment (group C), and 15 type 1/type 2 patients without any impairment (group D). The patients performed a cognitive function test (number connection test),
were introduced to the devices in random order, and were
asked to perform some mock injections before completing a
six-item standardized preference questionnaire.
Results
Dosing accuracy was better for FT when used by any of the
cohorts at all doses; however, dosing accuracy with FT for all
three subgroups was comparable (patients: 0.35–0.59 IU; HCP
& CG: 0.29–0.54 IU; n.s.). Dosing accuracy with V&S for the
three subgroups was not comparable: HCP and CG performed better with V&S than patients and delivered the doses
with higher accuracy (range of mean MAD; patients: 0.81–
2.54 IU; HCP & CG: 0.51–1.30 IU, p < 0.005 at all doses). FT was
ranked superior to V&S for all aspects of the PPQ. In the DPQ,
93% of the patients voted for FT.
Results
Conclusion
Patient dexterity skills may have an influence on device
preference, especially if the impairment is more pronounced.
FT was more accurate at all tested doses and was used with
similar accuracy by patients, HCPs, and CGs compared to
V&S. Using questionnaires only, and without dexterity assessment, study participants rated FT higher than V&S in
every component of the PPQ, and the vast majority of them
preferred FT. These findings suggest a better alternative for
dosing accuracy and improved adherence when using the
prefilled insulin pen compared to V&S for insulin delivery in
patients with diabetes.
Patients in all groups showed a strong preference for
FlexTouch. All unimpaired patients (100%, group D) preferred FlexTouch, as did the vast majority in all other groups.
Only 11% of the patients with impaired cognitive function
preferred InnoLet, as did a few patients with more severely
impaired dexterity or with visual impairment (group A 13%;
group B 3%; group C 14%).
Conclusions
Comment
A number of factors determine why we prefer a given
product (like a car), and the same holds true when it
comes to insulin pens. Therefore, preference studies are a
bit tricky to perform, and the reported outcome has to be
taken with a grain of salt. In view of a large group of
S-52
HEINEMANN
Comment
patients who use insulin pens and who have limited
dexterity and/or who are visually impaired, it is important to be careful with which group of patients such
studies are performed. This study focuses on a considerable number of patients with type 1 or type 2 and
stratifies them according to the factors mentioned. The
strong patient preference toward the newer insulin pen is
impressive and somewhat counterintuitive as the InnoLet was developed with this specific patient group in
mind. However, this device is not a pen by design. It
would have been better to use another modern insulin
pen as comparator.
This study confirmed that adding features to insulin pens
does not necessarily result in a measurable benefit such as
glycemic control. One would assume that adding a reminder or ‘‘memory’’ function to an insulin pen is helpful
in detecting missed insulin injections, etc., by registering
a number of parameters each time insulin is administered. However, this study with a considerable number
of patients with suboptimal metabolic control performed
across 32 sites in Germany showed no additional benefit
of having such a memory function integrated into the
pen; the observed improvement in HbA1c was comparable in both study groups. The authors discussed potential explanations for this negative study outcome:
facilitation of corrective insulin injections after a meal
when the preprandial insulin injection was forgotten, the
number of corrective actions taken was too small, and
also the handling of the basal insulin dose might have
minimized any effects of changing prandial insulin delivery. Despite the negative outcome of this study, one
can imagine many patients for whom monitoring insulin
therapy details with such a pen might be advantageous.
No effect of insulin pen with memory function on
glycemic control in a patient cohort with poorly
controlled type 1 diabetes: a randomized open-label study
Danne T1, Forst T 2, Deinhard J 3, Rose L 4, Moennig E 5,
Haupt A 5
1
Bult Diabetes Centre for Children and Adolescents, Hannover,
Germany; 2IKFE Institute for Clinical Research and Development,
Mainz, Germany; 3Accovion GmbH, Eschborn, Germany; 4Diabetologische Schwerpunktpraxis, Münster, Germany; and 5Lilly
Deutschland GmbH, Diabetes, Ban Homburg, Germany
Background
Injection compliance is a major problem in patients with type
1 diabetes. Using an insulin pen with memory function might
facilitate corrective dosing to reduce postprandial glycemic excursions and therefore might improve overall glycemic control.
Is the indicator magnifying window for insulin pens
helpful for elderly diabetic patients?
Lee JH 1, Hong ES 2, Ohn JH 2, Cho YM2
1
Department of Internal Medicine, Chungnam National University, Daejeon, Korea; and 2Department of Internal Medicine,
Seoul National University, Seoul, Korea
Diabetes Metab J 2013; 37: 149–51
Background
Methods
In this randomized, open-label, 24-week multicenter
study, patients with inadequately controlled type 1 diabetes
(HbA1c) ‡ 8% were randomized to use the HumaPen Memoir, an insulin pen device with memory function, for their
mealtime insulin injections or the conventional device HumaPen Luxura. HbA1c, hypoglycemia, and pen acceptance
were assessed at baseline and after 12 and 24 weeks.
Results
Of 263 patients randomized, 257 were eligible for analysis
(baseline HbA1c 9.09 – 0.99%; age 40 – 17 years; diabetes duration 16 – 11 years): HumaPen Memoir 129, HumaPen Luxura 128. Changes of HbA1c up to week 24 were not different
between the HumaPen Memoir [0.43% (- 0.59%, - 0.28%)] and
the HumaPen Luxura group [0.48% (0.64%, 0.32%); p = 0.669].
Also, the overall incidence of hypoglycemic episodes did not
differ between groups ( p = 0.982).
Conclusions
In this study, usage of a memory function pen was not
associated with superior glycemic control, suggesting that
adherence to mealtime injection schedules was not improved
in a relevant manner. However, the memory function might
be helpful for specific patient populations, for example, children or forgetful patients.
Patients with type 2 diabetes who require insulin therapy
are commonly elderly and have poor visual acuity. In this
study, we examined the clinical usefulness of the indicator
magnifying window (IMW) for elderly patients.
Methods
We recruited 50 patients aged > 60 years who use insulin
pens for insulin application. They were asked to set randomly
selected doses at the insulin pen with or without an IMW.
Dosing accuracy, convenience, self-confidence, need for eyeglasses, preference, and willingness to recommend the IMW
to other patients was assessed.
Results
Although the IMW did not improve the dosing accuracy or
convenience, it decreased the need for eyeglasses.
Conclusions
Overall, the clinical usefulness of the IMW is quite limited
in elderly patients with type 2 diabetes.
Comment
One might be tempted to smile at such a study; however, for elderly patients/patients with impaired visual
S-53
Methods
acuity—and this is a good portion of the patients treated
in daily practice—such aspects are of high relevance. One
might ask, why do IMWs exist if they apparently are of
no great help for the patients, and how can we do better?
Electronic gadgets exist or are in development that read
the dose selected on the pen (see previous article). Not
only do these gadgets allow the selected dose and the
time of administration to be stored, but also they could be
of help for patients in seeing the actual selected dose if
this information were displayed directly on a TV screen
or on their smart phone by means of a special app.
Inhaled Insulin
When it comes to inhaled insulin, we are playing a sort
of waiting game. The phase 3 studies with MannKind’s
ultra-rapid inhalable prandial insulin (Afrezza) have been
performed, and a new application for an Investigational
New Drug was submitted to the U.S. Food and Drug Administration (FDA). A good review of this pulmonary insulin
was published in 2012 (1). The tone of the press releases by
MannKind suggests that FDA approval is probable. The
question remains whether the FDA will ask for regular lung
function tests, etc. The answer to this question will have an
impact on the patient’s interest in using pulmonary insulin.
The next question is whether diabetologists would be willing
to prescribe inhaled insulin. This will depend to a certain
extent on how smart the marketing activities of MannKind
will be. It will be necessary to handle the burden of the Exubera failure and some safety concerns adequately. Nevertheless, if this inhaled insulin becomes available on the
market, this will be the first time in a number of years that an
insulin product not administered subcutaneously but via an
alternative route makes its way to the market. If this finds its
way into the armamentarium of diabetes therapy, this will be
encouraging for alternative routes of insulin delivery in general, as people will hopefully regain trust in this area of research and more venture capital will be invested again.
It is worth mentioning that some research and development in the area of inhaled insulin is still going on
(www.dancepharma.com/). In view of the involvement of
one of the godfathers of pulmonary application, John Patton,
this development and story are interesting and worth following closely.
Technosphere insulin effectively controls postprandial
glycemia in patients with type 2 diabetes mellitus
Zisser H 1, Jovanovic L 1, Markova K 1, Petrucci R 2, Boss A 2,
Richardson P 2, Mann A 2
1
2
Sansum Diabetes Research Institute, Santa Barbara, CA; and
MannKind Corporation, Valencia, CA
Eight subjects (7 men, 1 woman) with type 2 diabetes underwent dose optimization meal challenge (MC) visits (100%
CHO) and MCs with varied CHO meal contents (50%, 200%,
and 0% calculated CHOs). The observed change in postprandial glucose (PPG) excursions was the primary end point.
Results
Maximum PPG excursions with the 100% CHO meals
were - 13 – 15 mg/dL for breakfast (B) and - 14 – 15 mg/dL
for lunch (L). These increases were similar to those observed
after 50% CHO meals (B, - 17 – 16 mg/dL; L, + 14 – 10 mg/
dL). As anticipated the largest PPG excursions occurred
with the 200% CHO meals; however, they remained below the targets of the American Diabetes Association
(B, + 19 – 16 mg/dL; L, + 32 – 29 mg/dL). During 15 of the
MCs, subjects took their usual dose of the inhaled insulin
and then had no meal (0% CHO). In this case, the largest PPG excursions were - 33 – 9 mg/dL at 60 min (B)
and - 31 – 10 mg/dL at 60 and 90 min (L). Glycemic control
improved from an HbA1c of 7.82 – 1.04% at Week 1 to
6.18 – 0.46% ( p = 0.00091) at Week 19.
Conclusions
These results obtained with a small sample size suggest
that once an optimal dose of TI is determined, patients with
type 2 diabetes can ingest meals with considerable differences
in their CHO content—or even skip meals—without having
the risk of severe hypoglycemia. In this uncontrolled pilot
study, glycemic control improved significantly by - 1.63%.
Comment
For many patients with type 2 diabetes, it would be
sufficient to have a good dose of insulin administered
with each meal, even if it were not the ideal dose, as
some reduction in postprandial glycemic excursions
would be better than no reduction at all. The risk for
postprandial hypoglycemic events is quite low. To get
such a treatment accepted, it has to be quite easy and
convenient; it has to be an inhalation that can be done
easily and within seconds.
This meal study with a small sample size shows how
such a treatment could look. In this study, patients came
into the center for numerous visits to determine the
optimal insulin dose while eating meals with a considerable range of CHO content. Preprandial glycemia in
these patients appeared not to have been well controlled;
unfortunately, only changes in postprandial glycemic
excursions are shown, not absolute changes. The improvement in HbA1c in such an uncontrolled study has
to be interpreted with care. Nevertheless, in line with the
above-mentioned thoughts, this study discusses an
interesting new way of treating many patients.
Background
In this pilot trial, it was studied if an optimal dose of
Technosphere insulin (TI) inhalation powder (MannKind
Corp., Valencia, CA) could be used to control postprandial
glycemic excursions despite considerable variation in meal
carbohydrate (CHO) content.
Oral Insulin
This year, the literature search for publications on oral insulin (OI) resulted in less hits than in the years before. Ignoring the ‘‘usual’’ publications about promising new novel
S-54
OI formulations in pharmaceutical journals, the total number
of publications about clinical studies with human subjects
amounted to one (see below)! Despite this lack of published
data, a number of review articles about OI were published
[e.g., Fonte et al. (2) and Patel (3)]. Not a single publication
could be found about other routes of insulin administration
such as transdermal or nasal insulin.
According to a recent press release, Novo Nordisk is focusing its development work on a long-acting OI formulation
using the so-called GIPET platform, which was developed by
the Ireland-based partner company Merrion. All other companies are focusing on covering prandial insulin requirements
by OI. It is not easy to venture a guess about the progress of
these companies or how much further the respective developments are: Oramed has continued with its insulin development (ORMD 0801) from phase 2 to phase 3; Biocon was
able to find a partner (Bristol-Myers Squibb) for its OI IN-105.
However, it is not clear whether other companies such as
Tamarisk Technologies and Aphios have made it from the
preclinical to the clinical phase or not; at least, no clinical data
were published over the last year.
It appears that buccal insulin formulation by Generex is
ongoing (http://investor.generex.com/releases.cfm); positive
data from a phase 3 trial in India were reported recently.
However, one would be extremely interested in seeing convincing data from recent clinical–experimental studies and
double-blind clinical studies showing a good metabolic effect
with reasonable insulin doses.
Glucose-reducing effect of the ORMD-0801 oral insulin
preparation in patients with uncontrolled type 1
diabetes: a pilot study
Eldor R 1, Arbit E2, Corcos A 3, Kidron M 2
1
Diabetes Unit, Internal Medicine, Hadassah University Hospital,
Jerusalem, Israel; 2Oramed Pharmaceuticals, Jerusalem, Israel; and
3
Diabetes and Endocrine Clinic, General Health Services Affiliated
to Hadassah Medical School, Jerusalem, Israel
PLoS One 2013; 8: e59524
Background
In efforts to provide patients with a more compliable
treatment method, Oramed Pharmaceuticals tested the capacity of its OI capsule (ORMD-0801, 8 mg insulin).
Methods
Eight patients with type 1 diabetes in bad glycemic control
(HbA1c 7.5–10%) were monitored throughout the 15-day study
period by means of a blind continuous glucose monitoring
(CGM) device. Baseline patient glucose profiles were monitored over a 5-day pretreatment screening period. During the
ensuing 10-day treatment phase, patients were asked to treat
themselves as usual and to self-administer an OI capsule three
times daily, just prior to meal intake. CGM data sufficient for
glucose analyses were obtained from 6 of the 8 subjects.
HEINEMANN
crease in glucose area under the curve (66055 – 5547 vs.
55060 – 3068 mg/dL/24 hours, p = 0.023), with a greater decrease during the early evening hours.
Conclusions
The OI capsules in conjunction with SC insulin injections
were well tolerated and effectively reduced glycemia
throughout the day.
Comment
The results of this pilot study with a small sample size
and a nonblinded study design (uncontrolled!) have to be
interpreted with care, or as the authors stated it: ‘‘can
only be addressed as hypothesis forming for future larger
and longer trials planned.’’ The list of planned studies
mentioned subsequently in the publication is impressive.
Miscellaneous
Each year some studies are published that do not fit into
one of the above categories but that are clearly interesting for
insulin treatment in general. No human data have been
published thus far with a truly innovative approach in which
the insulin is activated by light (4).
Body mass index and the efficacy of needle-free jet
injection for the administration of rapid-acting insulin
analogs, a post hoc analysis
de Galan BE, Engwerda EEC, Abbink EJ, Tack CJ
Department of Internal Medicine, Radboud University Nijmegen
Medical Centre, Nijmegen, The Netherlands
Diabetes Obesity Metab 2013; 15: 84–86
Background
In a recent euglycemic glucose clamp study, it was shown
that using jet injectors rather than insulin pens improved the
time-action profiles of rapid-acting insulin analogs in healthy
volunteers.
Methods
In this subsequent analysis, the authors analyzed whether
the time-action profiles were modified by BMI and related
weight parameters. They defined subgroups by BMI, waistto-hip ratio, waist circumference, and insulin dose.
Results
After insulin pen administration, times to peak insulin levels
(T-INSmax) occurred 31.1 [95% confidence interval (CI) 13.7–
48.5] min later and time to maximum glucose requirement (TGIRmax) 56.9 (26.6–87.3) min later in more obese (BMI > 23.6 kg/
m2) than in lean subjects (BMI < 23.6 kg/m2). In contrast, T-INSmax and T-GIRmax were similar in subjects with high and low
BMI, when insulin was administered by jet injection.
Results
Treatment with OI was associated with a 24% reduction in
the frequencies of glucose readings > 200 mg/dL (60 – 8%
pretreatment vs. 45 – 5% with OI; p = 0.023) and a 17% de-
Conclusions
These data suggest that insulin administration by means of
a jet injector may be especially beneficial for obese subjects.
Comment
This quite active group from the Netherlands drives this
interesting development in a straightforward manner;
that is, they have published a number of articles about
administering insulin via an injector over the last years.
However, in view of the numerous attempts presented
previously (some injectors have been on the market for a
while), one cannot help but ask oneself if this will finally
become a success story this time.
The number of studies in which the impact of body
weight on insulin absorption has been studied is relatively small. This is somewhat surprising as in these
studies the BMI/body weight showed the considerable
impact of this parameter on insulin absorption/insulin
action. The data presented here confirm these data when
it comes to administering insulin by pen. It is clear that
the BMI has no impact when the insulin is administered
via the pulmonary route, as the absorptive surface in the
lung can be assumed to be similar in slim and overweight
subjects, but that the BMI has no impact on the absorption properties from the SC insulin depot when the
insulin is administered with an injector is of notable
interest. This most probably has to do with the ‘‘form’’ of
the SC insulin depot: with a needle, the administered
liquid sits in a circumscribed depot as compared with
when the insulin is administered in a distinct spraylike
dispersion pattern, ensuring a larger absorptive area.
S-55
These data suggest a benefit to administering prandial
insulin in obese subjects using such a device. It would be
of high practical relevance to repeat such studies with a
larger sample size and larger range of BMI; optimizing
insulin therapy in massively obese patients is difficult
with the devices currently available to administer insulin.
L.H. is a consultant for a number of companies developing
innovative diagnostic and therapeutic options for diabetes
therapy. He is active, for example, with Sanofi and Roche
Diagnostics. He is a partner and consultant for Profil Institut
für Stoffwechselforschung, Neuss, Germany and Profil Institut for Clinical Research, San Diego, CA.
References
1. Boss AH, Petrucci R, Lorber D. Coverage of prandial insulin
requirements by means of an ultra-rapid-acting inhaled insulin. J Diabetes Sci Technol 2012; 6: 773–79.
2. Fonte P, Araújo F, Reis S, Sarmento B. Oral insulin delivery:
How far are we? J Diabetes Sci Technol 2013; 7: 520–31.
3. Patel MM. Colon targeting: an emerging frontier for oral insulin delivery. Expert Opin Drug Deliv 2013; 10: 731–39.
4. Jain PK, Karunakaran D, Friedman SH. Construction of a
photoactivated insulin depot. Angewandte Chemie 2013; 52:
1404–9.
DOI: 10.1089/dia.2014.1507
ORIGINAL ARTICLE
Using Health Information Technology
to Prevent and Treat Diabetes
Neal Kaufman
Introduction
T
his is the fifth volume of the ATTD yearbook, and
while much has changed related to health information
technology in the past 5 years, much is still the same. There
have been extraordinary advances in the ability of mobile and
web-based applications and programs to deliver increasingly
sophisticated functionalities more conveniently and at an affordable cost. Examples include:
1 Providing timely and accurate data and information so
necessary for a clinician to support a patient and for a
patient to self-manage his or her diabetes
2 Monitoring and tracking over time: (a) key biometric
information (e.g., weight, heart rate, blood pressure,
blood glucose); (b) behaviors (e.g., observations of daily
living, medication adherence, steps, calories burned,
diet, social interaction); (c) attitudes and feelings (e.g.,
in-the-moment assessments of emotional well-being,
sources of anxiety, feelings before a behavior such as
smoking or overeating)
3 Making affordable and accessible mobile apps for nearly
every individual component of healthcare delivery and
patient self-management
4 Providing effective interventions using the range of
communications delivery mechanisms to create customizable and personalized programs that meet the needs
of specific target populations, including those targeting
clinicians and those targeting patients.
Unfortunately, there haven’t been concomitant advances in
the necessary policies and supports to bring these and other
innovations to scale. While changes in the financing and delivery of healthcare are occurring throughout the world, the
pace of change is quite slow and is falling far behind the rate of
change seen in the technology world. For example, while
millions of people are accessing medical information and
support via mobile devices and web-based programs, it is
extremely rare that the cost of these services is included in the
patient’s healthcare benefit package from insurance or from
the government. What will lead to the policy changes at all
levels of healthcare systems to accelerate the acceptance and
spread of these innovations? How can the pace be quickened
to improve the prevention and treatment of diabetes at a level
that impacts the millions of affected individuals? Typically,
before there are real and transformative healthcare-related
policy changes, the approaches embodied in the policies have
been tested and spread to a large enough segment of the
population to predict success when at scale. What is needed
for innovation to spread beyond the innovators and early
adopters? Over the past 60 years, advances in the science of
diffusion of innovations has led to some basic principles that
are worth applying to health information technology innovations. The key elements of particular innovations that predict the rate of spread include*:
1
2
3
4
5
6
7
8
Relative advantage
Trialability
Observability
Communication channels
Pace of innovation/reinvention
Norms, roles, and social networks
Opinion leaders
Infrastructure
The articles that are included in this chapter document innovations that are ready, or almost ready, to spread. Only
time will tell which ones will be successful.
CCHIT ACO HIT Framework
June 6, 2013 ª Certification Commission for Health Information
Technology
Background
Among the many factors that will contribute to the success
of an accountable care organization (ACO) is a focused health
UCLA Schools of Medicine and Public Health, Los Angeles, CA.
*Diffusion of Innovation in Health Care; Prepared for California HealthCare Foundation; Prepared by Institute for the Future; Authors: Mary
Cain and Robert Mittman; May 2002; ISBN 1-929008-97-X.
S-56
USING HEALTH INFORMATION TECHNOLOGY TO PREVENT AND TREAT DIABETES
information technology (HIT) roadmap that aligns the organization’s resources with its goals and objectives for accountable care. The Certification Commission for Health
Information Technology (CCHIT) ACO HIT Framework is a
guide to developing a technology roadmap that will mitigate
some of the risks associated with taking on accountability for
costs, quality of care, and patient loyalty.
accountable care organizations), it is quite appropriate
for any healthcare delivery system and the providers
within it. Regardless of the economic and administrative
structure, all systems and providers should attempt to
address these important aims, requirements, and processes. The challenges to successfully accomplish these
ambitious goals are made all the more difficult because,
with 64 different processes, the complexity associated
with integrating so many disparate technologies and
matching them with human processes is enormous. It is
almost as if each of the 64 processes is its own line of
business with many products and vendors and all-toooften limited ability to work together across business
lines. One can feel overwhelmed by the complexity of it
all, but the approach should be to acknowledge that the
technology needs at each level of the system (e.g., patients, individual clinicians, groups of clinicians, large
provider networks, health plans, payors, governments)
are analogous to the needs of all the other parts. Accepting this idea—the fractal nature of systems—can go a
long way to improve approaches at all levels.
Methods
CCHIT developed a publicly available ACO HIT Framework. The commission defined seven key processes required
to meet the aims of high-quality care, cost efficiency, and
customer loyalty; delineated the functions within each process; and identified HIT capabilities to support each function.
An advisory panel of healthcare experts was convened to
review, modify, and expand upon the initial work of the
commission.
Results
A listing of the defined aims, HIT requirements, and key
processes needed for comprehensive technology support are
seen below. The full article has more details of the 64 processes, which are organized by the 7 key processes.
Aims:
High-quality care
Cost efficiency
Customer loyalty: providers and patients
HIT requirements
Information sharing
Data collection and integration
Patient safety
Privacy and security
Key processes
Care coordination
Cohort management
Patient and caregiver relationship management
Clinician engagement
Financial management
Reporting
Knowledge management
Conclusion
The Framework represents a starting point for organizations wishing to build an HIT infrastructure that will support
varying levels of financial risk under the rubric of accountable
care while reengineering to improve quality, manage cost,
change clinician culture, and include patients as partners in
care. As the HIT needs of the delivery system are defined and as
HIT itself continues to evolve, the Framework will also evolve.
Comment
I selected this publication because it elegantly simplifies
the complex issues around health information technology and its use to improve patient care, outcomes, and
cost. While written for a specific U.S. approach (called
S-57
Interactive computer-based interventions for weight
loss or weight maintenance in overweight or obese
people (The Cochrane Collaborative Review)
Wieland LS 1, Falzon L 2, Sciamanna CN 3, Trudeau KJ 4,
Brodney S 5, Schwartz JE 6, Davidson KW 7
1
Center for Integrative Medicine, University of Maryland School
of Medicine, Baltimore, MD; 2Center for Behavioral Cardiovascular Health, Columbia University Medical Center, New York,
NY; 3Division of General Internal Medicine, Penn State College of
Medicine, Hershey, PA; 4Inflexxion, Inc., Newton, MA; 5The
Health & Wellness Institute, Providence, RI; 6Psychiatry and Behavioral Sciences, Stony Brook University, Stony Brook, NY; and
7
Behavioral Cardiovascular Health & Hypertension Program, Columbia College of Physicians & Surgeons, New York, NY
Cochrane Database Syst Rev 2012; Issue 8. Art. No.: CD007675.
DOI: 10.1002/14651858.CD007675.pub2.
Background
The standard treatment for overweight and obesity is to
help patients change their diet and exercise habits. Over the
past decade, web-based interventions have been developed
and tested for a range of behaviors and chronic conditions,
including weight control. Websites that attract enough users
can be provided at no cost to the users and remain profitable
when supported by advertising. In addition, web-based programs overcome the time and travel barriers of face-to-face
interventions and increasingly include social features similar
to the in-person experience. If it were possible to create effective web-based tools that were able to engage individuals
for the long-term, the reach of the Internet would give these
interventions the ability to have a major public health impact.
Behavioral weight control is the sum total of a great number
of practices that each influence caloric intake, caloric expenditure, or both. Traditional behavioral weight management programs typically include multiple components from multiple
theoretical approaches (e.g., cognitive-behavioral therapy, self-
S-58
regulation theory). Participants are taught a number of recommended practices, such as stimulus control, self-monitoring
(e.g., food records), and identification of high-risk situations for
relapse. As a result, interactive weight management interventions include features that mimic these components that would
traditionally be provided in-person, such as online goal setting
as opposed to face-to-face goal setting. While face-to-face interventions often include diaries of caloric intake and exercise and a
therapist compares these to the recommendations and goals for
the patient, this feedback can be computerized and provided
online without a therapist involved. Most of what is available,
therefore, in interactive interventions has been a computerization of what is available face-to-face. This includes online chat
sessions and message boards that are designed to replicate what
might happen in a group counseling session.
Methods
To assess the effects of interactive computer-based interventions for weight loss or weight maintenance in overweight
or obese people, the authors conducted a comprehensive literature search without limitation to language. Articles selected to be reviewed included randomized controlled trials
(RCTs) and quasi-RCTs with durations greater than 4 weeks
and in which loss to follow-up was < 20%. The primary outcomes were body weight, waist circumference, health-related
quality of life, well-being, and patient satisfaction. The secondary outcomes were physical-activity-related outcomes,
diet-related cost-effectiveness, and adverse events.
Results
The authors included 14 weight loss studies with a total of
2,537 participants, and four weight maintenance studies with a
total of 1,603 participants. The length of treatment ranged from
4 weeks to 30 months. Compared to no intervention or minimal
interventions (pamphlets, usual care), interactive computerbased interventions are an effective intervention for weight loss
and weight maintenance. At 6 months, computer-based interventions led to greater weight loss than minimal interventions
(mean difference - 1.5 kg) but less than in-person treatment
(mean difference 2.1 kg). At 6 months, computer-based interventions were superior to a minimal control intervention in
limiting weight regain (mean difference - 0.7 kg), but not superior to infrequent in person treatment (mean difference
0.5 kg). Greater amounts of intervention use, particularly selfmonitoring, were typically associated with greater amounts of
weight loss, though it was not clear what intervention elements
would best encourage greater use or whether encouraging
greater use would lead to larger effects. There were not enough
articles in which cost and cost-effectiveness were analyzed to
allow conclusions to be reached.
Conclusion
The impact of computer-based interventions appears relatively small compared to standard-of-care face-to-face interventions published elsewhere. In-person treatments tend to
lead to a loss of 7–10% of body weight in the first 6 months.
This is substantially more than the amount of weight lost at 6
months in the computer-based intervention groups included
in this review, which raises the question of what role these
interventions may play in addressing the epidemic of over-
KAUFMAN
weight and obesity. In the studies examined, adherence decreased dramatically in the first few months. Without
understanding what level of adherence was clinically significant over the long-term, it will be difficult for clinicians to
recommend and monitor the use of these interventions. Also,
using a web-based intervention is more complicated than
taking a pill, so physicians would need to understand what
compliance means to these interventions to be able to use
them routinely. This question will become more relevant
should interventions be shown, in the future, to lead to greater
effect sizes or clinical improvements. A major advantage of
computer-based interventions is their ability to reach large
numbers of people at a relatively low cost. However, the issue
of costs and cost-effectiveness in the area of computer-based
interventions is complex. Although cost analyses can be important tools to assist organizations in making decisions, it is
increasingly complicated to understand their significance.
This is especially true when the costs of obesity are felt in
a variety of sectors (healthcare, employer, health plan, etc.).
As overweight and obesity are increasingly considered
chronic illnesses, interventions will need to examine the costeffectiveness over time, as the comparator will increasingly be
surgery. Interactive technologies change quickly, so it is also
quite likely that what is reviewed here will be quite different
from the trials reviewed a few years from now.
Comment
This is somewhat encouraging news, though not a ringing endorsement of interactive computer-based interventions for weight loss. As technology improves and
more programs are created and tested, I have no doubt
we will see better results. This is especially true when the
interventions are created from effective programs originally designed to be delivered in-person and then faithfully transformed for a new technology-enabled delivery
approach. When these in-person approaches are also
cost-effective and/or cost saving, the impact of the derivative approach is even better. The challenge with most
in-person programs is that they are often unaffordable
(too high of a per-person price) and not scalable (unable to
find enough personnel, physical location, time, etc.) to be
provided to enough people to make a population-based
difference. As technology minimizes the going-to-scale
challenges, and if the price of the technology-enabled
program is significantly less than the in-person program
(e.g., 10–20%), even if the technology-enabled approach is
not as effective as the original (e.g., 50% as effective), it will
be quite effective at the population level.
School-based Internet obesity prevention programs
for adolescents: a systematic literature review
Whittemore R, Chao A, Popick R, Grey M
Yale School of Nursing, New Haven, CT
Yale J Biol Med 2013; 86: 49–62
Background
Prevention is advocated widely as an important strategy to
address the rising prevalence of obesity in adolescents, as
once youth become obese, treatment is difficult. School-based
Internet obesity prevention programs hold great promise in
reaching adolescents at risk for obesity as well as engaging
adolescents in learning strategies to improve health behaviors. Adolescents have demonstrated significant improvements in dietary behaviors, physical activity, and body mass
index (BMI) after participating in such programs, thus demonstrating the promise of this approach. However, programs
have been heterogeneous with respect to type of media used,
intervention components, quality, length of program, and
outcomes. The purpose of this systematic review is to describe, synthesize, and evaluate the research on school-based
Internet obesity prevention programs for adolescents. This
includes sample characteristics, geographical location, program framework and content, number of sessions, attendance, attrition, BMI, and behavioral outcomes.
Methods
The authors performed a systematic review on English
language, school-based obesity prevention Internet programs
for adolescents. Articles were included if they reported an
empirical study of a school-based obesity prevention program
for adolescents, evaluated BMI, nutrition behavior, or physical activity behavior, and had a comparison group.
Results
Of the 12 studies included in this review, 5 compared a
school-based Internet obesity prevention program to a notreatment control group, 3 studies compared an Internet
program to traditional classroom education, 2 studies compared an Internet program to a print program, and 2 compared two different Internet programs.
All Internet programs were developed from a theoretical
perspective, with six based on the transtheoretical model, four
based on social cognitive theory, two with a health promotion
model, two based on models of behavior change, and one
based on the theory of planned behavior. Content on both
nutrition and physical activity was included in six programs;
content on physical activity was included in only four programs; and content on nutrition was included in only two.
Overall, school-based Internet obesity prevention programs were effective in improving health behaviors of adolescents in the short-term (< 3–6 months). Across all studies,
researchers used self-reporting measures to assess health behaviors. Improvement in dietary behavior and/or physical
activity, regardless of theoretical perspective, content, or
number of modules, was reported for the majority of programs (n = 10). Improvements in adolescents’ self-efficacy for
healthy eating or being physically active were reported in
programs that targeted self-efficacy (n = 3). There were four
studies in which the program’s effect on BMI was evaluated.
In only one study, based on models of behavior change, there
was a significant decrease in BMI over time. One program
resulted in an increase in BMI over time, and in the other two
programs that evaluated BMI, no effect on BMI was found.
Conclusion
This review suggests that school-based Internet obesity
prevention programs are effective in improving health behaviors in the short-term. They reached diverse adolescents at
S-59
risk for overweight and obesity and appeared to be superior
to standard care and traditional classroom education. Schoolbased Internet obesity prevention programs have been successful in reaching high-risk students and changing behaviors
in the short-term, but incomplete reporting, brief duration of
follow-up, and a high risk of bias make it difficult to assess the
true success of these programs.
Comment
While preventing obesity in adolescents will not have
much short-term effect on the incidence or prevalence of
type 2 diabetes, it could have a major impact in 20–30
years. School-based approaches that modify the environment and improve student’s knowledge, attitudes,
and skills, leading to significant and long-lasting changes
in behaviors, are critical. It is encouraging to see that
technology-enabled intervention shows promise. Given
the strong association between child and adolescent
obesity and type 2 diabetes later in life, it is essential that
we are successful in preventing obesity as early as possible in the life course. Fortunately, the ill health effects of
obesity are not felt by most adolescents, but that makes
funding for prevention all the more difficult. Put bluntly,
there is almost no return on investment from pediatric or
adolescent obesity prevention to the healthcare system,
so other justifications need to be articulated. Other parts
of society (and the schools are good examples) need to be
involved if we are to see significant improvement.
Short message service (SMS) text messaging as an intervention medium for weight loss: a literature review
Shaw R, Bosworth H
Durham Veterans Affairs Medical Center, Duke University,
Durham, NC
Health Informatics J 2012; 18: 235
Background
Mobile devices such as mobile phones have emerged as a
mode of intervention delivery to help people improve their
health, particularly in relation to weight loss. Using mobile
phones as a medium to deliver weight loss interventions has
distinct advantages in that it reaches across geographic and
economic boundaries, can be delivered directly to people, and is
easy to use. Furthermore, short message service (SMS), also
known as text messaging, has grown in popularity as a way to
deliver health information owing to its simplicity, low cost, and
ability to serve as a cue to action. SMS is a messaging service of
up 160 characters in length to and from fixed-line and mobile
phone devices. Thus, the purpose of this review was to answer
the following question: What is the relationship between the use
of SMS as an intervention medium and weight loss?
Methods
A comprehensive search of the English-language literature
was used to find randomized or quasi-experimental intervention trials of participants who used SMS as the primary mode of
communication to reduce obesity, overweight, or promoting
weight loss. Studies were required to measure the impact of SMS
S-60
on a weight-loss-related variable postintervention, including
body weight, body–mass index (BMI), waist circumference,
physical activity, or diet. In addition, all studies had to be published in a peer-reviewed journal or under a similar peerreviewed process such as a dissertation.
Results
Fourteen studies were found from 2007 or later. Ten studies
used randomization and a comparison control group. Retention was above 80% for 8 of the 14 studies. Three studies
conducted a power analysis and recruited the respective required sample sizes. Many of the studies were pilot or feasibility and did not have a power analysis for sample size
calculation. All but two studies reported to use validated
scales. All 14 studies focused on increasing physical activity,
11 focused on improving dietary habits, 3 measured the effects of SMS on blood pressure (BP) as an outcome from
weight loss, and 10 assessed the acceptability or feasibility of
SMS as a mode of delivery for weight loss. SMS was found
feasible and acceptable in all seven studies in which it was
evaluated. One study found it feasible for children to selfreport data on eating, exercise, and emotions via SMS for 36
weeks. Additionally, several studies reported that people
were positive toward the SMS system. Of the three studies
that measured the effects of SMS on self-efficacy, two found
no significant change in physical activity self-efficacy. One
study showed a statistically significant increase ( p < 0.05) in
dietary self-efficacy in comparison with a control group. One
study measured social support, yet found no change from
baseline to postbaseline in comparison with a control group.
Three out of six studies that measured the frequency or duration of physical activity found a statistically significant increase. Four studies measured the effects of an SMS
intervention on dietary habits. One found a positive impact,
two found no impact, and one demonstrated weight loss but
did not report on dietary habits. Two of three studies that
measured the effect on BP from weight loss found SMS statistically and clinically significantly reduced BP ( p < 0.05).
Overall, 11 of the 14 studies had a statistically significant effect
( p < 0.05) on weight-loss-specific variables (i.e., weight,
physical activity or diet). Of the 10 studies that measured BMI
or weight as an outcome, 5 (50%) demonstrated a statistically
and clinically significant difference in BMI postintervention
( p < 0.05).
Conclusion
Results from this literature review demonstrate that SMS as
an intervention tool for weight loss is still in its infancy, as
indicated by the paucity of randomized clinical trials with
limited sample sizes. SMS was found to be feasible and acceptable as an intervention medium to transmit and receive
diet and exercise messages. Design of the interventions varied
significantly. Owing to the inconsistency of timing and delivery, it is difficult to understand how often and when people
should receive diet and exercise SMS. The effectiveness of
SMS longitudinally for weight loss remains undetermined at
present. SMS is often touted as an affordable and low-cost
method of delivering intervention to and communication
between patient and providers. However, among the studies
reviewed, there was limited discussion or evaluation on the
cost-effectiveness of SMS.
KAUFMAN
Continued research is needed on many fronts. Large randomized controlled trials with a significant sample size and
longitudinal measurements are needed to understand how to
best use and understand the benefits of SMS as an intervention medium. Informative research is required to find out
exactly what should be written in a message and to understand the best timing and frequency of message delivery. In
addition, it may not be that SMS is the most effective intervention approach, but just one of many that should be used in
combination to support and help people change their diet and
exercise lifestyle.
Comment
Text messaging as a way to provide education and support to patients certainly has its role. In low-income
populations, in developed and underdeveloped countries, SMS can provide a variety of interactions that can be
effective, low cost, and accessible to many people without the need for Internet access. For those with access to
the range of technologies, it would not surprise me if
some prefer the short-and-sweet approach of text messaging to other more time-consuming approaches. The
key will be to create text-messaging-based interventions
that are specifically designed for a target population,
proven to be effective, and able to evolve as wisdom
accumulates and technology improves.
Effects of type 2 diabetes behavioural telehealth
interventions on glycaemic control and adherence:
a systematic review
Cassimatis M 1,2, Kavanagh DJ 1
1
Institute of Health and Biomedical Innovation, Queensland
University of Technology, Brisbane, Australia; and 2Wesley Health
and Medical Research Institute, Wesley Hospital, Brisbane, Australia
Telemed Telecare 2012; 18: 447
Background
Telehealth applications, including telephone counseling,
videoconferencing, and educational telephone-based interventions, have been favorably received with good acceptability and uptake by type 2 diabetes patients. Telehealth
interventions have also shown efficacy in improving psychosocial, psychological, and clinical outcomes in diabetes.
While behavioral interventions and ongoing support are acknowledged as being cornerstones for effective type 2 diabetes self-management, the efficacy of behavioral telehealth
interventions specifically aimed at improving glycemic control and diabetes self-care remains uncertain.
Methods
The authors conducted a systemic literature review of the
effects of behavioral type 2 diabetes telehealth interventions.
Eligible studies were peer-reviewed journal articles published
in the English literature that reported evaluating the effects of
telehealth interventions on glycemic control and at least one
diabetes self-care outcome out of physical activity, diet, blood
glucose self-monitoring, and medication adherence. Studies
had to be randomized controlled trials and included either a
S-61
usual care comparison or an active treatment control (where
the telehealth conditions received the same treatment).
Effects of self-management health information technology
on glycaemic control for patients with diabetes:
a meta-analysis of randomized controlled trials
Results
Tao D, Or CKL
The search retrieved 1027 articles, from which 49 were selected based on their title and abstract. Fourteen articles (reporting 13 studies) met the eligibility criteria for inclusion.
Four studies reported significant improvements in glycemic
control. Five of eight studies on dietary adherence reported
significant treatment effects, as did five of eight on physical
activity, four of nine on blood glucose self-monitoring, and
three of eight on medication adherence. Considerable heterogeneity between study processes and outcomes meant that
it was difficult to draw firm conclusions. However, the present review demonstrated that behavioral telehealth interventions can significantly improve both glycemic and
diabetes self-care outcomes in type 2 diabetes patients. Of the
diabetes self-care outcomes that were examined, physical
activity and dietary adherence most commonly demonstrated
improvements in response to telehealth.
Department of Industrial and Manufacturing Systems Engineering, Faculty of Engineering, University of Hong Kong, Hong
Kong, China
Conclusion
Overall, behavioral telehealth interventions show promise
in improving the diabetes self-care and glycemic control of
people with type 2 diabetes. In order to optimize the effect of
telehealth for type 2 diabetes, systematic evaluations of different dosages and durations of interventions are also needed,
as are studies of specific subgroups of patients (e.g., insulin
dependent/nondependent). Research in this field also requires substantial improvements in study methodology, including blind assessment and allocation concealment. Clearer
reporting of study processes and outcomes would enable
methodological quality to be assessed and more confident
conclusions to be drawn from reviews.
Comment
While this review demonstrates the positive impact of telehealth programs on the health of people with type 2 diabetes, it also highlights the lack of high-quality studies. This
is not surprising for several reasons: (a) These are very expensive trials and while governments, foundations, industry, and others fund some outcome studies, it is much
harder to get adequate funding to perform high-quality,
longitudinal research with enough subjects to give results
that matter; (b) technology, by its very nature, is constantly
evolving, and given the calendar time it takes to plan, implement, and evaluate these kinds of studies, the technology being studied is usually obsolete and 2–3 generations
old by the time the study is published. We need a new
paradigm that lowers the cost and decreases the time necessary to evaluate technology-enabled behavioral interventions. The need to perform randomized controlled trials
severely limits research opportunities. Using statistical
methods from economics (which don’t require random
assignment) could go a long way to solving this problem. In
addition, studies should investigate the principles upon
which an intervention is based and how the program is
implemented in the real world, and less on the specific
functionalities of the technology.
J Telemed Telecare 2013; 19: 133
Background
The authors conducted a systematic review and metaanalysis of randomized controlled trials (RCTs) that had evaluated self-management health information technology
(SMHIT) for glycemic control in patients with diabetes. SMHIT
in this analysis refers to patient-focused, technology-mediated
applications that are designed to enable patients with diabetes to engage in self-care activities such as health signs
and symptoms monitoring, medication adherence, emotional
management, self-education, and information exchange and
communication to promote their health and well-being.
The authors hypothesize a number of advantages of
SMHIT as a method of healthcare intervention delivery. In
addition to its convenience, patients using these technologies
can easily monitor their own health signals and transmit the
data immediately to their clinicians, supporting better treatment adjustment decisions. They can also consult with the
clinicians directly for individual recommendations on better
self-management behavior. The benefits of SMHIT could also
include the standardization of intervention delivery, access to
online disease management resources, flexibility in the time
and location of access to healthcare services, a reduction in
outpatient visits, a reduction in the stigma of seeing a therapist, the delivery of tailored feedback to patients, and a reduction in hospital care costs. The hope is that the use of
SMHITs can facilitate patients’ self-management of their diabetes and deliver comprehensive healthcare services in a
way that retains healthcare quality.
Methods
A total of 43 RCTs were identified, which reported on 52
control-intervention comparisons. The glycosylated hemoglobin
(HbA1c) data were pooled using a random effects meta-analysis
method, followed by a meta-regression and subgroup analyses
to examine the effects of a set of moderators.
Results
The meta-analysis showed that use of SMHITs was associated with a significant reduction in HbA1c compared with
usual care, with a pooled standardized mean difference of
20.30% (95% CI 20.39 to 20.21, p, 0.001). Sample size, age,
study setting, type of application, and method of data entry
significantly moderated the effects of SMHIT use. The review
supports the use of SMHITs as a self-management approach
to improve glycemic control.
Conclusion
The present meta-analysis of RCTs shows that the use of
SMHIT is associated with improved glycemic control in
S-62
patients with diabetes. The analysis indicates that the effect of
SMHIT use is significantly greater when the technology is a
web-based application, when a mechanism for patients’
health data entry is provided (manual or automatic), and
when the technology is operated in the home or without location restrictions. Integrating these variables into the design
of SMHITs may augment the effectiveness of the interventions.
Comment
While meta-analysis is a flawed but accepted method to
see impact across disparate studies, this analysis reinforces the positive outcomes seen from a variety of approaches to helping individuals more efficiently and
effectively self-manage their diabetes. While self-management is the professed goal from nearly all clinicians
and clinical settings, it is often quite challenging to accomplish given the diversity of people receiving care and
varied issues that need to be addressed. Focusing on core
knowledge, attitudes, skills, and behaviors that are necessary for a person to succeed can go a long way. Technology has a role to play in ways that will be better
defined and redefined in the coming years.
Active assistance technology reduces glycosylated hemoglobin and weight in individuals with type 2 diabetes:
results of a theory-based randomized trial
Orsama A-L 1, Lähteenmäki J 1, Harno K 2, Kulju M 1,
Wintergerst E 3, Schachner H 3, Stenger P 3, Leppänen J 1,
Kaijanranta H 1, Salaspuro V 4, Fisher WA 5
1
VTT Technical Research Centre of Finland, Helsinki, Finland;
University of Eastern Finland, Kuopio, Finland; 3Bayer Diabetes
Care, Tarrytown, NY; 4Mediconsult Ltd., Helsinki, Finland; and
5
Departments of Psychology and Obstetrics and Gynaecology,
University of Western Ontario, London, Ontario, Canada
2
Background
Interactive technology support has been shown to improve
glycemic control in individuals with type 2 diabetes, but
success in this respect is determined primarily by frequent
contact between intervention patients and healthcare personnel. This increases use of healthcare resources and may not
be an option for all patients. On the other hand, extensive use
of behavioral change techniques via the Internet produces
larger effects than interventions with fewer techniques. The
rapid evolution of sophisticated information technologies and
mobile communication devices in the past decade has made it
possible to exploit technology to facilitate healthcare professional and self-management of diabetes. Remote patient reporting of relevant health parameters and linked automated
feedback via mobile telephone have potential to strengthen
self-management and improve outcomes. Remote patient reporting of blood glucose levels, blood pressure, weight,
physical activity, and nutrition can be linked, via mobile
telephone, intermittently or in real time, with human healthcare personnel or with automated feedback. Remote patient
reporting linked with theory-based health behavior change
KAUFMAN
automated feedback have potential to improve patient outcomes in type 2 diabetes and merit scaled-up research efforts.
Given the prevalence and consequences of diabetes and
the fact that healthcare professional management and selfmanagement of diabetes are time-, effort-, and cost-intensive,
the potential efficiency and effectiveness of automated feedback, articulated to remote patient reports and guided by
health behavior change theory, would seem to be considerable. In the clinical diabetes reality, ongoing healthcare provider support for diabetes self-management is not uniformly
available. At the same time, however, many, if not most, individuals with diabetes have mobile communication devices
that provide potential access to information technology-based
interventions, guided by health behavior models, from which
they may benefit at minimum cost. This research involved
development and evaluation of a mobile telephone-based
remote patient reporting and automated telephone feedback
system, guided by health behavior change theory, aimed at
improving self-management and health status in individuals
with type 2 diabetes.
Methods
The study was a randomized controlled trial that involved
development and evaluation of a mobile telephone-based
remote patient reporting system, linked to automated feedback and guided by the information–motivation–behavioral
skills model and evidence-based patient care guidelines. Inclusion criteria were diagnosis of type 2 diabetes, elevated
glycosylated hemoglobin (HbA1c) levels (range, 6.5–11%), or
use of oral diabetes medication, and 30–70 years of age. Intervention subjects (n = 24) participated in remote patient reporting of health status parameters and linked health
behavior change feedback. Knowledge-based reasoning
based on the user’s health data was linked in a dynamic
process to the delivery of self-management information, motivation, and behavioral skills messages. Control participants
(n = 24) received standard of care including diabetes education and healthcare provider counseling. Patients were followed for approximately 10 months. Assessment of HbA1c,
weight, and blood pressure at baseline and follow-up of a 10month study period, in intervention and control patients, was
used to gauge intervention impact on diabetes health-related
end points.
Results
Intervention participants achieved, compared with controls and controlling for baseline, a significantly greater mean
reduction in HbA1c of - 0.40% versus 0.036% ( p < 0.03) and
significantly greater weight reduction of - 2.1 kg versus
0.4 kg. Nonsignificant trends for greater intervention compared with control improvement in systolic and diastolic
blood pressure were observed. Postintervention reports indicated that 100% of intervention participants (24 of 24 who
responded to this question) regarded Monica, the mobile
telephone application, as ‘‘very easy’’ or ‘‘quite easy’’ to use.
More than 90% of respondents (21 of 23 who responded to this
question) reported that making health parameter measurements and reporting them was ‘‘very useful’’ or ‘‘quite useful,’’ and approximately 82% (18 of 22 who responded to this
question) of intervention participants regarded the automatic
feedback they received as ‘‘very useful’’ or ‘‘quite useful.’’
Conclusion
This study applied active assistance technology for automated processing of health information from patients in an
ongoing interaction with technology. This was achieved with
semantic information processing of patient-reported data and
delegation of decision making to the automated system,
which frees up healthcare personnel resources.
Comment
Although this study was quite small (only 24 subjects), it
was quite well thought out and expertly implemented
and evaluated. We are seeing the future and the future is
now. I fully expect that in the next few years there will be
many more of these approaches that will be proven to be
effective. I can only hope that the timeframe for adoption
of the proven approaches goes much faster than many
other medical innovations that often take decades to be
adopted. In the case of technology-enabled interventions,
the timeframe for innovations secondary to improved
technology is in years and, in some cases, months. This
will challenge all healthcare providers and healthcare
systems to be able to relatively quickly adopt new programs that work while constantly looking for new approaches that need to be investigated and proven
effective.
Internet psycho-education programs improve outcomes
in youth with type 1 diabetes
Grey M 1, Whittemore R 1, Jeon S1, Murphy K 2, Faulkner MS 3,
Delamater A 4; for the TEENCOPE STUDY GROUP
1
Yale University School of Nursing, New Haven, CT; 2Department
of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia,
PA; 3School of Nursing, University of Arizona, Phoenix, AZ; and
4
Department of Pediatrics, University of Miami, Miami, FL
Diabetes Care 2013; 36: 2475–82
Background
Considerable evidence indicates that in-person psychoeducational interventions, such as coping skills training (CST),
improve metabolic control of type 1 diabetes as well as psychosocial adjustment and quality of life (QOL) in youth.
However, implementing these evidence-based programs in
clinical care is challenging because of provider and organizational barriers, such as lack of time, resources, and expertise. Rapid advances in technology and access to the Internet
have made it not only a viable mode for the delivery of psychoeducational interventions but also a platform that can be
widely disseminated and implemented. Psychoeducational
interventions delivered via the Internet have demonstrated
efficacy in improving symptoms and health behaviors in
youth of different ages and illness experiences.
Methods
The purpose of this multisite randomized clinical trial was
to compare the efficacy of two Internet-based programs on the
primary outcomes of HbA1c and QOL and on the secondary
outcomes of stress, coping, self-efficacy, self-management,
S-63
social competence, and family conflict at 12 months. At the 12month follow-up, youth were invited to participate in the
alternate program, allowing the authors to explore the effect
of participating in two programs compared with participating
in only one.
TeenCope, a new Internet-based version of CST, was developed by the authors. It is based on social cognitive theory
and posits that improving coping skills will lead to improved
self-efficacy and self-management of diabetes that result in
better outcomes, as has been demonstrated in studies of CST
delivered in a group-based in-person format. Managing Diabetes was developed to serve as the control condition and was
a diabetes education and problem-solving program.
Each program consisted of five sessions with content tailored to transitioning adolescents with type 1 diabetes that
were released once per week for 5 weeks. TeenCope used a
cast of ethnically diverse characters with type 1 diabetes and a
graphic novel video format to model common problematic
social situations (i.e., parent conflict) and different coping
skills to solve the problems. The content of CST was based on
our previous studies and included communication skills, social problem solving, stress management, positive self-talk,
and conflict resolution.
The study was a multisite clinical trial of 320 youth (age 11–
14 years; 37% minority; 55% female) randomized to one of
two Internet-based interventions: TeenCope or Managing
Diabetes. Primary outcomes were HbA1c and QOL. Secondary outcomes included coping, self-efficacy, social competence, self-management, and family conflict. Data were
collected at baseline and after 3, 6, and 12 months online.
Youth were invited to cross over to the other program after 12
months, and follow-up data were collected at 18 months.
Analyses were based on mixed models using intent-to-treat
and per protocol procedures.
Results
Youth in both groups had stable QOL and minimal increases in HbA1c levels over 12 months, but there were no
significant differences between the groups in primary outcomes. After 18 months, youth who completed both programs
had lower HbA1c ( p = 0.04); higher QOL ( p = 0.02), social acceptance ( p = 0.01), and self-efficacy ( p = 0.03); and lower
perceived stress ( p = 0.02) and diabetes family conflict
( p = 0.02) compared with those who completed only one
program.
Conclusion
Internet interventions for youth with type 1 diabetes transitioning to adolescence result in improved outcomes, but
completion of both programs was better than only one, suggesting that these youth need both diabetes management
education and behavioral interventions. Delivering these
programs via the Internet represents an efficient way to reach
youth and improve outcomes.
Internet interventions allow for standardization of program content, can be targeted to specific ages and developmental phases, allow for social interaction, and can be easily
updated. Access to the Internet is increasingly available nationwide and has risen to its highest level ever, with 93% of
youth using the Internet regularly for school assignments,
hobbies, or special interests, entertainment, and connection
S-64
with others. The Internet, therefore, represents an efficient
way to deliver psychoeducational interventions to youth with
type 1 diabetes.
Internet-based interventions that can reach large numbers
of youth with diabetes have the potential to result in significant improvements in long-term health as well as reductions
in the costs of care for diabetes-related complications. They
also have the potential to improve access for diverse youth
with type 1 diabetes.
Comment
This elegantly designed, implemented, and evaluated
study is just what the doctor ordered. I am not surprised
that it didn’t demonstrate superiority of one approach
over the other and only modest improvement when the
youth decided to take both programs. It may be that
considerably more needed to be provided to help an
adolescent actually do what was in his or her best interest. Go figure. It is hard for any of us to change our behaviors, and this is all the more true for adolescents. It
was encouraging, and again not surprising, that adolescents enjoyed receiving education and support via technology. Since most young people with diabetes are using
a lot of technology already to manage their condition,
adding this approach would be quite natural. After all,
technology is how they are experiencing nearly everything else in their lives, so why not this?
Mobile health applications to assist patients with
diabetes: lessons learned and design implications
Årsand E1,2, Frøisland DH 3–5, Skrøvseth SO 1, Chomutare T 1,2,
Tatara N 1,2, Hartvigsen G1,2, Tufano JT 6
1
Norwegian Centre for Integrated Care and Telemedicine, University Hospital of North Norway, Tromsø, Norway; 2Department
of Computer Science, University of Tromsø, Tromsø, Norway;
3
Research Centre for Child and Youth Competence Development,
Lillehammer University College, Lillehammer, Norway; 4Faculty of
Medicine, University of Oslo, Oslo, Norway; 5Pediatric Department, Innlandet Hospital Trust, Lillehammer, Norway; and
6
University of Washington, Seattle, WA
Background
Self-management is critical to achieving diabetes treatment goals. Personal health applications (PHAs) developed
for use on mobile information and communication technology (ICT) platforms offer potential to address this need.
While there are increasing numbers of mobile PHAs for diabetes self-management support, their effectiveness is still
being determined. This study describes opportunities for
developing and leveraging mobile health (mHealth) interventions in diabetes treatment and self-management based
on various feature sets. Lessons learned and design implications are discussed.
Methods
A mHealth research platform—the Few Touch Application (FTA) was used to assess the impact of a variety of
KAUFMAN
mobile applications. The FTA consists of a mobile phone–
based diabetes diary, which can be updated both manually
from user input and automatically by wireless data transfer,
and which provides personalized decision support for the
achievement of personal health goals. Studies and applications (apps) based on FTAs have included (a) automatic
transfer of blood glucose (BG) data; (b) short message service
(SMS)–based education for type 1 diabetes mellitus (T1DM);
(c) a diabetes diary for type 2 diabetes mellitus (T2DM); (d)
integrating a patient diabetes diary with healthcare (HC)
providers; (e) a diabetes diary for T1DM; (f) a food picture
diary for T1DM; (g) physical activity monitoring for T2DM;
(h) nutrition information for T2DM; (i) context sensitivity in
mobile self-help tools; and (j) modeling of BG using mobile
phones. The authors analyzed the performance of these 10
FTA-based apps to identify lessons for designing the most
effective mHealth apps. The authors used user-centered
methods that incorporate focus groups, interviews, usability
testing, questionnaires, paper prototyping, functional software and hardware prototyping, and iterative design and
development cycles.
Results
The authors concluded that (a) automatic BG data transfer
is easy to use and provides reassurance; (b) SMS-based education facilitates parent–child communication in T1DM; (c)
the T2DM mobile phone diary encourages reflection; (d) the
mobile phone diary enhances discussion between patients
and HC professionals; (e) the T1DM mobile phone diary is
useful and motivational; (f) the T1DM mobile phone picture
diary is useful in identifying treatment obstacles; (g) the step
counter with automatic data transfer promotes motivation
and increases physical activity in T2DM; (h) food information
on a phone for T2DM should not be at a detailed level; (i)
context sensitivity has good prospects and is possible to implement on today’s phones; and (j) BG modeling on mobile
phones is promising for motivated T1DM users.
Conclusion
The authors expect that the following elements will be
important in future FTA designs: (a) automatic data transfer
when possible; (b) motivational and visual user interfaces; (c)
apps with considerable health benefits in relation to the effort
required; (d) dynamic usage, for example, both personal and
together with healthcare personnel, long-/short-term perspective; and (e) inclusion of context sensitivity in apps. They
conclude that mHealth apps will empower patients to take a
more active role in managing their own health.
Mobile applications for diabetes self-management:
status and potential
El-Gayar O 1, Timsina P 1, Nawar N 2, Eid W 3,4
Colleges of 1Business and Information Systems and 2Arts and
Sciences, Dakota State University, Madison, SD; 3St. Elizabeth
Healthcare Regional Diabetes Center, Covington, KY; and 4Division of Endocrinology, Department of Internal Medicine, Royal C.
Johnson VA Medical Center, Sanford School of Medicine, Sioux
Falls, SD
S-65
Background
Comment
Advancements in smartphone technology, coupled with
the proliferation of data connectivity, have resulted in increased interest and unprecedented growth in mobile applications for diabetes self-management. The objective of
this article is to determine, in a systematic review, whether
diabetes applications have been helping patients with type
1 or type 2 diabetes self-manage their condition and to
identify issues necessary for large-scale adoption of such
interventions.
These articles add to the literature that indicates that
mobile delivery of education and support can help patients improve outcomes. They also demonstrate the
evolving utility of single, focused mobile applications
that help patients self-manage their diabetes. As these
approaches become even more refined, they will no
doubt be able to better help support patients as they learn
to live and thrive with diabetes. The best of them will be
linked to clinicians who can help interpret unclear findings or observations and to interventions that help the
patient overcome barriers to be ready and able to benefit
from the data and information these apps provide.
Methods
The review covers peer-reviewed articles about commercial
applications available on the Apple App Store (as a representative of commercially available applications) and articles
published in relevant databases from January 1995 to August
2012. The review included all applications supporting any
diabetes self-management task in which the patient is the
primary actor.
Results
The studied applications support self-management tasks
such as physical exercise, insulin dosage or medication, blood
glucose testing, and diet. Other support tasks included decision support, notification/alert, tagging of input data, and
integration with social media. Fifteen out of 16 articles reviewed experimentally tested their application. Two studies
found no added benefit provided by the use of the application, whereas the remaining articles reported some type of
added benefit. Overall, the review indicates that mobile applications can be viable tools for diabetes self-management.
Mobile applications are generally preferred to web- or computer-based systems when it comes to usability. Regimen
adherence can be managed through the use of mobile applications, which affects self-efficacy and other enabling factors.
The review also seems to point out that diabetes self-management applications are useful to patients as well as providers. Limitations of the applications include lack of
personalized feedback; usability issues, particularly the ease
of data entry; and integration with patients and electronic
health records.
Conclusion
This review attests to the value and potential for mobile
applications to improve diabetes self-management. It is
important to note that mobile application–based selfmanagement is not a ‘‘silver bullet,’’ and it is critical to
understand that its effect is based on strong behavioral
change theory. Such interventions may not be suitable for
all patients with diabetes. Some patients abandon use
because of technical problems, and others cannot afford
the cost (phone and associated data plans). Research into
the adoption and use of user-centered and sociotechnical
design principles is needed to improve usability, perceived usefulness, and, ultimately, adoption of the technology. Proliferation and efficacy of interventions
involving mobile applications will benefit from a holistic
approach that takes into account patients’ expectations
and providers’ needs.
Video games for diabetes self-management:
examples and design strategies
Lieberman DA
University of California, Santa Barbara, CA
Background
Video games offer great promise for the delivery of diabetes self-management interventions because they provide
new and unique ways to motivate and support health behavior change. Serious games are entertainment video games
that have been designed to accomplish a beneficial purpose,
such as influencing learning, civic engagement, or health behavior change. The field of health games is an active and
innovative segment of the serious games field, with games
that address topics ranging from healthy lifestyle improvement to prevention to self-care to disease self-management,
and for healthcare providers, there are games that teach and
rehearse clinical skills and assist with diagnosis and delivery
of treatments.
Methods
This article briefly describes diabetes self-management video games and, when available, cites research findings on
their effectiveness. The games were found by searching
the Health Games Research online searchable database,
three bibliographic databases (ACM Digital Library, PubMed,
and Social Sciences Databases of CSA Illumina), and the
Google search engine, using the search terms ‘‘diabetes’’ and
‘‘game.’’ Games were selected if they addressed diabetes selfmanagement skills.
Results
The 14 diabetes self-management games described in this
article use a variety of game play genres, and the games
typically involve players in problem solving and decision
making in simulations of diabetes self-management, usually
by asking players to balance food and insulin to keep a game
character’s blood glucose within a normal range. This format
requires players to rehearse skills repeatedly until they win
the game, so these games provide practice and show cause
and effect, while also providing basic information about diabetes self-management. For example, this approach was
S-66
tested in a randomized controlled trial of the Packy & Marlon
game, which found improvements in diabetes-related
knowledge, self-efficacy, communication with family and
friends, self-care behaviors, and clinical utilization.
Conclusion
New ideas and theoretical models are emerging in the field
of diabetes self-management video games. These advances are
providing a strong evidence-based foundation of behavioral
health principles that could be integrated into the design of
future games to more successfully engage and motivate players, improve and support their diabetes self-management, and
lead to better health outcomes.
Comment
Video games are not just for kids, and the newer ones will
no doubt have more content, even better graphics, and
more impact. The challenge, not surprisingly, is the high
cost of creating a game when such a small number of
people will likely use them. This relegates their creation
to a limited number of well-funded organizations or
charities that have a mission to improve health outcomes.
Without a natural market for these games, the ability of
health-related games to reach large numbers of individuals is severely limited.
Local health department use of Twitter to disseminate
diabetes information, United States
Harris JK1, Mueller NL1, Snider D 2, Haire-Joshu D 1
1
Brown School and 2Center for Public Health Systems Science,
Washington University in St. Louis, St. Louis, MO
KAUFMAN
jurisdiction diabetes rate and the percentage of all tweets that
were about diabetes (r = 0.16; p = 0.049).
Conclusion
Health departments have a unique opportunity to use social media to provide this essential service, meeting several of
the standards required for accreditation and, potentially,
aiding in improving public health in their jurisdiction and
nationwide. LHDs are beginning to use social media to educate and inform their constituents about diabetes. An understanding of the reach and effectiveness of social media could
enable public health practitioners to use them more effectively. Future research is needed to better understand how
best to use social media as a tool for dissemination of health
information to constituents and as a way to engage people
living with and managing chronic disease.
Comment
I chose this article not because it demonstrates good
outcomes (no outcomes were presented) or that its conclusions are very profound—which they aren’t. I chose it
to demonstrate the limited research available about
tweeting as a method to improve the health of large
numbers of individuals. It takes time to develop a literature base that can demonstrate effects of new technologies. That is why it is essential for researchers to
determine the principles under which effective communication technology can be used to positively impact
patient outcomes. With these principles understood,
effective interventions can be developed that increase
the likelihood that a new technology—in this case, a
new communication channel—can make a significant
difference.
Prev Chronic Dis 2013; 10: 120215
Background
Educating and informing the public about health problems
is a service provided by local health departments (LHDs). The
objective of this study was to examine how LHDs are using
social media to educate and inform the public about diabetes.
Methods
In June 2012 we used NVivo 10 to collect all tweets ever
posted from every LHD with a Twitter account and identified
tweets about diabetes. We used a 2010 National Association of
County and City Health Officials survey to compare characteristics of LHDs that tweeted about diabetes with those that
did not. Content analysis was used to classify each tweet
topic.
Results
Of 217 LHDs with Twitter accounts, 126 had ever tweeted
about diabetes, with 3 diabetes tweets being the median since
adopting Twitter. LHDs tweeting about diabetes were in jurisdictions with larger populations and had more staff and
higher spending than LHDs not tweeting about diabetes.
They were significantly more likely to employ a public information specialist and provide programs in diabetes-related
areas. There was also a weak positive association between
Improving prompt effectiveness in diabetes care:
an intervention study
Bronner JP, Fontanesi J, Goel A
University of California, San Diego, CA
Am J Med Qual 2012; 27: 406–10
Background
A proposed advantage of electronic medical records
(EMRs) over paper charts is the ability to track patients with
complex and/or chronic disease such as diabetes and
‘‘prompt’’ providers to order monitoring tests within the
periodicity recommended by clinical practice guidelines.
EMR-generated prompts may be more likely to increase
ordering of recommended monitoring tests when clinic
workflow, staff training, and medical culture are incorporated into the prompt delivery. However, early experience
with prompts has had mixed results for improving the rate
and timeliness of test ordering. Prompt effectiveness may
be improved when implemented with an understanding of
the clinical workflow that recognizes the roles of all
healthcare team members. For example, targeting a testordering prompt to medical staff, rather than to a physician,
has been shown to be effective in diabetes management and
colon cancer screening.
S-67
Methods
The authors performed a nested, time-series, quasi-experimental design of EMR prompting in the internal medicine
and family medicine clinics at the University of California,
San Diego Medical Group (UCSDMG). The study was conducted within the context of a medical-group-wide quality
improvement initiative to increase appropriate diabetes
monitoring test ordering rates. The primary outcome of the
study was the missed opportunity rate (MOR).
appointments. It is encouraging that a relatively simple
intervention can help improve the quality of care provided. It is not surprising that when medical staff takes
over a specific task that is best done by them that they get
better results than a busy clinician. I was only surprised
that the medical staff was not already providing reminders that labs were needed for a specific visit. That is
what good teamwork is all about.
Results
Summary
The authors analyzed 16,511 visits performed on 3730 patients. The rate of ordering all indicated that tests at the time of
the visit increased from 29% with no prompts to 49%
( p < 0.001) with appropriately designed prompts and training
support. There was a 20% absolute decrease in missed opportunities to order all appropriate diabetes monitoring tests
for which an individual patient was eligible. An unintended
but reassuring finding of the study was the strong influence of
a visit with the primary care provider (PCP) on the adherence
to prompts. The absolute change in MOR for PCPs was 24%;
the change was 12.8% for non-PCPs. More than half of the
MOR reduction occurred when test ordering switched to the
medical staff, and the physician simply ‘‘approved’’ the order.
This shift in workflow relies on medical staff to help facilitate
test ordering and may be more contextually appropriate to
their role in healthcare delivery.
The articles reviewed in this chapter summarize advances
in technology that are making a real difference in the lives of
people with, or at risk for, diabetes. Many of the reviews point
the way to a consensus on what works, and the original research articles provide targeted wisdom about a more focused
element of the solution. While none of the articles will by
themselves lead to a time when technology can provide help
and support to all those who need it, it is hoped that these and
other publications can lead to a deeper understanding of what
works and why and for which people. This knowledge and
wisdom will go a long way to the goal of preventing diabetes
and improving the health of those affected by the disease.
Significant and lasting progress will happen when we have
a true partnership between academics, providers, and the
technology industry: Academics to continue pushing the envelope and creating approaches that work in the lab; healthcare providers who experiment with programs in real-world
settings to evaluate their effectiveness; and technology companies able to not only create something that works technically, but also provide what patients and clinicians actually
need to improve outcomes. We will know that the health information technology industry has fully arrived when more of
the companies are able to provide answers to what their
customers and patients need and want and not only what the
company is able to produce. Now, wouldn’t that be nice?
Conclusion
Although the physician is still ultimately responsible for
finalizing the test orders, this intervention should allow the
physician more time to focus on data analysis and implementation of a care plan rather than spending visit time
negotiating the indicated test-ordering process. In summary,
workflow-compatible, simplified prompts that accommodate
clinic workflow and team members’ scope of work can improve ordering rates of indicated diabetes tests.
Comment
This study is about a very specific technological support
for patient care, the use of EMR-driven prompts to increase notification adherence with expected tests and
N.K. has no conflict of interest with any of the reviewed
articles. He is the founder and co-owner of DPS Health, a
software development company based in Los Angeles, CA.
DPS Health creates and distributes web and cell phone based
weight management services.
DOI: 10.1089/dia.2014.1508
ORIGINAL ARTICLE
Technology and Pregnancy
Adrian Cotarelo1*, Homaira T. Zaman1*, Lois Jovanovič1, and Moshe Hod 2
Introduction
Objective
I
The incidence of pediatric obesity and diabetes is increasing
throughout the world, with children of ethnic backgrounds
being impacted more severely. This study observed the effects
of prepregnancy adiposity, weight gain during the pregnancy, and GDM on excess fetal growth to evaluate the susceptibility of various ethnic populations to adverse effects of
hyperglycemia.
n part because of the global obesity epidemic, pregnancies complicated by diabetes have grown into a widespread issue throughout all parts of the world. There are over
25 million people affected by diabetes in the United States
alone, with 12.6 million diabetic women aged 20 and over (1).
Maternal hyperglycemia can have devastating effects on
pregnancy when uncontrolled, including above-average birth
weight, macrosomia, birth defects, and an increased risk for
obesity and diabetes in the future. This year, we reviewed
1,299 articles and came to a final listing of 81 possible articles
to analyze. We selected 15 studies that we felt were representative of the research conducted in the field of technology,
treatment, and pregnancy over the course of the past year. A
large proportion of these original articles related to diagnostic
methods for determining gestational diabetes mellitus
(GDM). While this topic comprised much of the literature over
the past year, we chose to address this topic by citing the
National Institutes of Health (NIH) consensus article on the
matter. Studies were reviewed systematically and evaluated
for sample size, implications on diabetes care, and the validity
of their findings.
Gestational diabetes, pre-pregnancy obesity
and pregnancy weight gain in relation to excess
fetal growth: variations by race/ethnicity
Bowers K 1,2, Laughon SK 1, Kiely M 1, Brite J 3, Chen Z 4,
Zhang C 1
Methods
A retrospective observational study was formed from a
cohort of 228,562 births between 2002 and 2008 across 19
hospitals spread throughout the United States. Ethnicities and
races observed included non-Hispanic white, non-Hispanic
black, Hispanic, and Asian/Pacific Islander. Data were abstracted from electronic medical records. Exclusion criteria
included multiple gestation pregnancies, and limited available data on relevant statistics such as GDM, prepregnancy
body–mass index (BMI), and birth weight. The final cohort
consisted of 105,985 pregnancies. High pregnancy weight
gain was defined as that which was greater than the median
weight gain observed in the cohort. Each of three factors
(prepregnancy adiposity, weight gain during the pregnancy,
and GDM) were evaluated independently for association with
large-for-gestational-age (LGA) and macrosomic infants.
Each was then weighed together in order to observe the joint
effects between the presence of one, two, or all three factors.
Results
1
Epidemiology Branch and 4Biostatistics Branch, Division of Epidemiology, Statistics, and Preventive Research, Eunice Kennedy
Shriver National Institute of Child Health and Human Development, Rockville, MD; 2Present address: Division of Biostatistics
and Epidemiology, Cincinnati Children’s Hospital Medical Center,
Cincinnati, OH; and 3CUNY Institute of Demographic Research
and CUNY School of Public Health at Hunter College City University of New York, New York, NY
All three factors were found to be independently associated
with an increased risk for LGA births. This was true for all
races with the exception of non-Hispanic white women, who
did not observe an increase in LGA births from GDM alone.
10,689 neonates were LGA, and 8,682 were macrosomic. In
general, LGA and macrosomic infants were more likely to be
born to women with GDM, as well as those who had a previous macrosomic infant. Birth weight was linearly associated
with prepregnancy BMI, with the highest proportion of LGA
1
Helen Schneider Hospital for Women, Rabin Medical Center, Petah Tikva, Israel.
*These two authors contributed equally to this work.
2
S-68
TECHNOLOGY AND PREGNANCY
S-69
and macrosomic infants born to mothers with a prepregnancy
BMI over 30 kg/m2. Asian and Pacific Islander (PI) women had
the highest percentage of LGA infants and GDM, while white
non-Hispanic women had the lowest. Asian and PI women
were also less likely to be overweight or obese before the
pregnancy. A significant interaction was observed between
race, BMI, and GDM incidence. With the exception of nonHispanic white women with GDM, the presence of any of the
observed factors was significantly associated with LGA infants.
The presence of two factors increased the risk further across all
races. The presence of all three did not increase the risk by a
significant amount further in Asian women, while they nearly
doubled the risk for Hispanic and non-Hispanic white women
compared with being exposed to only two factors.
Faculty of Medicine; 2Department of Laboratory Medicine and
Pathobiology, Faculty of Medicine; 4Department of Medicine; and
6
Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada; Departments of 3Pathology and Laboratory
Medicine and 5Medicine, Mount Sinai Hospital, New York, NY;
and 7Department of Medicine, Women’s College Research Institute, Women’s College Hospital, Toronto, Ontario, Canada
Conclusions
1
GDM, prepregnancy adiposity, and pregnancy weight gain
were each associated with an increased birth weight, while
combinations of these factors increased the risk for LGA and
macrosomia even further. The degree to which these combinations of factors affected the risk for LGA and macrosomic
births depended on race. This may be a genetic difference or
due to physiological differences in fat storage or glucose
metabolism between races. Due to differences in body size
between races and genders, it is not appropriate in a clinical
setting to identify a general cut-off weight for LGA and
macrosomia. Race must also be considered due to these differences in genetics and physiology. GDM was greatly associated with an increased risk of an LGA or macrosomic birth,
including those who were underweight and of normal
weight. This increase in risk varied by race, prepregnancy
BMI, and pregnancy weight gain, with an increased joint effect that varied by race. A woman’s race should be considered
when evaluating the prevention strategy for excess fetal
growth in a pregnancy complicated by GDM.
Comment
This study had an impressively large and varied sample
size from throughout the United States, granting their
result’s generalizability. One limitation addressed in the
article is the combination of Asian and Pacific Islander
races. These were factored in together because of the organization of the Consortium of Safe Labor database,
which provided the patient data for the study. Differences in risk for LGA and macrosomia have been noted
between Asian and Pacific Islander women, and this may
have affected the findings relating to this group. However, the study makes a strong case for a further consideration of race among women with GDM. The
observation of a synergistic effect of the three additional
factors evaluated by the study allows for a more aggressive treatment plan for women presenting with the
relevant risk factors for their race and should be considered in future GDM care.
Association between serum 25-hydroxyvitamin D in
early pregnancy and risk of gestational diabetes mellitus
Parlea L1, Bromberg IL 2,3, Feig DS 3–5, Vieth R 2,3,6,
Merman E 1, Lipscombe LL 4,7
1
Diabet. Med. 2012; 29: e25–e32
Vitamin D deficiency in pregnancy and gestational
diabetes mellitus
Burris HH 1,2, Rifas-Shiman SL 7, Kleinman K 7, Litonjua AA 4,5,
Huh SY 3, Rich-Edwards JW 6,8, Camargo CA Jr.4,10,
Gillman MW 7,9
Department of Neonatology, Beth Israel Deaconess Medical
Center, Boston, MA; Divisions of 2Newborn Medicine and 3Gastroenterology and Nutrition, Department of Pediatrics, Children’s
Hospital Boston, Boston, MA; 4Channing Laboratory, 5Division of
Pulmonary and Critical Care, and 6Division of Women’s Health,
Department of Medicine, Brigham & Women’s Hospital, Boston,
MA; 7Obesity Prevention Program, Department of Population
Medicine, Harvard Medical School, and Harvard Pilgrim Health
Care Institute, Boston, MA; Departments of 8Epidemiology and
9
Nutrition, Harvard School of Public Health, Boston, MA; and
10
Department of Emergency Medicine, Massachusetts General
Hospital, Harvard Medical School, Boston, MA
Am J Obstet Gynecol 2012; 207: 182.e1–8.
Objective
Both of the above studies aimed to evaluate whether or
not low levels of 25-hydroxyvitamin D in pregnancy were
associated with an increased risk of developing GDM. The
Parlea study measured vitamin D levels in the first trimester
between weeks 15 and 18, while the Burris study tested for
vitamin D levels during the second trimester between weeks
26 and 28.
Methods
The Parlea study was a nested case–control study that
gathered data from March 1, 2008, to December 31, 2009, and
116 cases of women with GDM were compared with 219
control subjects. 25-Hydroxyvitamin D levels were obtained
from antenatal blood samples. The Burris study was a prospective cohort of 1,314 women enrolled into the study before
the 22nd week of their pregnancy. 25-Hydroxyvitamin D
levels were measured during a GDM screening involving a 1hour 50 g glucose challenge test.
Results
In the Parlea study, GDM patients had significantly lower
25-hydroxyvitamin D levels in the first trimester than control subjects. Vitamin D levels below the top quartile
( < 73.5 nmol/L) were associated with a doubled likelihood of
developing GDM. During the Burris study, patients with a
vitamin D level below 25 nmol/L were associated with an
increased risk for GDM. Both studies resulted in an odds ratio
of 2.2 for increased risk of GDM when 25-hydroxyvitamin D
levels were low.
S-70
Conclusions
Both studies arrived at the conclusion that low 25hydroxyvitamin D levels resulted in a significantly increased
risk for GDM. While they tested for vitamin D levels at different points in the pregnancy, the association with GDM was
the same. As vitamin D may affect glucose tolerance, future
treatment of GDM patients should monitor vitamin D levels
in order to better care for pregnant patients.
Comment
The Burris study had a large sample size, adding to the
validity of its results. While the Parlea study was smaller
by almost 10-fold, both analyses came to the same conclusions. As vitamin D levels appear to have a significant
impact on the incidence of GDM, it may be worthwhile
for providers to consider the findings of these studies for
future care of pregnant patients already at risk for developing GDM.
National institutes of health consensus development
conference statement: diagnosing gestational
diabetes mellitus, March 4–6, 2013
Consensus Development Panel: VanDorsten1 et al.
1
Division of Maternal–Fetal Medicine, Medical University
of South Carolina, Charleston, SC
Obstet Gynecol 2013; 122: 358–69
Objective
At the present, the standard screening for GDM recommended by the American College of Obstetricians and
Gynecologists involves first performing a glucose challenge test
in which serum glucose is measured 1 hour after a woman
drinks a 50 g glucose solution. If these results are abnormal, an
oral glucose tolerance test (OGTT) is then performed. The
OGTT requires that a woman’s blood is drawn four times over
3 hours as she drinks a 100 g glucose solution. The International
Association of the Diabetes and Pregnancy Study Groups
(IADPSG) has proposed a one-step approach for GDM diagnosis involving a 2-hour OGTT with three blood sugar measurements: one fasting blood glucose, and one at the 1-hour and
2-hour marks. If any of the three are abnormal, GDM is diagnosed. This proposed method is estimated to at least double the
number of GDM diagnoses in the United States. The purpose of
this statement is to determine if, at this point in time, the NIH
can recommend that the United States begin to adopt the onestep approach to diagnosing GDM.
Methods
The Eunice Kennedy Shriver National Institute of Child
Health and Human Development, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of
Nursing Research, Office of Research on Women’s Health,
Centers for Disease Control and Prevention, and the NIH
Office of Disease Prevention convened to review the available
scientific evidence in order to assess the official stance on
GDM diagnoses. The panel included experts in many fields
including, but not limited to, maternal and fetal medicine,
COTARELO ET AL.
healthcare economics, and obstetrics and gynecology. A
planning committee developed seven questions to be addressed by the Consensus Development Panel.
Considerations
The panel evaluated current screening and diagnostic
methods for GDM, the thresholds for these approaches, and
how these thresholds were chosen. The impact of a one-step
diagnostic tool for GDM on the U.S. healthcare system, as well
as the health outcomes of undiagnosed women and their
children, were assessed. Finally, the panel considered which
diagnostic approach for GDM should be recommended, as
well as any research gaps in the approach to GDM diagnosis.
Conclusions
The one-step approach offers some advantages over the
current method, primarily used in the United States alone.
There is value in adopting the international standard for GDM
diagnosis in terms of both future research and outcome
comparison between nations. Additionally, it would allow the
diagnosis of GDM to be completed in one visit rather than
two. There are concerns involving the large increase in the
number of GDM diagnoses if the one-step method were implemented. There is also a lack of research to determine
whether these additional GDM women would gain benefit
from the treatment, and if it is worth the additional cost toward healthcare. The panel does not believe that there is
sufficient evidence to adopt the one-step approach recommended by the IADPSG. Additional research is needed
before the one-step approach can be recommended.
Comment
While the panel considered many effects that the conversion to the one-step approach will have on the United
States, we feel that the one-step approach is entirely appropriate and should be adopted in the United States.
While the one-step would increase the number of GDM
diagnoses, and the associated costs involved with diagnosis
and treatment, the United States is among the few that are
not yet on board with this diagnostic method, calling into
question the conclusion that further research is necessary.
Maternal smoking during pregnancy and daughters’
risk of gestational diabetes and obesity
Mattsson K1, Källén K 1, Longnecker MP 2, Rignell-Hydbom A 1,
Rylander L 1
1
Division of Occupational and Environmental Medicine, Institute
of Laboratory Medicine, Lund University, Lund, Sweden; and
2
Epidemiology Branch, National Institute of Environmental Health
Sciences, NIH, DHHS, Research Triangle Park, NC
Objective
This study aimed to examine the risk of developing GDM
after being exposed to tobacco smoke in utero. Patients were
also assessed for an increased risk of obesity or type 1 or type 2
diabetes mellitus.
Methods
Data from 80,189 pregnancies were collected from the Medical Birth Register of Sweden. In utero tobacco exposure was
classified as nonsmoker, moderate exposure (1–9 cigarettes/
day), and heavy exposure (10 cigarettes/day or more). Maternal
smoking habits during the pregnancy were obtained via selfreport by trained midwives during their first antenatal visit.
Data were collected for pregnancies that occurred from 1982 to
2010. These mothers were flagged as generation 1 (G1), and
their children as generation 2 (G2). G2 women were observed
for outcomes of GDM, nongestational diabetes, and obesity.
Results
The adjusted odds ratio for gestational diabetes and obesity
was increased in those women who had been exposed both
moderately and severely to in utero tobacco smoke. Women
exposed to heavy tobacco smoke had a decreased adjusted
odds ratio for nongestational diabetes. Obesity appeared to
have a dose–response association with in utero tobacco exposure, with heavily exposed women having an increased
risk over moderately exposed women.
Conclusions
Women who were exposed to tobacco smoke in utero are at
a higher risk for developing gestational diabetes and obesity
later in life. A decreased risk of nongestational diabetes was
observed for women exposed heavily to tobacco in utero. This
association remained even after adjusting for age, parity, BMI,
gestational age, mode of delivery, birth weight, and age of the
mother. While the majority of nongestational diabetes cases
observed in the study were type 1, this is similar to the
prevalence of type 1 diabetes throughout Sweden.
Comment
Few studies are available on the effects of in utero tobacco
exposure later in life. The information on smoking was
obtained via self-report, which could contain a large
source of error. People may not report honestly, particularly on a subject that may be taboo such as smoking
habits during a pregnancy. The Sweden Medical Birth
Register (MBR) has very high levels of completion to its
data; however, the MBR does not record what week of
gestation the first antenatal visit occurs. Therefore, it is
not possible to tell if the meeting influenced smoking
status for later parts of the pregnancy. The study concludes that heavy smoking during pregnancy decreases
type 1 and type 2 diabetes later in life, while at the same
time increasing the risk for obesity.
S-71
Center for Diabetes in Pregnancy, St. Joseph’s Hospital, Berlin,
Germany
J Clin Endocrinol Metab: DOI: 10.1210/jc.2013-1614
Objective
Angiopoietin-like protein 4 (ANGPTL4) is an inhibitor of lipoprotein lipase (LPL) activity. Past studies have suggested that
changes in LPL activity affect the transfer of fatty acids to the
fetus and affect growth. This study aimed to evaluate the impact on neonatal fat mass (FM) by concentrations of ANGPTL4
and triacylglycerols (TAG) in maternal blood samples and
umbilical cord blood of pregnant women with GDM.
Methods
Fasting maternal blood samples were drawn during pregnancy no longer than 1 week before delivery, and umbilical
cord blood was taken after the vaginal delivery during 80
pregnancies complicated by GDM and 90 controls without
GDM. All neonates were grouped based on FM for the 25th
percentile or lower, 25th to 75th percentile, or 75th to 100th
percentiles. Controls matched for age and pregestational BMI.
Results
The highest concentrations of TAG and nonesterified fatty
acids (NEFA) were found in the maternal blood samples
of women with GDM whose infants were born with the
highest FM. These women also showed the lowest levels of
ANGPTL4. Lower levels of ANGPTL4 were observed in both
GDM cases and controls among infants born with the highest
FM. Glucose and insulin concentrations were independent
of any change to FM. Umbilical cord blood of infants born
with the highest FM of women with GDM had higher concentrations of insulin and lower TAG levels than those with
lower FM. There was no appreciable difference in NEFA or
ANGPTL4 levels between GDM cases and controls.
Conclusions
Low levels of ANGPTL4 were associated with an increased
placental transfer of lipids. This observation was found in both
control cases and women with well-controlled GDM. Higher
neonatal FM and TAG levels, along with a decreased ANGPTL4,
were observed in pregnancies with well-controlled GDM. Increased maternal TAG was associated with a decreased TAG
level in the umbilical cord blood. An increased transfer of lipids
across the placenta would contribute to higher fetal FM. GDM
pregnancies tended to have higher levels of insulin, and the
effect of LPL may have been impacted by the hyperinsulinemia.
Comment
Decreased concentrations of the lipoprotein lipase
inhibitor angiopoietin-like protein 4 and increased
serum triacylglycerol are associated with increased
neonatal fat mass in pregnant women
with gestational diabetes mellitus
Ortega-Senovilla H 1, Schaefer-Graf U 2, Meitzner K 2,
Abou-Dakn M 2, Herrera E 1
1
Faculties of Pharmacy and Medicine, University CEU San Pablo,
Madrid, Spain; and 2Department of Obstetrics and Gynecology,
Because of the apparent effect of ANGPTL4 levels on
neonatal birth weight, it may be worth considering this
laboratory value in a clinical setting when assessing
GDM patients. However, it is important to consider the
relatively small sample size of this study. There may have
been a trend simply among the group of patients, as all
cases came from the same institution. Despite the sample
size, the findings of the study appear valid and should be
considered in future clinical care of GDM patients.
S-72
1,5-Anhydroglucitol as a marker of maternal glycaemic
control and predictor of neonatal birthweight
in pregnancies complicated by type 1 diabetes mellitus
COTARELO ET AL.
model for predicting macrosomia resulted from a combined
analysis of both the HbA1c and 1,5-AG levels.
Nowak N 1, Skupien J 1,2, Cyganek K 3, Matejko B 1,
Malecki MT 1,3
Comment
Prevalence of macrosomia may be because of the HbA1c
target itself (6.0%) being too high and not attributed to
the HbA1c readings themselves. 1,5-AG appears to be a
valid, useful marker of recent hyperglycemic levels.
However, point-of-care HbA1c is more practical in a
primary care setting as it can be measured more immediately. Additionally, if 1,5-AG is not associated with
hypoglycemia, it may be dangerous to observe this value
alone. In the future it may be valid to consider both
HbA1c and 1,5-AG levels in the second and third trimesters in order to predict macrosomia in the babies of
type 1 diabetic women.
1
Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland; 2Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston, MA; and 3Department of
Metabolic Diseases, University Hospital, Krakow, Poland
Objective
Despite reaching HbA1c goals, women with diabetes are
still faced with an increased risk of macrosomic infants. This
study aimed to measure the use of 1,5-anhydroglucitol (1,5AG) in monitoring glycemic control in pregnant women
compared with the standard observation of HbA1c levels.
Methods
Eighty-two pregnant type 1 diabetic women were observed over the course of 4 years. Every trimester, their 1,5AG as well as HbA1c levels were monitored, and 58 of these
women also had continuous glucose monitoring system
(CGMS) data that were analyzed over a 7-day period before
1,5-AG and HbA1c values were collected. CGMS data and
birth weight were then analyzed against 1,5-AG and HbA1c
levels using linear and logistic regression models, and receiver operating characteristic (ROC) analysis was used to
model the association between third-trimester 1,5-AG levels
and macrosomia. Macrosomia was defined as a birth weight
over the 90th percentile.
Results
Throughout the trial, the women met HbA1c targets and
maintained good glycemic control. HbA1c levels were not
correlated with 1,5-AG levels; however, 1,5-AG levels were
strongly correlated with CGMS mean glucose levels. 1,5-AG
levels correlated with hyperglycemia, but not with hypoglycemia. About 80% of macro soma cases occurred in
women with HbA1c levels < 6.0%. However, the average
1,5-AG levels in the second and third trimester were significantly lower in women with macrosomic infants, with
third-trimester 1,5-AG levels as the stronger indicator of
macrosomia. In the ROC analysis, the area under the curve
resulted in a significantly better model for predicting birth
weight when HbA1c and 1,5-AG levels were considered in
tandem.
Conclusions
This study indicates that 1,5-AG is a more valuable marker
than HbA1c for observing episodes of hyperglycemia in
pregnant women with type 1 diabetes. These values were
strongly correlated to the CGMS data and were a stronger
predictor of macrosomia than HbA1c alone. Because 1,5-AG
levels change rapidly with glucose levels, they may improve
treatment and dosage modifications in pregnant type 1 diabetic patients. Third-trimester 1,5-AG levels were strongly
associated with infant birth weights, and an even stronger
A randomized trial comparing perinatal outcomes
using insulin detemir or neutral protamine Hagedorn
in type 1 diabetes
Hod M 1, Mathiesen ER 2–4, Jovanovic L 5, McCance DR 6,
Ivanisevic M 7, Durán-Garcia S 8, Brøndsted L 9, Nazeri A 9,
Damm P 2,4,10
1
Helen Schneider Women’s Hospital, Rabin Medical Center,
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;
2
Center for Pregnant Women with Diabetes, Rigshospitalet, 3Department of Endocrinology, and 4Faculty of Health Sciences,
University of Copenhagen, Copenhagen, Denmark; 5Sansum Diabetes Research Institute, Santa Barbara, CA; 6Metabolic Unit,
Royal Victoria Hospital, Belfast, United Kingdom; 7Department of
Obstetrics and Gynecology, University Hospital of Zagreb, Zagreb, Croatia; 8Catedra de Endocrinologia, Unidad de Diabetes y
Embarazo, Hospital Universitario de Valme, Seville, Spain; 9Novo
Nordisk A/S, Søborg, Denmark; and 10Department of Obstetrics,
Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
J Matern Fetal Neonatal Med 2013 June 5: [Epub ahead of print]
Maternal efficacy and safety outcomes in a randomized,
controlled trial comparing insulin detemir with NPH
insulin in 310 pregnant women with type 1 diabetes
Mathiesen ER 1–3, Hod M 4, Ivanisevic M 5, Duran Garcia S 6,
Brøndsted L 7, Jovanovic L 8, Damm P 1,3,9, McCance DR 10;
on behalf of the Detemir in Pregnancy Study Group
1
Center for Pregnant Women with Diabetes, Rigshospitalet, 2Department of Endocrinology, and 3Faculty of Health Sciences,
University of Copenhagen, Copenhagen, Denmark; 4Helen
Schneider Women’s Hospital, Rabin Medical Centre, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 5Department of Obstetrics and Gynecology, University Hospital of
Zagreb, Zagreb, Croatia; 6Catedra de Endocrinologia, Unidad de
Diabetes y Embarazo, Hospital Universitario de Valme, Seville,
Spain; 7Novo Nordisk A/S, Søborg, Denmark; 8Sansum Diabetes
Research Institute, Santa Barbara, CA; 9Department of Obstetrics,
Rigshospitalet, University of Copenhagen, Copenhagen, Denmark;
and 10Metabolic Unit, Royal Victoria Hospital, Belfast, United
Kingdom
Diabetes Care 2012; 35: 2012–17
S-73
Objective
Comment
In nonpregnant diabetic patients, short- and long-acting insulin analogs have been shown to be more effective than human
insulins at facilitating healthy glycemic control; however, few
studies have tested the use of long-acting insulin analogs in
pregnant women with type 1 diabetes. This is the first clinical
trial to compare the safety and efficacy of the basal insulin analog, detemir (IDet), with human neutral protamine Hagedorn
(NPH), both in combination with rapid-acting insulin aspart
(IAsp), in pregnant women with type 1 diabetes. The publication by Hod et al. reports the perinatal and obstetric outcomes,
while a separate article by Mathiesen et al. reports the maternal
outcomes of the pregnant women in the same trial.
IDet features an advantage over NPH in its convenience
of administration; IDet has a mean lifetime of 12 hours
within the patient and can be injected twice daily, while
NPH has a mean lifetime of 8 hours and must be taken
three times to account for a 24-hour period. We note,
however, that in this trial, basal insulin was administered
once or twice daily across both treatment arms. This
method would favor optimal FPG levels in the IDet
group because of inadequate insulin dosing in the NPH
group. Further studies may confirm whether IDet truly
facilitates lower FPG levels in comparison to NPH insulin
that is administered three times daily.
Methods
This was a randomized, controlled noninferiority trial involving 310 women with type 1 diabetes conducted at 79 sites
in 17 countries. The women were either randomized to IDet
(49.0%) or to NPH (51.0%). The primary endpoint analyzed
was HbA1c at 36 gestational weeks as an indicator of glycemic
control. Perinatal outcomes across the two treatment arms,
reported in Hod et al., were analyzed in terms of three main
categories: fetal death, termination of pregnancy, and live
birth. The composite pregnancy outcome was defined as the
incidence of at least one of the following secondary outcomes:
small/large (< 10th or > 90th percentile) for gestational age,
early fetal death, perinatal or neonatal mortality, congenital
malformations, and/or preterm delivery. Maternal efficacy
endpoints, as described in Mathiesen et al., included HbA1c
values at 8–12, 14, and 24 gestational weeks, fasting plasma
glucose (FPG) levels, number of hypoglycemic episodes, insulin dose, and weight gain during pregnancy.
Results
The primary endpoint, estimated mean HbA1c at 36 gestational weeks, did not statistically differ across the IDet and
NPH treatment arms. The composite pregnancy outcomes
detailed in Hod et al. were comparable between the two
groups. Gestational age at delivery was significantly greater
for the offspring of women treated with IDet compared with
those of women treated with NPH. No other statistically
significant differences in perinatal outcomes were found between the two treatment groups. As described in Mathiesen
et al., estimated mean FPG levels were significantly lower in
IDet patients compared with NPH patients at both 24 and 36
gestational weeks. No statistically significant differences were
observed with regard to weight gain, insulin dose, or number
of hypoglycemic episodes between the two groups.
Conclusions
This study demonstrates that the use of IDet during pregnancy is safe and effective with respect to both maternal and
perinatal/obstetric outcomes, and is noninferior to NPH for
glycemic control in type 1 diabetic mothers. Additionally,
maternal FPG levels are significantly lower in IDet-treated
subjects compared with NPH-treated subjects, without an
accompanying increase in the number of hypoglycemic episodes. A larger sample size is required to analyze the occurrence of uncommon perinatal outcomes with statistical
significance.
Insulin resistance and impaired pancreatic
beta-cell function in adult offspring of women
with diabetes in pregnancy
Kelstrup L 1,2,4, Damm P 1,2,5, Mathiesen ER 1,3,5, Hansen T 6,7,
Vaag AA 3,5,8, Pedersen O 5,6,9, Clausen TD 1,2,10
1
Center for Pregnant Women with Diabetes, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Departments of
2
Obstetrics and 3Endocrinology, University of Copenhagen, Copenhagen, Denmark; 4Danish PhD School of Molecular Metabolism, Odense C, Denmark; 5Faculty of Health Science, University
of Copenhagen, Denmark; 6Novo Nordisk Foundation Center for
Basic Metabolic Research, Metabolics Genetics, Faculty of Health
Science, University of Copenhagen, Denmark; 7Faculty of Health
Sciences, University of Southern Denmark, Denmark; 8Diabetes
and Metabolism, Department of Endocrinology, Rigshospitalet,
Copenhagen, Denmark; 9Faculty of Health Sciences, University of
Aarhus, Aarhus, Denmark; and 10Department of Obstetrics and
Gynecology, Hilleroed Hospital, University of Copenhagen, Hilleroed, Denmark
J Clin Endocrinol Metab 2013; 98: 3793–801
Objective
It is known that maternal hyperglycemia during pregnancy puts offspring at greater risk for metabolic diseases
later in life. The purpose of this study was to examine the
effects of either GDM or type 1 diabetes in pregnant Caucasian women on insulin sensitivity and/or insulin release
in their adult offspring.
Methods
In this prospective cohort study, 597 individuals born
between 1978 and 1985 were followed up between the ages
of 18 and 25 and assessed for insulin sensitivity, absolute
insulin release, and disposition index (a measure of insulin
release that factors into a hyperbolic relationship with insulin sensitivity). Exposed adult offspring were organized
into 2 groups based on their mode of exposure to intrauterine hyperglycemia: offspring of women with GDM
during pregnancy and offspring of women with type 1 diabetes. Also included were 2 reference groups unexposed to
intrauterine hyperglycemia: the offspring of non-GDM women at high risk for developing GDM, and the offspring of
women of the background population, at low risk for developing GDM.
S-74
Results
Offspring of women with GDM during pregnancy
(O-GDM), of women with type 1 diabetes during pregnancy
(O-Type1), and of nondiabetic women at higher risk for developing GDM (O-NoGDM) all had significantly reduced
insulin sensitivities compared with the offspring of women at
low risk for developing GDM (O-BP). Similar trends were
observed regarding reduced disposition index in the O-GDM,
O-Type1, and O-NoGDM groups in comparison to the O-BP
group, although there were no significant differences in absolute insulin response between the four groups.
Conclusions
The adult offspring of women with either type 1 or gestational diabetes present with lower insulin sensitivity and
lower insulin response than their counterparts with no maternal risk factors. Impaired insulin action and secretion puts
such offspring at greater risk for developing type 2 diabetes,
although further studies are needed in order to evaluate the
overall risk when compounded with other factors.
Comment
While intrauterine hyperglycemia appears to put offspring at risk for developing impaired insulin action and
secretion levels, it is also noteworthy that the O-NoGDM
subjects, whose mothers were not diabetic but were at
risk for developing GDM, demonstrated insulin sensitivity and insulin response levels similar to their counterparts in the two exposed groups. These results suggest
that genetic predisposition may play as significant a role
as exposure to intrauterine hyperglycemia in promoting
insulin resistance and impaired pancreatic b-cell function. Nonetheless, the authors note that the mothers of
the O-NoGDM subjects demonstrated slightly higher
glucose levels than the mothers of the O-BP subjects, so
intrauterine hyperglycemia cannot yet be discounted as a
risk factor until further studies are conducted. Pregnant
women with GDM are encouraged to continue maintaining healthy glycemic control to prevent metabolic
diseases and other health problems in their offspring later
in life.
Comparison of insulin lispro protamine suspension
with NPH insulin in pregnant women with type 2
and gestational diabetes mellitus: maternal
and perinatal outcomes
Colatrella A 1, Visalli N 2, Abbruzzese S 2, Leotta S 2,
Bongiovanni M 1, Napoli A 1
1
Department of Clinical and Molecular Medicine, S. Andrea
Hospital, Faculty of Medicine and Psychology, Sapienza University, Rome, Italy; and 2Unit of Dietology, Diabetology and
Metabolic Diseases, Sandro Pertini Hospital, Rome, Italy
Int J Endocrinol 2013; 2013: Article ID 151975, 8 pages
COTARELO ET AL.
basal insulin for pregnant diabetic women. Insulin lispro
protamine suspension (ILPS), an intermediate-acting basal
insulin analog, shows promise as a valuable option for glycemic control; however, no studies regarding its use during
pregnancy were performed prior to this study. This study
aimed to demonstrate the efficacy of ILPS in facilitating positive maternal and perinatal outcomes in pregnant women
with type 2 and gestational diabetes.
Methods
This study was a retrospective cohort study of 89 pregnant
women with type 2 or GDM recruited from January 2008 to
August 2010 in two hospitals in Rome. In addition to medical
nutrition therapy and short-acting insulin analogs, subjects
were treated with either ILPS (60%) or NPH (40%) as basal
insulins. Outcomes measured included glycemic control, insulin dose, hypoglycemic episodes, hypertension, and mode
of delivery.
Results
Maternal outcomes, such as glycemic control, rates of hypertension, and number of hypoglycemic episodes, were
comparable between the ILPS and NPH treatment groups.
Differences were observed in the ponderal indices of newborns, as subjects from the NPH treatment group gave birth to
3 newborns with a ponderal index of > 2.85%, compared with
zero subjects in the ILPS treatment group. Additionally, while
subjects in both groups used similar doses of intermediateacting insulin, ILPS-treated women required smaller total
dosages of insulin than their NPH-treated counterparts.
Conclusions
The use of either ILPS or NPH intermediate-acting insulin
in pregnant women with type 2 or gestational diabetes leads
to comparable maternal and pregnancy outcomes, with the
exception of a greater prevalence of high-ponderal-index
infants and greater total insulin dosages for NPH-treated
women. The use of either insulin during pregnancy seems
safe.
Comment
This study demonstrates that the efficacy of ILPS is
comparable to that of NPH. According to pharmacokinetic and glucodynamics studies, ILPS may also feature a
longer duration of action than NPH, similar to detemir
and glargine, reducing the total insulin dosage requirement. Because insulin analogs can potentially interact
with IGF-1 or insulin receptors in different ways from
human insulin, it is noteworthy that ILPS presents a
possible advantage over NPH in preventing LGA infants;
however, larger studies are needed to confirm these effects.
Objective
The effect of maternal obesity on pregnancy outcomes
of women with gestational diabetes controlled with diet
only, glyburide, or insulin
While rapid-acting insulin analogs such as lispro and aspart are now widely used, human NPH remains the primary
Joy S1, Roman A 2, Istwan N 3, Rhea D 3, Desch C 3,
Stanziano G 3, Saltzman D 2
S-75
1
Carolinas Medical Center, Charlotte, NC; 2Maternal Fetal Medicine Associates, PLLC, New York, NY; and 3Alere Health, Women’s and Children’s Health, Department of Clinical Research,
Atlanta, GA
meticulously because of the association of lower-risk
cases of GDM with oral hypoglycemic agents, in contrast
to injected insulin treatments. In summary, glyburide is
not recommended for use in women with GDM until
definitive results are collected regarding its safety and
efficacy during pregnancy, particularly concerning potential transplacental transfer. It is also critical that all
women found to have GDM strive to maintain healthy
glycemic control and body weight in order to achieve
optimal pregnancy outcomes.
Am J Perinatol 2012; 29: 643–48
Objective
The purpose of this study was to examine the effects of
maternal obesity in women with GDM on pregnancy and
neonatal outcomes. Additionally, the authors compared the
effectiveness of diet-only, glyburide, and insulin treatments in
controlling GDM across obese and nonobese populations.
Methods
In this retrospective cohort study, the data of 7,020 women
with GDM during singleton pregnancies were collected and
analyzed for maternal characteristics and pregnancy outcomes. The outcomes for obese versus nonobese women were
evaluated across three treatment groups: diet-only, glyburide,
and insulin. Logistic regression analysis was employed to
compare the efficacy of the three treatment plans independent
of maternal characteristics.
Results
Across all three treatment groups, obese women were
more likely to develop pre-eclampsia, have a cesarean delivery, or give birth to infants with macrosomia. Furthermore, logistic regression results indicate that the newborn
offspring of women treated with glyburide were more than
two times as likely to develop hyperbilirubinemia. Glyburide treatment was also associated with a greater risk of preeclampsia in GDM patients, even after correcting for obesity
and parity.
Conclusions
This study provides evidence to support that obese
mothers with GDM are at a greater risk for adverse maternal
and perinatal outcomes in comparison to their nonobese
counterparts, even when obese mothers achieve safe glycemic levels. In addition, preliminary results suggest that the
use of glyburide during pregnancy is unsafe for both the
mother and the fetus, with heightened risks of pre-eclampsia
and hyperbilirubinemia. Further randomized controlled
studies are needed in order to directly examine the risks
associated with glyburide use for glycemic control during
pregnancy.
Comment
Potential adverse outcomes may be associated with glyburide use, including a greater incidence of fetal macrosomia. Although this study was not designed to compare
the efficacy of glyburide and insulin in GDM patients, the
results regarding elevated risks for pre-eclampsia and
hyperbilirubinemia call for further caution when moving
away from insulin as the primary treatment for gestational diabetes. In addition to the suggested adverse
physiological effects, GDM women receiving glyburide
treatment are less likely to monitor blood glucose levels
The effect of real-time continuous glucose monitoring
in pregnant women with diabetes: a randomized
controlled trial
Secher AL 1–3, Ringholm L 1,2, Andersen HU 4, Damm P 1,3,5,
Mathiesen ER 1–3
1
Center for Pregnant Women with Diabetes, Rigshospitalet, Copenhagen, Denmark; 2Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark; 3Faculty of Health Sciences, University
of Copenhagen, Denmark; 4Steno Diabetes Center, Gentofte,
Denmark; and 5Department of Obstetrics, Rigshospitalet, Copenhagen, Denmark
Diabetes Care 2013; 36: 1877–83
Objective
Pregnant women with type 1 or type 2 diabetes are at
greater risk for maternal hyper- and hypoglycemia and adverse pregnancy outcomes, such as LGA infants. The purpose
of this study was to determine whether intermittent real-time
continuous glucose monitoring (CGM) facilitates superior
glycemic control for women with diabetes in comparison to
the traditional method of self-monitored plasma glucose
(SMPG) several times daily.
Methods
This was a randomized controlled trial involving 123 women with type 1 diabetes and 31 women with type 2 diabetes
from February 2009 to February 2011, all of whom accepted
participation in the study before completing the 14th week of
gestation. While all women in the study received routine
pregnancy care, 79 women (51%) were also randomized to
intermittent use of real-time CGM. Results on HbA1c values
and insulin doses were recorded during five antenatal clinic
visits at 8, 12, 21, 27, and 33 gestational weeks. The primary
outcome of the study was defined as the prevalence of LGA
infants, and the secondary combined endpoint was defined as
the prevalence of preterm delivery and/or severe neonatal
hypoglycemia.
Results
The primary outcome, the prevalence of LGA infants, was
comparable between the two treatment arms ( p = 0.19), as was
the secondary combined outcome, the prevalence of preterm
delivery and/or severe neonatal hypoglycemia ( p = 0.36).
Maternal glycemic control, gauged by HbA1c levels, SMPG
values, and hypoglycemic events, was also similar between
the CGM and control groups.
S-76
Conclusions
No statistically significant differences were observed in
maternal glycemic control or pregnancy outcomes between
subjects using real-time CGMs and control subjects receiving
only routine pregnancy care. According to the results of this
trial, the use of CGMs by pregnant women with pregestational diabetes provides no discernible advantages over
SMPG.
Comment
As real-time CGM technology is significantly costlier
than SMPG, it is gratifying to note that traditional fingersticks can be just as effective as CGMs at facilitating
glycemic control in diabetic pregnant mothers. This
study serves as a reminder that medical nutrition therapy
and lifestyle modification have the greatest impact on
positive pregnancy outcomes. However, it is also noteworthy that very few women in this trial were willing to
use real-time CGM continuously, which may have contributed to the lack of significant differences in outcome.
It will be interesting to see in future studies how real-time
CGMs may benefit patients with higher baseline HbA1c
levels than those included in this trial.
COTARELO ET AL.
insulin dose. Perinatal outcomes, such as rates of neonatal
morbidity and LGA ( > 90th percentile) infants, were also
reported.
Results
Many outcomes, such as HbA1c levels and rates of hyperglycemia, were comparable between the two treatment
arms. However, women treated with detemir were administered larger doses of long-acting insulin at 8 and 33 weeks,
and were also more likely to receive 2 or more daily injections
of long-acting insulin at 8 and 33 weeks. Furthermore, a
greater incidence of LGA infants was observed in the detemir
treatment group ( p = 0.046). Both treatment groups experienced low incidences of congenital malformations, and no
perinatal deaths were reported.
Conclusions
Glycemic control and pregnancy outcomes are comparable
in women treated with the insulin analogs detemir and glargine, with low rates of maternal and perinatal adverse events
in both groups. Larger studies are needed to confirm the
higher prevalence of LGA infants in women treated with
detemir.
Treatment with the long-acting insulin analogues
detemir or glargine during pregnancy in women
with type 1 diabetes: comparison of glycaemic
control and pregnancy outcome
Comment
Some of the different outcomes between the two treatment arms in this study may not be attributed to the
insulin analogs used by the subjects, but rather because of
poor glycemic control; mean HbA1c levels were high in
both groups at 8 and 33 weeks of gestation, ranging from
6.1% to 6.8%. Additionally, the finding that a greater
number of women in the detemir group required two or
more daily injections of long-acting insulin is not surprising, given that detemir features a shorter duration of
action (12 hours) in comparison to glargine (18–30 hours).
Inadequate doses of long-acting insulin and a greater
proportion of gravida 1 mothers ( p = 0.02) may have been
factors leading to a greater incidence of LGA infants in
the detemir treatment arm.
Callesen NF 1,2, Damm J 1,2, Mathiesen JM 1,2, Ringholm L1,2,
Damm P 1,3,4, Mathiesen ER 1–3
1
Center for Pregnant Women with Diabetes, Rigshospitalet,
Copenhagen, Denmark; 2Department of Endocrinology,
Rigshospitalet, Copenhagen, Denmark; 3Faculty of Health
Sciences, University of Copenhagen, Denmark; and
4
Department of Obstetrics, Rigshospitalet, Copenhagen, Denmark
J Matern Fetal Neonatal Med 2013; 26: 588–92
Objective
Long-acting insulin analogs are becoming increasingly
popular for glycemic control in nonpregnant diabetic patients,
as they are associated with a lower incidence of nocturnal
hypoglycemia than human insulins. However, few studies
have been conducted to investigate the use of these analogs in
pregnancies complicated by type 1 diabetes. This is the first
study to compare glycemic control and pregnancy outcomes
in type 1 diabetic women between two such long-acting insulin analogs, detemir and glargine.
Global methylation in the placenta and umbilical
cord blood from pregnancies with maternal
gestational diabetes, preeclampsia, and obesity
Nomura Y1,2, Lambertini L 3,4, Rialdi A 3, Lee M 4,
Mystal EY 1,2, Grabie M 1,2, Manaster I 2, Huynh N 1,2,
Finik J 1,2, Davey M 2, Davey K 2, Ly J 1,2, Stone J 5, Loudon H 5,
Eglinton G 6, Hurd Y 2,7, Newcorn JH 2,8, Chen J 3,8,9
1
Methods
This was a retrospective cohort study conducted at a
single diabetes clinic in Rigshospitalet, Copenhagen, Denmark, from January 2007 to August 2011. Of the 113 women
involved in the study, 67 received insulin detemir and 46
received glargine from conception to delivery. Subjects were
evaluated based on maternal outcomes such as HbA1c levels
at 8 and 33 weeks, SMPG values 7 times daily, number of
hypoglycemic events, number of daily injections, and total
Department of Psychology, Queens College, CUNY, Flushing,
NY; Departments of 2Psychiatry, 3Preventive Medicine, 5Obstetrics, Gynecology, and Reproductive Science, 8Pediatrics, and
9
Oncological Sciences, Mount Sinai School of Medicine, New York,
NY; 4Department of Obstetrics and Gynecology, Indiana University, Indianapolis, IN; 6Department of Obstetrics and Gynecology, Weill Medical College of Cornell University, Flushing,
NY; and 7James J. Peters VA Medical Center, Bronx, NY
Reprod Sci 2013 June 13: [Epub ahead of print]: DOI: 10.1177/
1933719113492206
Objective
Epigenetic modifications to the genome during early development can cause permanent changes in gene expression
and physiological processes. It has also been observed that
nonideal maternal conditions, such as GDM, pre-eclampsia,
and obesity, are risk factors for future diseases in the offspring. The purpose of this study was to investigate the link
between global methylation levels in the placenta and umbilical cord blood, and maternal risk factors such as gestational diabetes, pre-eclampsia, and obesity.
Methods
In a pilot study at a low-income clinic in New York City,
50 women were followed from the second trimester of
pregnancy to delivery. All subjects were screened for GDM,
pre-eclampsia, and obesity during pregnancy. Following
delivery, matched samples of placenta and umbilical cord
blood were collected for DNA/RNA extraction, and global
methylation levels were measured with the Lumino-metric
Methylation Assay. Multivariable analyses with a general
linear model were conducted to examine the associations
between global methylation levels, maternal risk factors, and
neonatal outcomes.
Results
No associations were observed with global methylation
levels in the umbilical cord blood and any of the three maternal risk conditions under study (GDM, pre-eclampsia, and
obesity), or with any of the four neonatal outcomes (birth
weight, gestational age, head circumference, and body
length). However, women with GDM or pre-eclampsia had
lower levels of global methylation in the placenta tissue, and
women with obesity had higher levels of global methylation
in the placenta tissue in comparison to their lower-risk
counterparts. In addition, a suggestive correlation was found
between higher levels of global methylation in the placenta
and reduction in infant body length and head circumference,
although these results did not attain statistical significance.
S-77
and obesity, influence global methylation levels in the placenta, which may in turn cause adverse changes in fetal
growth in the offspring.
Comment
The emerging field of epigenetics provides a biological
mechanism for the propagation of health risk factors
from pregnant women to offspring. It will be exciting to
see the results of future studies that further investigate
the developmental trajectories of these offspring into
childhood and adolescence. However, no definitive
conclusions about global methylation levels in the placenta can be made without larger sample sizes and a
more diverse cohort of subjects with regard to ethnicity,
living environment, and socioeconomic background.
Conclusion
In summary, research on diabetic complications of pregnancy has expanded significantly over the past year. It was
more difficult than ever to narrow down our selection of articles, with over 1,200 relevant publications on the subject.
Hyperglycemia has the potential to lead to a variety of negative outcomes for both the mother and child, and so this
renewed interest in the field will have a tangible impact on
patients affected by diabetes. During pregnancy, many women will be willing to make lifestyle changes for the benefit of
their baby. Providers should strive not only to treat maternal
hyperglycemia, but also to provide health education that will
enable the patient to understand the importance of controlling
the disease. The explosion of varied research is exciting, and
will surely drive future studies to promote a stronger understanding of maternal hyperglycemia, improving the care
and outcomes of pregnancies complicated by diabetes.
Reference
Conclusions
This study presents preliminary evidence that maternal risk
conditions during pregnancy, such as GDM, pre-eclampsia,
1. Diabetes Statistics. Data from the 2011 National Diabetes
Fact Sheet (released Jan. 26, 2011). Available online at www
.diabetes.org/diabetes-basics/diabetes-statistics/
DOI: 10.1089/dia.2014.1509
ORIGINAL ARTICLE
Metabolic Surgery Is No Longer Just Bariatric Surgery
E. Charles Moore and Walter J. Pories
Introduction
B
ariatric surgery was aptly named in 1953, after the
Greek word ‘‘ba’qp2’’ for weight, when Varco first attempted to treat severe obesity with a bypass of the small
intestine. However, since then the focus in this field has expanded far beyond obesity with the recognition that bypassing parts of the gut can also control a far more dangerous set
of diseases that include type 2 diabetes mellitus (T2DM) and
other expressions of the metabolic syndrome.
This year’s articles reflect this maturation of ‘‘bariatric’’
surgery to ‘‘metabolic surgery,’’ because of its broad impact
on the chemical processes occurring within a living cell or
organism necessary for the maintenance of life.
The selected publications address the following current
issues:
If metabolic surgery is the most effective treatment for
T2DM, why should it be limited to patients with a body
mass index (BMI) > 35?
Metabolic surgery produces remission not only of
T2DM but also other manifestations of the metabolic
syndrome such as hypertension and hyperlipidemia.
Should it therefore also be considered as a useful therapy for these diseases?
If the surgery is so effective, why are over 99% of eligible patients denied access?
What is the rate of erosion of the beneficial effects of
metabolic surgery, and what are the factors that affect
long-term outcomes?
The sleeve gastrectomy (SG), an operation rapidly
gaining in popularity because of its less demanding
technical requirements, is also effective in the control of
obesity and diabetes. How does it compare to the gastric
bypass operation, long the gold standard?
The Swedish Obesity Study is the longest ongoing
population study of patients who subjected to metabolic
surgery. What are the latest results?
These are critical questions. T2DM is now the most expensive disease in the United States, with costs of $245 billion in 2012 compared with $174 billion only 5 years earlier.
Not only has the cost of treatment risen, but also the prev-
alence has exploded, with the prevalence of T2DM doubling
in the last 10 years. Today, in the United States, one out of
every four adults over 65 has diabetes. In spite of major
advances in the medical therapies that include diet, exercise,
insulin secretagogues, agents to increase insulin sensitivity,
and newer forms of insulin, these therapies have had limited
success. In spite of increased expenditures on these agents,
diabetes still remains the primary cause of blindness, amputations, and renal failure leading to dialysis. T2DM is also
a major cause of heart attacks and strokes. Pretty frustrating.
Fortunately, surgery appears to be providing more hopeful
answers.
Effects of gastric bypass surgery in patients
with type 2 diabetes and only mild obesity
Cohen RV 1, Pinheiro JC1, Schiavon CA 1, Salles JE 2,
Wajchenberg BL 3, Cummings DE 4
1
The Center of Excellence in Bariatric and Metabolic Surgery,
Oswaldo Cruz Hospital, and Marcia Maria Braido Hospital, São
Paulo, Brazil; 2Department of Endocrinology, Diabetes Division,
Santa Casa Medical School, São Paulo, Brazil; 3Diabetes Unit,
Heart Institute, University of São Paulo, and Diabetes Center,
Oswaldo Cruz Hospital, São Paulo, Brazil; and 4Diabetes and
Obesity Center of Excellence and Veterans Affairs Puget Sound
Health Care System, University of Washington School of Medicine, Seattle, WA
Diabetes Care 2012; 35: 1420–28
Background
To determine the impact of Roux-en-Y gastric bypass
(RYGB) on patients with severe (9.7% – 1.5% HbA1c) and
longstanding (12.5 – 7.4 years) diabetes and low BMIs, 30–
35 kg/m2.
Methods
Sixty-six patients who underwent RYGB with diabetes and
BMI between 30 and 35 kg/m2 were followed for a median
period of 5 years. Primary outcomes were safety and resolution of diabetes (HbA1c < 6.5% without use of medication).
Brody School of Medicine, East Carolina University, Greenville, NC.
S-78
METABOLIC SURGERY IS NO LONGER JUST BARIATRIC SURGERY
Results
Long-term remission occurred in 88% of the patients. Mean
HbA1c fell from 9.7% – 1.5% to 5.9% – 0.1% ( p < 0.001). Weight
loss failed to correlate with diabetes remission, suggesting an
alternative method for diabetes resolution. There was also an
increase in C-peptide, suggesting increased b-cell function. There
were no mortalities or major surgical morbidities in the study.
Conclusion
RYGB is a safe and effective way to induce remission of
diabetes in patients with lower BMIs.
Comment
The setting of the BMI (kg/m2) standard makes for a curious
story. In the early days of bariatric surgery, in spite of increasing evidence that it was the most effective therapy for
severe obesity, we were unable to convince the commercial
carriers to provide coverage for these operations. Finally, in
the NIH Consensus Conference of 1991 (1), we were able to
reach a common standard that made it possible to allow
Medicare to recommend reimbursement for bariatric surgery for patients with a BMI ‡ 40 and for those with a BMI
‡ 35 who also had significant comorbidities such as diabetes
or hypertensions. At the time, this was a great victory.
In the intervening two decades, it became evident that
this was a pyrrhic victory. First, the BMI is not an accurate
measure of adiposity. It fails to account for fitness and
muscularity. For example, at East Carolina University we
studied a man who was 5¢8† and weighed 307 lbs. with a
BMI of 46.7, certainly a candidate for bariatric surgery.
The problem was that we could not catch him. He was the
fastest running back on our football team. The BMI is also
unigender and, accordingly, fails to account for the major
differences in adiposity between men and women. It fails
to account for the increased marbling of muscle in aging.
Most important, however, it discriminates against Asians
and African Americans who are much more likely than
Caucasians to develop diabetes and hypertension at
lower BMIs. Thus, an Asian woman with a BMI of 32
has the same chance of developing the comorbidities of
severe obesity as her white sister with a BMI of 35. In
essence, the rule denies surgery to those who need it most.
Others have previously shown that even a limited
bypass, that is, the duodenojejunal bypass, will produce
full remission of T2DM even in lean individuals. Ramos
et al. of Brazil (2) reported small groups with dramatic
restoration of normal Hb1Ac and fasting glucose levels.
This article by Cohen et al., also from Brazil, provides
scientific basis with a long enough follow-up period to
eliminate the unfortunate BMI ‡ 35/40 standard. We
hope this will convince Medicare and the private carriers
to eliminate this unfair and dangerous standard.
Roux-en-Y gastric bypass vs intensive medical
management for the control of type 2 diabetes,
hypertension, and hyperlipidemia
Ikramuddin S1, Korner J 6, Lee W-J 8, Connett JE 2, Inabnet WB10,
Billington CJ 4, Thomas AJ 2, Leslie DB 1, Chong K 11,
S-79
Jeffery RW 3, Ahmed L 7, Vella A 12, Chuang L-M 9, Bessler M 7,
Sarr MG 13, Swain JM 14, Laqua P 5, Jensen PD 12, Bantle JP 4
1
Department of Surgery; 2Division of Biostatistics; 3Epidemiology
and Community Health; 4Division of Endocrinology and Diabetes,
Department of Medicine, School of Public Health; and 5Berman
Center for Clinical Research, University of Minnesota, Minneapolis,
MN; 6Division of Endocrinology, Department of Medicine, and
7
Department of Surgery, Columbia University Medical Center, New
York, NY; 8Departments of Surgery and 9Division of Metabolism
and Endocrinology, Department of Internal Medicine, National
Taiwan University Hospital, Taipei, Taiwan; 10Department of
Surgery, Mount Sinai Medical Center, New York, NY; 11Department of Endocrinology, Min-Sheng General Hospital, Taoyuan,
Taiwan; 12Division of Endocrinology and Diabetes, Department of
Medicine, and 13Department of Gastroenterologic and General Surgery, Mayo Clinic, Rochester, MN; and 14Scottsdale Healthcare Bariatric Center, Scottsdale, AZ
JAMA 2013; 309: 2240–49
Background
There is a significant lack of randomized clinical trials directly comparing intensive medical management to gastric
bypass surgery (RYGB).
Methods
In an unblinded randomized trial that took place at four
teaching hospitals that directly compared 120 participates
(n = 60 intensive medical therapy and n = 60 RYGB surgery),
the primary end points were to reduce HbA1c < 7.0%, lowdensity lipoprotein cholesterol levels <100 mg/dL, and systolic blood pressure <130 mmHg.
Results
After 12-month follow-up, 49% of the gastric bypass patients and 19% of the medically treated group achieved the set
endpoints. The bypass group required three fewer medications but had more serious adverse events and more nutritional deficiency than the medical group.
Conclusion
Adding RYGB to lifestyle modification is associated with a
greater chance of reducing surrogate end points for cardiovascular disease (HbA1c%, low-density lipoprotein cholesterol levels, and systolic blood pressure [SBP] levels).
Comment
The Look AHEAD trial advocating intensive medical
management and lifestyle modifications in obese type 2
diabetics showed early promise. Participants achieved
significant weight loss, blood pressure reduction, glycemic control, and reduction of cardiovascular risk factors. However, in July 2013, at a median follow-up
analysis of 9.6 years, this study was halted because of
futility (3,4). Controlling diabetes and cardiac risk factors
with intensive lifestyle modifications over the long-term
was not an effective approach.
Conversely, RYGB has proven to be a useful adjunct to
lifestyle modification in the reduction of cardiac risk
S-80
MOORE AND PORIES
Background
factors. In the ATTD 2012 Yearbook, we reviewed two
prospective, randomized clinical trials by Schauer et al.
(9) and Mingrone et al., published in the April 2012 issue
of the New England Journal of Medicine, which documented the marked superiority of surgery over intensive
medical management of T2DM. This article adds more
evidence that the traditional approaches to the treatment
of T2DM need reexamination.
In this study, 49% of the surgery group achieved the
established diabetic and cardiovascular management
goals compared with only 19% of the medical management group. These results show promise and a
useful alternative to intensive medical management.
The short duration of follow-up of only 12 months
raises concern, but these benefits match or exceed the
composite goals of the Look AHEAD trial at the same
period. Detractors state that the problem is not the
dramatic resolution of T2DM associated with RYGB
but the paucity of long-term follow-up, but long-term
studies by our group and that of Sjostrom have
already proven this complaint baseless with long-term
remissions, although there is some erosion of the full
‘‘cure’’ rate over the years.
It is frustrating that, in spite of the mounting evidence,
less than 1% of those who could benefit from metabolic
surgery have access to this therapy. Obesity and T2DM
are two of society’s most economically devastating
diseases (5). According to the Centers for Disease
Control, the prevalence of T2DM has doubled (yes,
doubled) in the last decade. The war against both is
valiantly being waged by family practitioners, endocrinologists, internists, obstetricians, and even pediatricians, but without access to the most effective therapies.
Recent estimates show that close to 32% of American
adults meet the criteria for obesity and 13% of all adults
have diabetes (6). Deaths related to diabetes are projected
to double between 2005 and 2030 (7). These statistics
make it imperative that the physicians dealing with the
twin epidemics have a full armament of treatments.
Despite 20 years of data showing 70–80% remission rates
for patients who undergo RYGB and SG, less than 1% of
patients with BMI > 40 kg/m2 have undergone weight
loss procedures (8). Physician perception of bariatric
surgery, referral patterns, and disparity among thirdparty payers for reimbursement seem to be leading to this
underutilization of surgery for treatment. The real issue is
informing prospective patients about their options to
treat, providing access to meaningful care, and overcoming barriers to that care.
Physicians attitudes about referring their type 2
diabetes patients for bariatric surgery
Sarwer DB 1,2, Ritter S1, Wadden TA 1, Spitzer JC1,
Vetter ML 3, Moore RH 1,4
Departments of 1Psychiatry, 2Surgery, 3Medicine, and 4Biostatistics and Epidemiology, Perelman School of Medicine,
University of Pennsylvania, PA
Surg Obes Relat Dis 2012; 8: 381–86
Evidence is mounting about the benefits of bariatric surgery, but little is known about physicians’ attitudes toward
referring patients of surgery.
Methods
Physicians who were likely to treat T2DM were surveyed
about their perceptions and the efficacy of bariatric surgery.
Results
Respondents had an overall positive view of bariatric surgery as a treatment for obesity and T2DM, but only 20.85%
would refer their patients with BMI 30–34.9 kg/m2 and T2DM
to a randomized research trial.
Conclusion
The sample of physicians in this survey had a favorable response to bariatric surgery for the treatment of obesity and
T2DM. Despite this, there is a relative reluctance to refer patients
with lower BMI (30–34.5 kg/m2) and T2DM for bariatric procedures. This represents a large barrier to studying the effects of
bariatric surgery on patients with lower BMIs and T2DM.
Comment
A central theme in the United States is access to affordable healthcare. Obesity and T2DM produce a major and
growing burden of expense. So far, the medical therapies
including diets, exercise, drugs, behavioral modification,
nationwide publicity campaigns, and the traditional diabetes drugs have shown marginal effectiveness. Accordingly, the increasing documentation that metabolic
surgery produces full, durable, and safe remissions of
severe obesity, diabetes, and other expressions of metabolic syndrome should be welcome news and rapid
adoption. Studies have shown that up to 80% of patients
with T2DM who have undergone RYGB experience
complete remission of the disease (9). In contrast, intense
lifestyle modification and pharmacotherapy have not
shown the same impressive results as surgery.
Even so, a minority of the patients who could benefit
from surgery are actually instructed about the operative
alternatives and/or referred to a surgeon. Although most
physicians have a positive outlook about bariatric
surgery, they still are often not comfortable with referring
patients for surgery.
Sarwer et al. address this reluctance in this cited
publication. Their results are interesting, challenging,
and in accord with the experience of most metabolic
surgeons. Even though physicians have a favorable view
of the operations and, in fact, are generally well informed
about the indications, results, and risk/benefits, most are
reluctant to recommend the surgery to their patients. In
addition, not studied in this article, many surgeons,
including us, frequently encounter resistance by the
patients who are far more afraid of the reality of pending
surgery than the concerns about late-term effects of the
disease. This reluctance is reflected in the plateauing of
metabolic surgery at about 200,000 per year.
Perhaps, with time, this challenge will be resolved as
the public recognizes the physical, medical, and emotional burdens of severe obesity and the tragic consequences of diabetes. A solution cannot come soon
enough.
Understanding the preoperative risk factors that precede these failures will help physicians stratify these
patients into the best possible treatment regiments. It will
also avoid subjecting patients to invasive procedures that
will not derive benefit. This is especially important as we
turn to using surgery as a treatment for T2DM in patients
with lower BMIs (30–35 kg/m2). Multiple studies suggest
that the length of time a person has T2DM is a predictor
of failure. Hall et al. (11) showed that a preoperative
history greater than 10 years was a predictor of remission
failure. In this study, preoperative HbA1c were also
higher (8.3 – 1.2% vs. 7.8 – 1.7%) in the nonresponder
group than in the responder group. These two factors
suggest that the earlier we can intervene in the disease
process, the better the outcome. To date, no conclusions
have been drawn on what type of surgery has the best
remission rates. In the future, developing consensus
criteria for responders and nonresponders is critical in
driving research forward. The ability to predict gastric
bypass results will make it a viable treatment in the fight
against not only obesity but also T2DM.
This article by Jurowich et al. provides an update on the
search for explanations for the variable responses. Their
findings match those of others interested in this question,
that is, that patients with advanced T2DM, of longer
duration, with higher Hb1Ac levels and who were being
treated with a greater number of medications were less
likely to achieve full remission. Others have observed
that there are also racial differences, with African
Americans not responding as well as Caucasians. Age
has also been implicated by some, with older patients
having a lower response rate.
The important implication of these results is that
metabolic surgery should be considered early in the
treatment of the disease before irreversible changes occur
in the islets, liver, and blood vessels. In many ways, the
history of bariatric surgery recapitulates the rise of cardiac
surgery in which the surgery for the first few decades was
limited to the cases with the highest risk. The high failure
rates then, naturally, discouraged referrals. Today, the
cases are referred early with clear improvements in
outcomes. Similar beginnings, guided by the timeless
injunction ‘‘first, do no harm’’ occurred also in thoracic
surgery, hip replacements, and transplantation. In each of
these, the value of early intervention is now clear. It’s time
for metabolic surgery to learn from this history.
Improvement of type 2 diabetes mellitus (T2DM) after
bariatric surgery—who fails in the early postoperative
course?
Jurowich C1, Thalheimer A 1, Hartmann D 1, Bender G 2,
Seyfried F 1, Germer CT 1, Wichelmann C 1
1
Department of General, Visceral, Vascular and Pediatric Surgery,
Centre for Obesity and Metabolic Surgery, University Hospital of
Würzburg, Würzburg, Germany; and 2Department of Endocrinology, Clinic for Internal Medicine, University Hospital of
Würzburg, Würzburg, Germany
Obes Surg 2012; 22: 1521–26
Background
Identification of factors preoperatively for responders and
nonresponders to bariatric surgery in regard to T2DM.
Methods
Eighty-two of 235 patients with T2DM who underwent
bariatric surgery were studied. Univariate and multivariate
analyses were used to identify the predictors for metabolic
response to bariatric surgery.
Results
Diabetes did not improve in 17 of 82 patients. There was no
correlation between excess weight loss and response. Univariate analysis showed that duration of diabetes, higher
preoperative HbA1c levels, and preoperative use of multiple
medications were significant in predicting nonresponse after
surgery. Multivariate analysis revealed that age, preoperative
dose of insulin, and preoperative oral antidiabetics showed
positive correlation to nonresponse. RYGB showed the lowest
failure rate.
Conclusion
The ability to predict responders from nonresponders for
the treatment of T2DM before surgery is imperative to selecting patients that would derive the most benefit from an
invasive procedure.
Comment
When, in 1980, we first noted that gastric bypass produced
full remission of T2DM within a few days after surgery,
we followed this observation with the study of 837 patients for a mean of 16 years with a follow-up of 95% (10).
In that study we documented that full remission was only
seen in 83%, an observation that has been corroborated in
several later series with some variation but always revealing that some patients responded better than others.
S-81
Comparable early changes in gastrointestinal hormones
after sleeve gastrectomy and Roux-en-y gastric bypass
surgery for morbidly obese type 2 diabetic subjects
Romero F 1, Nicolau J 1, Flores L1–3, Casamitjana R1–3,
Ibarzabal A 1, Lacy A 1,3, Vidal J 1–3
1
Obesity Unit, Endocrinology and Diabetes Department, Hospital
Clinic Universitari, Barcelona, Spain; 2Centro de Investigación
Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain; and 3Institut d’Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain
Surg Endosc 2012; 26: 2231–39
S-82
MOORE AND PORIES
Background
believed by some to lead to resolution of glucose
intolerance even before significant weight loss has
occurred (12). After RYGB, studies, including the SOS
study, have shown a positive and durable response up to
20 years after bypass (13). We recently saw one of our
patients, 32 years after her RYGB, still free of the T2DM
with which she presented in 1980! Time will tell whether
SG will yield similar long-term results. Obviously, this
study was limited by population size but provides
significant insight to the mechanism of SG.
These articles also lead us to ask whether surgical
intervention can prevent T2DM. Historically, most studies look at weight loss as a primary end point in bariatric
surgery. Remission rates of diabetes after surgery were
often secondary. Data over the last decade have shown
that gastric bypass can lead to durable remission to
T2DM. Lifestyle modification and medical treatment are
the current standard used to decrease the micro and
macro effect of diabetes. These strategies have met with
mixed results especially in obese populations (BMI
‡ 35 kg/m2) (14). Most randomized medical management
studies show good results in the initial period (< 3 years)
with relapse within 10 years. To our knowledge, there are
no studies that look at gastric surgery for the prevention
of T2DM. This study takes a novel approach to answer
the question: Is gastric bypass a protective strategy
against the development of T2DM? As we enter an era
where prophylactic mastectomy and oophorectomy are
now indicated for BRCA mutations, this is not an idle
question.
The mechanisms for resolution of T2DM in both RYGB and
SG have not fully been elicited. This study compares the early
changes in gastrointestinal hormones in patients undergoing
SG and RYGB.
Methods
Twelve subjects were compared as to levels of glucose, glucagon-like peptide (GLP-1), glucose-dependent insulintropic
polypeptide (GIP), and GLP-2 after a standardized mixed liquid
meal before and 6 weeks after both RYGB and SG.
Results
Six weeks postoperatively, 5 of 6 patients in each group had
remission of their T2DM. The indices for both the RYGB and
SG had similar insulin and glucagon secretion; the GLP-1,
GLP-2, and GIP response increased in both surgical groups.
Conclusion
SG and RYGB are comparable for glucose tolerance and
exhibit similar changes in gastrointestinal hormones.
Comment
The gold standard in metabolic surgery for the last three
decades has been the RYGB. Surprisingly, even before
durable weight loss has occurred, RYGB leads to improved glucose control. The last decade has seen the
emergence of a simpler operation that requires only
partial resection of the stomach and no anastomosis. It
also does not alter the stream of digesting food with bypasses of portions of the foregut.
The SG has now been shown to be a safe alternative to
the RYGB, with comparable T2DM remission rates. These
results provide a critical new clue in the mystery of how
metabolic surgery leads to not only weight loss but also
resolution, in only a matter of days before there is
significant weight loss, that is, reduction in adiposity, of
T2DM, hypertension, dyslipidemias, nonalcoholic steatohepatitis (NASH), gastrointestinal reflux diseases,
polycystic ovary syndrome, and pseudotumor cerebri,
among others.
These observations force us to reconsider the explanation that the ‘‘metabolic factor signals’’ arise in the
duodenum; they question the tenets of the foregut and
hindgut theories and, at the same time, stimulate new
concepts about not only the effects of the surgery but also
a long-needed reexamination of the pathophysiology of
T2DM and the relationships of that entity to the other
diseases in the metabolic syndrome.
This article by Romero et al. documents that both
RYGB and SG are associated with similar increases of
GLP-1, GIP, and GLP-2 in the early periods after surgery,
although other reports dispute these findings, claiming
that the RYGB produces far greater changes in GLP-1.
Both surgeries led to similar paracrine profiles in this
patient population. These increased incretinic effects
from L-cell-derived hormones with their significant
insulintropic actions and glucagonostatic properties are
Bariatric surgery and prevention of type 2 diabetes
in Swedish obese subjects
Carlsson L 1, Peltonen M 1,5, Ahlin S 1, Anveden A 1,
Bouchard C 6, Carlsson B 1, Jacobson P 1, Lonroth H 2,
Maglio C1, Naslund I 4, Pirazzi C 1, Romeo S 1, Sjoholm K 1,
Sjostrom E1, Wedel H 3, Svensson P-A 1, Sjostrom L 1
1
Institutes of Medicine and 2Department of Surgery, Sahlgrenska Academy at the University of Gothenburg, Gothenburg,
Sweden; 3Nordic School of Public Health, Gothenburg, Sweden;
4
Department of Surgery, University Hospital, Örebro, Sweden;
5
Department of Chronic Disease Prevention, National Institute
for Health and Welfare, Helsinki, Finland; and 6Pennington
Biomedical Research Center, Louisiana State University System,
Baton Rouge, LA
N Engl J Med 2012; 367: 695–704
Background
Studies that take into consideration behavior modifications
and medical management to protect against T2DM have been
met with mixed results. This study examined the effects of
bariatric surgery on the prevention of T2DM.
Methods
In total, 1,658 patients were followed prospectively after
one of three types of bariatric surgery (adjustable band 19%,
vertical band gastroplasty 69%, or gastric bypass 12%) and
compared with obese match-controlled nonoperative patients
for the rate of incidence of T2DM. The participants were followed for 15 years.
Results
During the follow-up period, T2DM developed in 392 patients in the nonsurgical group and in only 110 patients in the
gastric bypass group. The incidence rates were 28.4 case per
1,000 person-years for the nonoperative group and only 6.8
cases per 1,000 person-years in the gastric bypass group. The
postoperative mortality was 0.2%, and 90-day re-operative
rate was < 3.0%.
S-83
the breast, colon, prostate, and ovary fall by > 70% within 5
years after the surgery.
These studies highlight some of the important milestones
that have taken place in the evaluation of diabetes and gastric
bypass surgery over the last year. We still face major challenges in our fight against diabetes and obesity. Unfortunately, key stumbling blocks still remain, such as access
to care, response to care, and cost containment. Samuel
Johnson said, ‘‘Great works are performed not by strength but
by perseverance.’’
Conclusion
Bariatric surgery seems to prevent the onset on T2DM in
obese patients without T2DM.
Comment
This study’s novel approach to proactively follow obese
patients for the development of T2DM is unique. Results
suggest that bypass can also be an effective way to prevent the onset on T2DM in obese patients. In 2012,
Schauer et al. received a significant amount of media attention with the NEJM article. Schauer concluded that
gastric bypass is a safe and effective way to achieve
glycemic control and yielded statistically better results
when compared to intensive medical therapy (9). This
study goes one step further and suggests that bypass is
also an effective way to prevent the onset of T2DM in
obese patients without preexisting diabetes. Despite this
novel approach, there are severe limitations to the study
and how it translates to diabetes care. First, a majority of
the patients in the study underwent a vertical band gastroplasty for their weight loss procedure (70%). This now
represents a very small portion of gastric bypass procedures in the United States, and it would be difficult to
interpret results from these data. In the future, it would
be beneficial to do a subset analysis on the specific bypass
procedures and their rates of diabetes prevention. The
second shortcoming was the low participation rate at the
15-year mark; 36.2% of the patients had dropped out of
the study and 30.9% had not reached the follow-up exam
time. Despite this percentage of patients lost to follow-up
in the study, there were still 502 participants (n = 392
control group and n = 110 bypass group) who were
available for analysis. It will be interesting to see if this
protective strategy of gastric bypass continues as the remaining third of the study group reaches the 15-year
follow-up examination.
Conclusion
It was an exciting year not only for metabolic surgery but
also for T2DM, hypertension, dyslipidemias, and NASH,
among others. These are no longer hopeless diseases but illnesses that can, finally, be treated successfully with marked
improvements in mortality and morbidity. The discipline has
also provided great hope for the prevention of solid cancers,
with the demonstration that the prevalence of malignancies of
References
1. Burguera B, Agusti A, Arner P, Baltasar A, Barbe F, Barcelo
A, Breton I, Cabanes T, Casanueva FF, Couce ME, Dieguez
C, Fiol M, Fernandez Real JM, Formiguera X, Fruhbeck G,
Garcia Romero M, Garcia Sanz M, Ghigo E, Gomis R, Higa
K, Ibarra O, Lacy A, Larrad A, Masmiquel L, Moizé V,
Moreno B, Moreiro J, Ricart W, Riesco M, Salinas R, Salvador
J, Pi-Sunyer FX, Scopinaro N, Sjostrom L, Pagan A, Pereg V,
Sánchez Pernaute A, Torres A, Urgeles JR, Vidal-Puig A,
Vidal J, Vila M. Critical assessment of the current guidelines
for the management and treatment of morbidly obese patients. J Endocrinol Invest 2007; 30: 844–52.
2. Ramos AM, Pellanda LC, Vieira PL, Ribeiro DP, Menti E,
and Portal VL. Prognostic value of fasting glucose levels in
elderly patients with acute coronary syndrome. Arquivos
Brasileiros de Cardiologia 2012; 98: 203–10.
3. Jakicic JM, Jaramillo SA, Balasubramanyam A, Bancroft B,
Curtis JM, Mathews A, Pereira M, Regensteiner JG, Ribisl
PM. Effect of a lifestyle intervention on change in cardiorespiratory fitness in adults with type 2 diabetes: results from
the Look AHEAD Study. Look AHEAD Study Group. Int J
Obes (Lond) 2009; 33: 305–16.
4. Look AHEAD Research Group, Wing RR, Bolin P, Brancati
FL, Bray GA, Clark JM, Coday M, Crow RS, Curtis JM, Egan
CM, Espeland MA, Evans M, Foreyt JP, Ghazarian S, Gregg
EW, Harrison B, Hazuda HP, Hill JO, Horton ES, Hubbard
VS, Jakicic JM, Jeffery RW, Johnson KC, Kahn SE, Kitabchi
AE, Knowler WC, Lewis CE, Maschak-Carey BJ, Montez
MG, Murillo A, Nathan DM, Patricio J, Peters A, Pi-Sunyer
X, Pownall H, Reboussin D, Regensteiner JG, Rickman AD,
Ryan DH, Safford M, Wadden TA, Wagenknecht LE, West
DS, Williamson DF, Yanovski SZ. Cardiovascular effects of
intensive lifestyle intervention in type 2 diabetes. N Engl J
Med 2013; 369: 145–54.
5. Brixner DI, Bron M, Bellows BK, Ye X, Yu J, Raparla S,
Oderda GM. Evaluation of cardiovascular risk factors,
events, and costs across four BMI categories. Obesity (Silver
Spring) 2013; 21: 1284–92.
6. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of
obesity and trends in body mass index among US children
and adolescents, 1999–2010. JAMA 2012; 307: 483–90.
7. Guariguata L. Contribute data to the 6th edition of the IDF
Diabetes Atlas. Diabetes Res Clin Pract 2013; 100: 280–81.
8. Bermudez DM, Pories WJ. New technologies for treating
obesity. Minerva Endocrinol 2013; 38: 165–72.
9. Schauer PR, Kashyap SR, Wolski K, Brethauer SA, Kirwan
JP, Pothier CE, Thomas S, Abood B, Nissen SE, Bhatt DL,
Mingrone G, Panunzi S, De Gaetano A, Guidone C, Iaconelli
A, Leccesi L, Nanni G, Pomp A, Castagneto M, Ghirlanda G,
S-84
and Rubino, F. Bariatric surgery versus intensive medical
therapy in obese patients with diabetes. N Engl J Med 2012;
366: 1567–85.
10. Pories WJ, Swanson MS, MacDonald KG, Long SB, Morris
PG, Brown BM, Barakat HA, deRamon RA, Israel G, Dolezal
JM, et al. Who would have thought it? An operation proves
to be the most effective therapy for adult-onset diabetes
mellitus. Ann Surg 1995; 222: 339–50; discussion 350–52.
11. Hall TC, Pellen MG, Sedman PC, et al. Preoperative factors
predicting remission of type 2 diabetes mellitus after Rouxen-Y gastric bypass surgery for obesity. Obes Surg 2010; 20:
1245–50.
12. Jacobsen SH, Olesen SC, Dirksen C, Jørgensen NB, BojsenMøller KN, Kielgast U, Worm D, Almdal T, Naver LS,
Hvolris LE, Rehfeld JF, Wulff BS, Clausen TR, Hansen DL,
MOORE AND PORIES
Holst JJ, Madsbad S. Changes in gastrointestinal hormone
responses, insulin sensitivity, and beta-cell function within 2
weeks after gastric bypass in non-diabetic subjects. Obes
Surg 2012; 22: 1084–96.
13. Dar MS, Chapman WH 3rd, Pender JR, Drake AJ 3rd,
O’Brien K, Tanenberg RJ, Dohm GL, Pories WJ. GLP-1 response to a mixed meal: what happens 10 years after Rouxen-Y gastric bypass (RYGB)? Obes Surg 2012; 22: 1077–83.
14. Florez H, Pan Q, Ackermann RT, Marrero DG, BarrettConnor E, Delahanty L, Kriska A, Saudek CD, Goldberg
RB, Rubin RR. Impact of lifestyle intervention and metformin on health-related quality of life: the diabetes prevention program randomized trial. Diabetes Prevention
Program Research Group. J Gen Intern Med 2012; 27:
1594–601.
DOI: 10.1089/dia.2014.1510
ORIGINAL ARTICLE
Immune Intervention for Type 1 Diabetes, 2012–2013
Jay S. Skyler
Introduction
Results
T
Teplizumab (14-day full dose) reduced the loss of C-peptide
mean area under curve (AUC; a prespecified secondary endpoint) at 2 years versus placebo. In analyses of subsets at entry,
U.S. residents, patients with C-peptide mean AUC > 0.2 nmol/L,
those randomized < 6 weeks after diagnosis, HbA1c < 7.5%
(58 mmol/mol), insulin use < 0.4 U/kg/day, and ages 8–17, each
had greater teplizumab-associated C-peptide preservation than
their counterparts. Exogenous insulin needs tended to be reduced versus placebo. Antidrug antibodies developed in some
patients without apparent change in drug efficacy. No new safety
or tolerability issues were observed during year 2.
his chapter of the ATTD 2013 Yearbook reviews the key
articles that have appeared between July 2012 and August
2013 in the area of immune intervention in type 1 diabetes.
Also included are two studies dealing with beta-cell regeneration or replacement. The first three studies discussed deal
with anti-CD3 monoclonal antibody therapy.
Teplizumab preserves C-peptide in recent-onset type 1
diabetes: 2-year results from the randomized,
placebo-controlled Protege trial
Hagopian W 1, Ferry RJ Jr 2, Sherry N 3, Carlin D 4, Bonvini E 4,
Johnson S 4, Stein KE 4, Koenig S 4, Daifotis AG 4, Herold KC 5,
Ludvigsson J 6; for the Protégé Trial Investigators
1
Pacific Northwest Diabetes Research Institute, Seattle, WA; 2Division of Pediatric Endocrinology and Metabolism, Le Bonheur Children’s Hospital and University of Tennessee Health Science Center,
Memphis, TN; 3Massachusetts General Hospital, Boston, MA;
4
MacroGenics, Rockville, MD; 5Departments of Immunobiology and
Internal Medicine, Yale University, New Haven, CT; and 6Division
of Pediatrics, Department of Clinical and Experimental Medicine,
Faculty of Health Sciences, Linköping University, Linköping, Sweden
Conclusion
Anti-CD3 therapy reduced C-peptide loss and thus preserved b-cell function for 2 years.
Diabetes 2013 Jun 25: [Epub ahead of print]; DOI: 10/2337/db13-0236
Background
Two years ago we discussed the 1-year results of the Protégé
phase 3 study using teplizumab. The primary outcome
measure—a composite of the percentage of patients with insulin use of < 0.5 U/kg per day and HbA1c of < 6.5% at 1 year—
was not met. However, exploratory analyses suggested that
teplizumab could help preserve b-cell function—as measured
by C-peptide—at 1 year, particularly in subgroups such as
children. This report describes the 2-year results from this study.
Methods
Of the 516 subjects randomized, 462 completed 2 years of
follow-up. Treatment was given both at study entry and 6
months later.
Comment
Previous reports have shown that a short course of humanized anti-CD3 monoclonal antibody—either with
teplizumab or otelixizumab—preserved b-cell function
as measured by C-peptide. The Protégé study selected a
different primary outcome measure—a composite of the
percentage of patients with insulin use of < 0.5 U/kg/
day plus HbA1c of < 6.5% at 1 year. That outcome was
not met, and thus many have labeled the Protégé study a
failure. Yet, in the original report, teplizumab was found
to preserve b-cell function at 1 year. The current article
demonstrates that this effect was maintained at 2 years.
As noted in our earlier discussion of the 1-year results,
there was no prior basis for the outcome measure selected. Moreover, taking two continuous variables (insulin use and HbA1c) and converting them to a single
combined dichotomous variable reduces the statistical
power of assessment of continuous variables. The Cpeptide results, both at 1 year and at 2 years, highlight the
problem. Thus, although the original primary outcome
was not met, we are still learning from the Protégé study.
Division of Endocrinology, Diabetes, & Metabolism, and Diabetes Research Institute, University of Miami Miller School of Medicine,
Miami, FL.
S-85
S-86
SKYLER
Teplizumab treatment may improve C-peptide
responses in participants with type 1 diabetes
after the new-onset period: a randomised
controlled trial
Comment
This study initiated therapy with anti-CD3 at a later time
point after diagnosis than has been done in previous
studies. Treatment may reduce the decline of C-peptide
in patients with established disease of up to 1-year duration. Nonetheless, subjects did better if enrollment occurred between a 4- and 8-month duration of type 1
diabetes. Given the success with anti-CD3 in recent-onset
type 1 diabetes, this study indicates that if one is a bit late
in initiating therapy, then there is still likely to be benefit,
particularly if the HbA1c is well controlled. This gives
clinicians more time to offer this treatment to potential
subjects.
Herold KC 1, Gitelman SE 2, Willi SM 3, Gottlieb PA 4,
Waldron-Lynch F1, Devine L1, Sherr J 5, Rosenthal SM 2,
Adi S 2, Jalaludin MY 3, Michels AW 4, Dziura J 6, Bluestone JA 2
1
Departments of Immunobiology and Internal Medicine, Yale
University, New Haven, CT; 2Departments of Pediatrics and Internal Medicine, University of California at San Francisco, San
Francisco, CA; 3Department of Pediatrics, Children’s Hospital of
Philadelphia, Philadelphia, PA; 4Department of Internal Medicine,
University of Colorado Anschutz Medical Campus, Aurora, CO;
and Departments of 5Pediatrics and 6Emergency Medicine, Yale
University, New Haven, CT
Background
Previous studies with anti-CD3 monoclonal antibodies
have been conducted in subjects with recent-onset type 1
diabetes, generally initiated within 2–4 months from diagnosis. This study, known as the DELAY study, using teplizumab, enrolled subjects with type 1 diabetes for 4–12
months.
Methods
Fifty-eight subjects were recruited. They received a 14-day
course of either intravenous teplizumab or placebo.
Results
The primary outcome analysis showed a 21.7% higher
C-peptide response in the teplizumab-treated group (0.45
vs. 0.371; difference, 0.059 [95% CI 0.006, 0.115] nmol/L)
( p = 0.03), when corrected for baseline imbalances in
HbA1c levels, the C-peptide levels in the teplizumabtreated group were 17.7% higher (0.44 vs. 0.378; difference,
0.049 [95% CI 0, 0.108] nmol/L, p = 0.09). A greater proportion of placebo-treated participants lost detectable Cpeptide responses at 12 months ( p = 0.03). The teplizumab
group required less exogenous insulin ( p < 0.001), but
treatment differences in HbA1c levels were not observed.
Teplizumab was well tolerated. A subgroup analysis
showed that treatment benefits were larger in younger
individuals and those with HbA1c < 6.5% at entry. Subjects enrolled between 4 and 8 months after diagnosis
showed better effect than those enrolled between 9 and 12
months after diagnosis.
Teplizumab (anti-CD3 mAb) treatment preserves
C-peptide responses in patients with new-onset type 1
diabetes in a randomized controlled trial: metabolic
and immunologic features at baseline identify
a subgroup of responders
Herold KC 1, Gitelman SE 6, Ehlers MR 2, Gottlieb PA 7,
Greenbaum CJ 8, Hagopian W 9, Boyle KD 5, Keyes-Elstein L 5,
Aggarwal S 4, Phippard D 4, Sayre PH 2, McNamara J 3,
Bluestone JA 6; the AbATE Study Team
1
Department of Immunobiology and Internal Medicine, Yale
University, New Haven, CT; 2Immune Tolerance Network, San
Francisco, CA; 3National Institutes of Allergy and Infectious
Diseases, Bethesda, MD; 4Immune Tolerance Network, Bethesda,
MD; 5Rho Federal Systems Division, Chapel Hill, NC; 6University
of California–San Francisco, San Francisco, CA; 7Barbara Davis
Center, University of Colorado, Aurora, CO; 8Benaroya Research
Institute, Seattle, WA; and 9Pacific Northwest Diabetes Research
Institute, Seattle, WA
Diabetes 2013 July 8: [Epub ahead of print]; DOI: 10.2337/db-0345
Background
This study, known as ABATE, looked at whether two
courses of teplizumab (at entry and 1 year later) could help
preserve b-cell function—as measured by C-peptide—at 2
years. The other goal of the study was to identify characteristics of responders.
Methods
Fifty-two subjects were randomized. The active group
received a 14-day course of teplizumab both at study entry
and 12 months later. The comparison group was randomized but did not receive placebo. The primary outcome was
at 2 years.
Results
Conclusion
The secondary outcomes suggest that anti-CD3 therapy
reduced C-peptide loss and thus preserved b-cell even when
therapy was initiated after the recent-onset period. However,
the magnitude of the effect is less than during the recent-onset
period. The analyses identified age and HbA1c as characteristics that may identify participants most likely to respond to
drug treatment.
In the intention to treat analysis of the primary endpoint,
teplizumab-treated patients had a reduced decline in Cpeptide at 2 years [mean (95% CI), - 0.28 ( - 0.36, - 0.20) nmol/
L vs. control, - 0.46 ( - 0.57, - 0.35) nmol/L; p = 0.002], a 75%
improvement. In a post hoc analysis, clinical responders (identified by having maintained C-peptide better than the randomized comparison group at 24 months) were found to have
metabolic (lower HbA1c and less insulin use) and immunologic
IMMUNE INTERVENTION FOR TYPE 1 DIABETES, 2012–2013
features (lower frequency of CD4 + CCR4 + memory and naı̈ve
T cells, CD4 + CCR6 + -naı̈ve CD4 + T cells, naı̈ve CCR4 +
CD8 + T cells, and IFNc-producing CD8 + T cells at baseline,
and a higher number of activated CD8 + terminally differentiated effector and CD8 + effector-memory T cells) that distinguished this group from nonresponders to teplizumab.
Conclusion
Anti-CD3 therapy reduced C-peptide loss and thus preserved b-cell function for 2 years.
Comment
In this study, although the overall response showed
significant improvement in retention of C-peptide, the
most interesting aspect was the identification of two
groups of subjects—responders and nonresponders. Responders constituted 45% of the subjects treated with
anti-CD3. The responders maintained beta-cell function
for 2 years, whereas the nonresponders lost beta-cell
function at a rate similar to the control group. It is not
known why some subjects respond and others fail to
respond. Nonetheless, the lower HbA1c levels and lower
insulin doses in responders imply that these individuals
may have had a milder disease or be earlier in the course
of the disease. This reinforces the notion that therapy
with anti-CD3 should be as early as possible in the disease process. The next group of articles discusses other
intervention approaches.
Interleukin-1 antagonism in type 1 diabetes of recent
onset: two multicenter, randomized double-masked,
placebo-controlled trials
Moran A1, Bundy B 2, Becker DJ 3, DiMeglio LA 4,
Gitelman SE 5, Goland R 6, Greenbaum CJ 7, Herold KC 8,
Marks JB 9, Raskin P 10, Sanda S 7, Schatz D 11, Wherrett D 12,
Wilson DM 13, Krischer JP 2, Skyler JS14 for the Type 1 Diabetes
TrialNet Canakinumab Study Group; and Pickersgill L15,
de Koning E 16, Ziegler A-G17, Böehm B18, Badenhoop K 19,
Schloot N 20, Bak JF 21, Pozzilli P 22, Mauricio D 23,
Donath MY 24, Castaño L 25, Wägner A 26, Lervang HH 27,
Perrild H 28, Mandrup-Poulsen T 29 for the AIDA Study Group
1
University of Minnesota, Minneapolis, MN; 2University of
South Florida, Tampa, FL; 3University of Pittsburgh, Pittsburgh,
PA; 4Indiana University School of Medicine, Indianapolis, IN;
5
University of California San–Francisco, San Francisco, CA;
6
Columbia University, New York, NY; 7Benaroya Research Institute, Seattle, WA; 8Yale University, New Haven, CT; 9University of Miami Diabetes Research Institute, Miami, FL;
10
University of Texas Southwestern Medical School, Dallas, TX;
11
University of Florida, Gainesville, FL; 12Hospital for Sick
Children, University of Toronto, Toronto, ON, Canada; 13Stanford University, Stanford, CA; 14Diabetes Research Institute,
University of Miami Miller School of Medicine, Miami, FL;
15
Steno Diabetes Center, Gentofte, Denmark;16Leiden University
Medical Center, Leiden, The Netherlands; 17Institute of Diabetes
Research, Helmholtz Zentrum München, and Forschergruppe
Diabetes, Klinikum rechts der Isar, Technische Universität,
München, Germany; 18Ulm University, Ulm, Germany; 19Uni-
S-87
versity of Frankfurt-am-Main, Frankfurt, Germany; 20German
Diabetes Center, Düsseldorf, Germany; 21Hospitalsenheden Vest,
Aarhus University Hospital, Aarhus, Denmark; 22Unit for Diabetes Prevention, University Campus Bio-Medico, Rome, Italy;
23
Hospital Arnau de Vilanova, Lleida, Spain; 24University Hospital Basel, Basel, Switzerland; 25Hospital Universitario Cruces,
Bilbao, Spain; 26Complejo Hospitalario Universitario Insular
Materno-Infantil, Las Palmas de Gran Canaria, Spain; 27Aalborg
Hospital, Aalborg, Denmark; 28Bispebjerg Hospital, Copenhagen,
Denmark; and 29Department of Biomedical Sciences, Faculty of
Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Lancet 2013; 381: 1905–15
Background
Innate immunity may contribute to the pathogenesis
of type 1 diabetes. This article reports two randomized
trials that evaluated two approaches to blockade of the
innate immune mediator interleukin-1 (IL-1)—an anti-IL-1
antibody canakinumab and an IL-1 receptor antagonist
anakinra.
Methods
In the canakinumab trial, 69 subjects (age 6–45) were randomized, 47 to canakinumab and 22 to placebo, with the
dosage being 2 mg/kg subcutaneously monthly for 12
months. In the anakinra trial, 69 subjects (age 18–35) were
randomized, 35 to anakinra and 34 to placebo, with the dosage being 100 mg/day for 9 months. The primary outcome
measure was C-peptide area under curve (AUC) from a
mixed-meal tolerance test, at 12 months for canakinumab and
at 9 months for anakinra.
Results
The difference in C peptide AUC between the canakinumab
and placebo groups at 12 months was 0.01 nmol/L (95% CI
- 0.11 to 0.14; p = 0.86), and between the anakinra and the
placebo groups at 9 months was 0.02 nmol/L ( - 0.09 to 0.15;
p = 0.71).
Conclusion
Canakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset type 1
diabetes.
Comment
In these studies, there was no benefit on beta-cell function
from blocking the effects of IL-1. Although the innate
immune system may be critically important in the evolution of type 1 diabetes, blocking inflammation by itself
may be insufficient to alter the course of the disease. On
the other hand, decreasing inflammation may prove to be
a crucial component of a combination therapy approach
to interrupting the type 1 diabetes disease process. That
canakinumab was safe and was used successfully in
children as young as age 6 supports its use in future
studies using a combination approach.
S-88
SKYLER
Plasmid-encoded proinsulin preserves C-peptide while
specifically reducing proinsulin-specific CD8 + T cells
in type 1 diabetes
number of subjects studied at each dose was small, and
there did not appear to be statistical adjustment for
multiple comparisons. There were no safety issues. It is
now incumbent upon the authors and study sponsor to
conduct an adequately powered randomized controlled
clinical trial to ascertain whether the effects that they
claim to be seeing are confirmed.
Roep BO1, Solvason N 2,3, Gottlieb PA 4, Abreu JR1,
Harrison LC 5, Eisenbarth GS 4, Yu L 4, Leviten M 2,
Hagopian WA 6, Buse JB 7, von Herrath M 8, Quan J 2,
King RS 2, Robinson WH 2,9,10, Utz PJ 2,9,10, Garren H 2,10;
the BHT-3021 Investigators, Steinman L 2,9,10
1
Department for Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands; 2Bayhill
Therapeutics, Palo Alto, CA; 3Foothill College, Los Altos, CA;
4
Barbara Davis Center for Childhood Diabetes, Aurora, CO; 5Division of Molecular Medicine, Walter and Eliza Hall Institute for
Medical Research, Parkville, Victoria, Australia; 6Pacific Northwest Diabetes Research Institute and University of Washington,
Seattle, WA; 7Diabetes Center for Research, University of North
Carolina, Chapel Hill, NC; 8La Jolla Institute for Allergy and
Immunology, La Jolla, CA; 9Departments of Medicine and Neurological Sciences, Stanford University School of Medicine, Stanford, CA; and10Tolerion Inc., Portola Valley, CA
Sci Transl Med 2013; 5: 191ra82
Background
Because proinsulin is a major target of adaptive immunity
in type 1 diabetes, the authors hypothesized that an engineered DNA plasmid encoding proinsulin would preserve
beta-cell function in type 1 diabetes through reduction of
insulin-specific T-lymphocytes.
Methods
Sixty-nine subjects over age 18 diagnosed with type 1 diabetes within 5 years were randomized 2:1 to receive intramuscular injections of plasmid or placebo weekly for 12 weeks. Four
dose levels of plasmid were evaluated: 0.3, 1.0, 3.0, and 6.0 mg.
C-peptide served as an exploratory measure of efficacy and
safety. Islet-specific CD8 + T-cell frequencies were assessed
with multimers of monomeric HLA class I molecules loaded
with peptides containing pancreatic or unrelated antigens.
Results
No serious adverse events related to plasmid occurred. The
authors claim that C-peptide levels were improved relative to
placebo at all doses, most notably at 1 mg at 15 weeks ( + 19.5%
with plasmid versus - 8.8% with placebo, p < 0.026). Proinsulinreactive CD8 + T-cells, but not T-cells against unrelated islet or
foreign molecules, declined in the plasmid arm ( p < 0.006).
Conclusion
The authors concluded that a plasmid encoding proinsulin
reduces the frequency of CD8 + T-cells reactive to proinsulin
while preserving C-peptide over the course of dosing.
Comment
Although the authors assert that there is benefit to betacell function in this study, it is really unclear whether
there is such a benefit or not. The effect was seen in but
one of four doses tested and at one time point. The
Autologous umbilical cord blood infusion followed
by oral docosahexaenoic acid and vitamin D
supplementation for C-peptide preservation
in children with type 1 diabetes
Haller MJ 1, Wasserfall CH 2, Hulme MA 2, Cintron M 1,
Brusko TM 2, McGrail KM 2, Wingard JR 3, Theriaque DW 4,
Shuster JJ 4, Ferguson RJ 2, Kozuch M 5, Clare-Salzler M 2,
Atkinson MA 2, Schatz DA1
1
Department of Pediatrics; 2Department of Pathology; 3Department
of Medicine; 4Department of Epidemiology and Health Policy Research and the Clinical Research Center; and 5Department of
Physiological Sciences, College of Veterinary Medicine; The University of Florida, Gainesville, FL
Biol Blood Marrow Transplant 2013; 19: 1126–29
Background
A previous study demonstrated apparent safety of autologous umbilical cord blood (UCB) infusion accompanied by
postinfusion increase in regulatory T-lymphocytes (Treg). In
an attempt to provide synergy in altering autoimmunity, the
current study was designed to augment UCB by the addition
of two agents generally regarded as safe (GRAS) and with
immunomodulatory properties—vitamin D (Vit D) and docosoahexaenoic acid (DHA).
Methods
The study was an open-label, 2:1 randomized study in
which 15 subjects with type 1 diabetes and stimulated Cpeptide > 0.2 pmol/mL received either (a) autologous UCB
infusion, 1 year of daily oral Vit D (2,000 IU) and DHA
(38 mg/kg), and intensive diabetes management, or (b) intensive diabetes management alone. Treated (n = 10) and
control (n = 5) subjects had median ages of 7.2 and 6.6 years,
respectively.
Results
While the absolute rate of C-peptide decline was slower in
treated versus control subjects, intergroup comparisons failed
to reach significance ( p = 0.29). C-peptide declined and insulin
use increased in both groups ( p £ 0.01). Not surprisingly, Vit
D levels remained stable in treated subjects but declined in
controls ( p = 0.01), and DHA levels rose in treated subjects
versus controls ( p = 0.003). CD4:CD8 ratio remained stable in
treated subjects but declined in controls ( p = 0.03). No changes
were seen in regulatory T cell frequency, total CD4 counts, or
autoantibody titers. No severe adverse events were observed.
Conclusion
Autologous UCB infusion followed by daily supplementation
with Vit D and DHA was safe but failed to preserve C-peptide.
Comment
If one is looking for efficacy, this study once again illustrates the futility of the conduct of pilot studies with a
very small sample size. The study did not reveal any
severe adverse effects, allowing the authors to claim that
the intervention is safe. Yet one should always be cautious with drawing conclusions about safety in small
trials. Only 10 subjects were exposed to the intervention.
It is easy to miss a serious adverse event. Although I do
not suspect that to be an issue with the particular intervention used—autologous UCB and two GRAS substances—the principle should be appreciated that such
small trials usually are impossible to interpret.
S-89
change in C-peptide AUC of - 0.195 pmol/mL (95% CI
- 0.292 to - 0.098), and the placebo group had a mean change
of - 0.239 pmol/mL ( - 0.361 to - 0.118) ( p = 0.591). All except
one subject in the ATG group had both cytokine release
syndrome and serum sickness. Acute T-lymphocyte depletion
occurred in the ATG group, with slow reconstitution over 12
months; yet, effector memory T-lymphocytes were not depleted, and the ratio of regulatory to effector memory Tlymphocytes declined in the first 6 months and stabilized
thereafter. ATG-treated patients had 159 grade-3–4 adverse
events, many associated with T-lymphocyte depletion, compared with 13 in the placebo group. However, there were no
between-group differences in incidence of infectious diseases.
Conclusion
Antithymocyte globulin treatment for patients
with recent-onset type 1 diabetes: 12-month results
of a randomised, placebo controlled, phase 2 trial
Gitelman SE 1, Gottlieb PA 2, Rigby MR 3, Felner EI 4,
Willi SM 5, Fisher LK 6, Moran A 7, Gottschalk M 8, Moore WV 9,
Pinckney A10, Keyes-Elstein L10, Aggarwal S11, Phippard D11,
Sayre PH 9, Ding L12, Bluestone JA1, Ehlers MR13,
and the START Study Team
The authors concluded that a brief course of ATG did not
result in preservation of beta-cell function 12 months later in
patients with recent-onset type 1 diabetes, and that generalized T-lymphocyte depletion in the absence of specific depletion of effector memory T-lymphocytes and preservation
of regulatory T-lymphocytes seems to be an ineffective treatment for type 1 diabetes.
Comment
1
University of California San Francisco, San Francisco, CA; 2Barbara Davis Center, University of Colorado, Aurora, CO; 3Indiana
University and Riley Children’s Hospital, Indianapolis, Indianapolis, IN; 4Emory University, Atlanta, GA; 5Children’s Hospital of Philadelphia, Philadelphia, PA; 6Children’s Hospital of Los
Angeles, Los Angeles, CA; 7University of Minnesota, Minneapolis,
MN; 8University of California San Diego, San Diego, CA; 9Children’s Mercy Hospital, Kansas City, MO; 10Rho Federal Systems
Division, Chapel Hill, NC; 11Immune Tolerance Network, Bethesda,
MD; 12National Institute of Allergy and Infectious Diseases, Bethesda, MD; and13Immune Tolerance Network, San Francisco, CA
The full story from this study remains to be told, in my
opinion. Post hoc analyses showed that there were differences between the 0–6-month change and the 6–12month change in C-peptide in the antithymocyte globulin
(ATG) group, with an apparent early decline in beta-cell
function and then stabilization. If the early decline was
caused by a cytokine storm—a postulate that would have
greater support had there been an assessment of C-peptide at 3 months—then there might be continued stable
C-peptide during the ongoing follow-up through 24
months. That might validate the potential benefit of ATG
and support further testing at lower doses and/or in
combination therapy, such as that being done with lowdose ATG together with granulocyte colony-stimulating
factor. The next articles provide insights about potential
interventions that could be evaluated in type 1 diabetes.
Lancet Diabetes Endocrinol 2013 Aug 28; [Epub ahead of print]: DOI:
10.1073/PNAS.1220637110
Background
Type 1 diabetes results from T-lymphocyte-mediated destruction of beta-cells. Antithymocyte globulin (ATG) suppresses T-lymphocytes and has been used in transplantation
and in other autoimmune diseases. Therefore, this study
evaluated ATG in subjects with recent-onset type 1 diabetes.
Methods
Fifty-eight subjects, age 12–35, with recent-onset type 1 diabetes, were randomized (38 to the ATG arm and 20 to the placebo
arm). They received 6.5 mg/kg ATG or placebo over a course of 4
days. The primary endpoint was the baseline-adjusted change in
2-hour area under the curve (AUC) C-peptide response to mixed
meal tolerance test from baseline to 12 months.
Acute metabolic effects of exenatide in patients
with type 1 diabetes with and without residual
insulin to oral and IV glucose challenges
Ghazi T1, Rink L1, Sherr JL2, Herold KC 1
1
Departments of Immunobiology and Internal Medicine
and 2Department of Pediatrics, Yale University School
of Medicine, New Haven, CT
Diabetes Care 2013 Aug 12: [Epub ahead of print]; DOI: 10.2337/
dc13-1169
Results
Background
About 12 months after randomization, the change from
baseline in the ATG group did not differ from that in the
placebo group for the primary outcome (2-hour AUC of mealstimulated C-peptide) or for secondary outcomes (HbA1c and
insulin dose). Participants in the ATG group had a mean
Treatment with GLP-1 analogs is used for type 2 diabetes.
Patients with type 1 diabetes, particularly those with residual
beta-cell function, may also respond to treatment. In type 1 diabetes, the acute metabolic effects of GLP-1 analogs on both oral
and IV glucose challenges have not been well characterized.
S-90
SKYLER
Methods
Methods
Seventeen patients with type 1 diabetes, eight of whom
had residual insulin production, underwent two mixed meal
tolerance tests (MMTT), and two intravenous glucose tolerance tests (IVGTT), with and without pretreatment with
exenatide. Glucose excursions, insulin secretion rates (ISR),
glucagon, gastric emptying, and incretin levels (endogenous
GLP-1 and GIP) were measured following the meal or glucose loads.
The authors used a mouse model of insulin resistance that
induces dramatic pancreatic beta-cell proliferation and betacell mass expansion.
Results
During the MMTT, glucose levels were suppressed with
exenatide in patients with or without residual insulin production ( p = 0.0003). Exenatide treatment did not change the
absolute ISR, but the ISR to glucose levels were increased
( p = 0.0078). Gastric emptying was delayed ( p = 0.0017) and
glucagon was suppressed ( p = 0.0015). None of these hormonal or changes in glucose were detected during the IVGTT
with exenatide administration.
Results
The authors were able to identify a hormone, betatrophin,
which is primarily expressed in liver and fat, that correlates
with beta-cell proliferation. Transient expression of betatrophin in mouse liver significantly and specifically promoted
pancreatic beta-cell proliferation, expanded beta-cell mass,
and improved glucose tolerance.
Conclusion
Betatrophin treatment could be used to increase the number of endogenous insulin-producing cells in diabetes.
Comment
This article describes a new hormone, betatrophin, that
stimulates beta-cell proliferation and expands islet betacell mass. Although to date only studied in rodents, the
analogous human sequence has been identified. If betatrophin can be produced, such as by recombinant DNA
technology, it could undergo animal toxicology testing to
clear the way for initiation of human clinical trials. This
represents a most exciting possibility that potentially
could be combined with immune intervention for alteration of the course of type 1 diabetes.
Conclusion
Exenatide, given before an oral meal, lowered glycemic
excursions in patients with type 1 diabetes, involving glucagon suppression and gastric emptying, while preserving increased insulin secretion. GLP-1 analogs may be useful as an
adjunctive treatment in type 1 diabetes.
Comment
GLP-1 analogs have been thought about as potential
adjunctive therapy in type 1 diabetes, and several
small studies have suggested that they may have
potential benefit. The current study evaluated the potential mechanisms by which such therapy may be operating. Using but a single dose of exenatide before a
meal, there was sufficient glucagon suppression and
delay of gastric emptying to flatten postmeal glycemic
excursions even in subjects without residual insulin secretion. This bodes well for the potential use of GLP-1
analogs in type 1 diabetes, for which several larger
studies are currently under way. Because GLP-1 analogs
may also contribute to beta-cell health, they may be a
useful component of a combination therapy approach
directed at recent-onset type 1 diabetes.
Betatrophin: a hormone that controls pancreatic
b cell proliferation
Yi P, Park JS, Melton DA
Department of Stem Cell and Regenerative Biology, Harvard Stem
Cell Institute, Howard Hughes Medical Institute, Harvard University, Cambridge, MA
Cell 2013; 153: 747–58
Brief demethylation step allows the conversion of adult
human skin fibroblasts into insulin-secreting cells
Pennarossa G 1, Maffei S 1, Campagnol M 1, Tarantini L 2,3,
Gandolfi F1, Brevini TA1
1
Laboratory of Biomedical Embryology, UniStem, Center for Stem
Cell Research; 2Department of Clinical and Community Sciences;
and 3Istituto di Ricerca e Cura a Carattere Scientifico Maggiore
Hospital, Mangiagalli and Regina Elena Foundation, Università
degli Studi di Milano, Italy
Proc Natl Acad Sci USA 2013; 110: 8948–53
Background
The advent of induced pluripotent stem cell technology enabled the conversion of adult cells into any other cell type
passing through a stable pluripotency state. Unfortunately, indefinite pluripotency is unphysiological, is inherently labile,
and makes cells prone to culture-induced alterations. The direct
conversion of one cell type to another without an intermediate
pluripotent stage is also possible but requires viral transfection
of appropriate transcription factors, limiting its therapeutic
potential. The aim of this study was to investigate possible direct conversion of skin fibroblasts by exposing them to a demethylating agent immediately followed by culture conditions
aimed at differentiating the cells to insulin-secreting cells.
Background
Replenishing insulin-producing pancreatic beta-cell mass
will benefit both type 1 and type 2 diabetes. In adults, pancreatic beta-cells are generated primarily by self-duplication.
Methods
Adult human skin fibroblasts were exposed for 18 hours to
the DNA methyltransferase inhibitor 5-azacytidine, followed
by a three-step protocol for the induction of endocrine pancreatic differentiation that lasted 36 days.
Results
With this treatment, 35 – 8.9% of fibroblasts became pancreatic converted cells that acquired an epithelial morphology, produced insulin, and then released the hormone in
response to a physiological glucose challenge in vitro. These
pancreatic converted cells were able to protect recipient mice
against streptozotocin-induced diabetes, restoring physiological responses to glucose tolerance tests.
Conclusion
It is possible to convert adult fibroblasts into insulin-secreting cells.
Comment
This article represents a remarkable achievement that has
the potential to provide insulin-secreting cells from a
person’s own skin fibroblasts. To use these for beta-cell
replacement would obviate the need to deal with alloimmunity responsible for rejection, although the potential for recurrent autoimmunity would still exist.
Nonetheless, if further studies demonstrate the clinical
feasibility of this approach, it could be quite remarkable.
S-91
Overall Commentary
This year has produced some very exciting articles, although many describe preliminary studies and need further
development. As noted in previous years, this author believes
many of these potential interventions hold promise, particularly if they are used as components of combination therapy.
Even by itself, anti-CD3 deserves testing in a well-designed
phase 3 trial in recent-onset type 1 diabetes. It also is being
explored as a preventative measure in individuals with very
high risk of progression to type 1 diabetes. ATG is being explored further at lower doses and in combination with granulocyte colony-stimulating factor. Plasmid containing
proinsulin has been demonstrated to be safe and is worthy of
further study, perhaps as the antigen-specific component of a
combination approach. Another component of combination
therapy could be a GLP-1 analog to improve beta-cell health.
One could envision adding in betatrophin to expand beta-cell
mass, and if beta-cells have already been depleted, one could
even imagine using an individual’s skin fibroblasts to make
new pancreatic islets. This is all science fiction today. Yet,
development of the component parts has been proceeding
with vigor. I predict that we are embarking on a decade that
will see enormous progress in eradicating type 1 diabetes.
J.S. has no competing financial interests related to this review.
DOI: 10.1089/dia.2014.1511
ORIGINAL ARTICLE
Physical Activity and Exercise
Michael Riddell1, Sophie Pollack 2, Homadis Shojaei1, Joshua Kalish 2, and Howard Zisser 2
Introduction
E
xercise has been prescribed for diabetes treatment
since at least 600 B.C. The early East Indian text, the
Shushruta, described a reduction in the sweetness of urine
from diabetic patients after exercise. One might think that
very little could be left to discover in the field of exercise and
diabetes, yet surprisingly this is far from the truth. Ongoing
research is refining the exercise prescription for patients of all
ages, with the main types of diabetes (gestational, type 1, and
type 2) and discovering new ways in which exercise has
benefits. Alterations in metabolism caused by diabetes and
new types of exercise modalities are also actively being researched. A search of several hundred articles on exercise
published between July 1, 2012, to June 30, 2013, uncovered
the following 9 articles we felt had the most relevance to patients with diabetes or prediabetes.
crossover design. The protocols lasted from 6 to 12 weeks.
Protocol 1: Core temperature was increased by treadmill exercise and decreased by palm cooling in order to study effects
of changing temperature on bench press volume. Protocol 2:
Palm cooling was used as a means of extracting heat to study
its influence on pull-up and bench-press work volume training response. Protocol 3: Strength-training response to changes in body core temperature was assessed with and without
palm cooling. In all protocols, heat extraction was performed
by a palm-cooling device, which comprised a stainless steel
plate with a temperature-controlled water bath located underneath the plate. Since heat dissipation for the whole body
is done partially through the palms, cooling the palms results
in significant core-temperature reduction that can be monitored via a thermocouple probe.
Results
It has previously been shown that attenuating the rise in the
body’s core temperature improves aerobic exercise endurance
capacity in athletes. Temperatures above the optimal range appear to reduce contractile force production capacity of skeletal
muscles. Thus, heat extraction may be one way to help increase
exercise performance and involvement. In this study, the benefits of core-temperature reduction are investigated with respect
to resistance exercise capacity in healthy men.
Protocol 1: Palm cooling reduced the rise in core temperature
that occurred with treadmill exercise (esophageal temperature
after treadmill exercise = 38.4 – 0.2C with palm cooling vs.
39.0 – 0.1C without palm cooling, n = 8; p = 0.01). Bench press
volume was higher with interset palm cooling during rest
compared with interset rest only (total reps/trial: 42 – 7 reps
after palm cooling vs. 36 – 7 reps after no cooling; p < 0.001).
Protocol 2: Subjects with and without prior pull-up training
showed greater rate of training response with palm cooling than
without palm cooling. The improvement rate was 13 – 8 pullups/trial with palm cooling compared with 3 – 4 pull-ups/trial
without palm cooling. The same trend was observed for bench
press exercise. The final-to-initial total repetition ratio with interset palm cooling was 1.4 – 0.1 and without interset palm
cooling was 1.1 – 0.1. Protocol 3: Interset palm cooling increased
the strength training response (an increase by *13 kg in the
fourth set), whereas there were no observed changes in strength
with training using interset rest only.
Methods
Conclusion
Sixty-seven healthy men were self-selected within the age
range of 19–23 years. Three protocols were carried out in a
Palm cooling, as a means of improved core-temperature
regulation, improves work volume and resistance exercise
Work volume and strength training responses
to resistive exercise improve with periodic heat
extraction from the palm
Grahn DA, Cao VH, Nguyen CM, Liu MT, Heller HG
Department of Biology, Stanford University, Stanford, CA
J Strength Cond Res 2012; 26: 2558–69
Background and Rationale
1
2
School of Kinesiology and Health Science, York University, Toronto, Canada.
S-92
PHYSICAL ACTIVITY AND EXERCISE
training response. Temperature regulation may potentially be
an effective means of enhancing exercise and sport performance. The palm cooling device may be a breakthrough for
training efficiency for athletes and to help them conquer their
conditioning plateaus.
Comment
The study illustrates the effectiveness of the innovative
palm-cooling technology for improving athletic performance by enhancing heat dissipation. This technology
may have significant implications in terms of alleviation
of symptoms of premature fatigue in patients with diabetes. Indeed, both impaired heat dissipation (1) and
premature fatigue (2) are characteristic of people with
type 2 diabetes mellitus (T2DM). In addition, the cooccurring complications as well as the medications required for their treatment appear to reduce skin blood
flow and lower sweating volume, which impairs cooling.
Therefore, the likelihood of heat-related diseases is
higher in diabetic patients than in the healthy population
(1). One key drawback of the study design, however, is
that for the first part of the training experiment, subjects
had interset rest only, and for the following section subjects exercised with interset palm cooling at rest. The
order effect would be biased toward favoring palm
cooling’s effect on training.
S-93
Average heart rates above 150/min were encouraged by
giving ‘‘points,’’ which were exchanged for prizes at the end
of each week. The hormones testosterone and estradiol were
measured in males and females, respectively, to control for the
effects of puberty on insulin resistance. To compare intergroup outcomes, insulin area-under-the-curve (AUC) analysis, percent body fat, visceral fat mass, and aerobic fitness
were measured by an oral glucose tolerance test, dual-energy
X-ray absorptiometry, magnetic resonance imaging, and a
VO2 peak exercise test, respectively.
Results
The improvements in insulin AUC, body fat, visceral fat, and
aerobic fitness in the exercise groups were significantly larger
than the changes observed in the controls. Moreover, there were
better improvements in insulin AUC, body fat, and visceral fat in
the high-dose exercise group compared with the low-dose exercise group. However, these differences between 20 and
40 min/day did not reach statistical significance in all parameters
measured. Similar fitness gains were observed in the two exercise
groups. The adjusted mean changes for body mass index (BMI)
z-scores and subcutaneous abdominal fat were significantly
higher in the high-dose exercise group than in the low-dose
exercise group ( - 0.05; 95% confidence interval [CI], - 0.10 to
- 0.01; p = 0.02, and - 8.62; 95% CI, - 17.2 to - 0.08; p = 0.048).
Conclusions
Exercise dose and diabetes risk in overweight
and obese children: a randomized control trial
Davis CL1, Pollock NK 1, Bassali R1, Boyle CA1, Waller JL 2,
Allison JD 3, Dennis BA 4, Meléndez A 5, Gower BA 6
Departments of 1Pediatrics, 2Biostatistics, 3Radiology, and
Medicine, Georgia Prevention Center, Institute for Public and Preventive Health, Medical College of Georgia, Augusta, GA; 5Polytechnic University of Madrid, Madrid, Spain; and 6Department of
Nutrition Sciences, University of Alabama, Birmingham, AL
4
JAMA 2012; 308: 1103–12
Obesity and excess body weight are highly prevalent
among U.S. children. It has been reasonably well established
that regular exercise reduces the risk of both excess body
adiposity and T2DM development in adults with prediabetes,
but less is known about adolescents at risk for T2DM. The
purpose of this study was to explore the relationship between
various aerobic exercise volumes and T2DM risk factors in
overweight and obese children. This information would allow
health practitioners to more accurately prescribe exercise that
is optimal for limiting T2DM risk factors in youth.
Methods
In this pretest–posttest randomized control trial, 222 sedentary obese or overweight children (7 to 11 years old) were
recruited from 15 elementary schools. The duration of the
study was 13 weeks for each cohort. The subjects were randomly assigned to control, low-dose aerobic exercise (20 min/
day), or high-dose aerobic exercise (40 min/day) and stratified by race and sex. An intention-to-treat analysis was used.
Supervised aerobic exercise for 20 or 40 min/day for 13
weeks was shown to improve insulin sensitivity, fitness, and
adiposity in sedentary obese and overweight children, thus
reducing the risk of developing T2DM.
Comment
Combined aerobic and resistance exercise is thought to be
best for adults living with T2DM (3,4). However, sufficient information is not readily available on the optimal
prescription of exercise for youth at elevated risk of developing the disease. Given the increasing prevalence of
childhood T2DM (5), understanding the dose–response
relationship between aerobic exercise and T2DM risk
factors in children is invaluable. Furthermore, this new
research should enable health professionals to provide
better exercise recommendations to children to reduce
probability of developing T2DM. This study shows that
with increasing exercise duration from 20 to 40 min/day,
there is a decreasing trend in many of the risk factors for
developing T2DM in youth aged 7–11 years. Future
studies should be conducted to further examine the duration, type, and intensity of exercise that will result in
maximal benefits to reducing T2DM risks in children.
Effects of Tai Chi exercise on glucose control, neuropathy scores, balance, and quality of life in patients with
type 2 diabetes and neuropathy
Ahn S, Song R
College of Nursing, Chungnam National University, Daejeon,
South Korea
J Altern Complement Med 2012; 18: 1172–78
S-94
RIDDELL ET AL
are suitable for this population. In this study, Tai Chi was
shown to be very effective in improvement of neuropathic symptoms and in reduction of blood glucose levels. Regardless of the diabetes status, balance and falls are
a common concern for the elderly, although the concern
is more prominent in the diabetic population because is
results in further postural instability. This study illustrates that Tai Chi is effective in improving balance in this
patient group. One drawback of the study was the nonrandom assignment of subjects to the groups. Even
though there was no significant difference between the
groups at baseline, a clear trend was observed. Specifically, at baseline, subjects who would participate in Tai
Chi had better scores in almost all study variables.
Nevertheless, it should be concluded that Tai Chi is an
effective exercise for treating complications associated
with diabetes. It may be a simple and fun mode of exercise that is practical for almost everyone!
Diabetic peripheral neuropathy (DPN) is highly prevalent
among patients with diabetes. It has debilitating effects on
quality of life by impairing stability and increasing risk of
falling. A small number of observational studies have shown
that Tai Chi is beneficial for patients from a glucose control
perspective, although its effect on DPN is unclear. The focus of
this study is on Tai Chi’s impact on DPN. Glucose control,
peripheral sensory function, balance, and quality of life were
measured to evaluate potential benefits.
Methods
A 12-week prospective study was conducted on 59 patients
with diabetes type 2 and neuropathy, of which 39 patients
completed the study. Average age of the subjects was 65
years. Data were analyzed based on 20 patients in the intervention group and 19 patients in the control group. Enzymatic
assay, turbidimetric immunoassay, and Semmes-Weinstein
monofilament examination and total neuropathy symptom
scores were utilized to measure fasting blood glucose, HbA1c
levels, and peripheral sensory function, respectively. Balance
was measured by the amount of time subjects could stand on
one leg. The quality of life was measured by the Korean version of the 36-Item Short Form Health Survey. In this quasiexperimental design, subjects were not randomly assigned to
groups. However, there were no significant differences in
neuropathy scores, balance, glucose control, and quality of life
between the groups at baseline.
Results
Posttests showed that glucose control (mean value changed
from 137 to 125 mg/dL in the treatment group vs. 143 to
155 mg/dL for the controls; t = 2.23; p = 0.036), HbA1c (mean
value changed from 7.63% to 7.20% in the treatment group vs.
8.02% to 8.32% for the controls; t = 3.11; p = 0.004), balance
(mean value changed from 22.37 to 30.02 sec for single-leg
stance in the treatment group vs. 15.71 to 14.27 in the controls), and total symptom scores were significantly better in
the intervention group than in the control (mean change from
0.86 to 0.91 in the treatment group vs. 1.19 to 2.83 for the
controls; t = 2.09; p = 0.042).
Conclusion
DPN is a common comorbidity of diabetes that leads to
many complications, such as falls, injury, and reduced exercise adherence. Previous studies lasting longer than 12 weeks
showed vascular improvements in diabetic patients with Tai
Chi exercise. In this 12-week Tai Chi program, it was shown
that this type of exercise modality helps improve glucose
control, balance, and symptom scores of neuropathy in patients with T2DM. The authors note that Tai Chi shows great
potential in terms of limiting the prognosis of diabetes.
Comment
DPN is a long-term complication frequently faced by the
diabetic population. Since elderly patients are more likely
to have had diabetes for a long time and therefore suffer
from DPN, it is wise to study DPN treatment options that
Differences in the acute effects of aerobic
and resistance exercise in subjects with type 2 diabetes:
results from the RAED2 randomized trial
Bacchi E1, Negri C1, Trombetta M1, Zanolin ME 2, Lanza M 3,
Bonora E1, Moghetti P1
1
Section of Endocrinology, Diabetes and Metabolism, Department
of Medicine, University and Azienda Ospedaliera Universitaria
Integrata of Verona, Verona, Italy; 2Section of Epidemiology and
Medical Statistics, Department of Public Health and Community
Medicine, University of Verona, Verona, Italy; and 3Section of
Motor Sciences, Department of Neurological, Neuropsychological,
Morphological and Movement Sciences, University of Verona,
Verona, Italy
PLoS One 2012; 7:e49937
It has been shown in previous studies that HbA1c levels
are reduced with chronic aerobic or resistance exercise. This
improvement in glycemic control is thought to be caused by
increases in non-insulin-mediated glucose disposal during
the exercise and by increased insulin sensitivity in resting
muscle. Additive reduction of blood glucose by antidiabetic
medications may increase the risk of hypoglycemia.
Therefore, understanding the acute effects of exercise on
blood glucose levels will allow appropriate modifications
to diet and/or medication tailored to the exercise prescription, if needed. The objective of this study was to investigate the acute effects of aerobic and resistance exercise
on blood glucose levels.
Methods
Twenty-five patients with T2DM participated in this
randomized control trial over an *12-week training period.
Group 1 did aerobic exercise, while group 2 did resistance
exercise. A continuous glucose monitoring system was inserted after 10.9 + 0.4 weeks of training to study blood
glucose levels during exercise and over the following 47
hours.
S-95
Results
There were no significant differences in interstitial glucose
AUC between the aerobic and the resistive exercise groups
over the 48 hours after exercise. In the aerobic group, the
glucose AUC during exercise was significantly lower than
the corresponding period in the nonexercise day ( p = 0.04).
The trend held true for the nocturnal sleeping period that
followed the exercise day and the corresponding period in the
nonexercise day for the aerobic group ( p = 0.02). Conversely,
in the resistive exercise group, there were no significant differences in the glucose concentration AUC between exercise
and nonexercise day and in the nocturnal sleeping period.
Exercise is commonly prescribed to T1DM patients; however, it may be causing metabolic disturbances. There is a lack
of knowledge in the metabolic responses of T1DM population
to exercise. The aim of this study was to investigate metabolic
responses to acute exercise in T1DM patients and compare
these responses with the responses in healthy controls. Understanding metabolic responses to acute exercise is valuable
and will allow exercise prescription with higher accuracy and
safety.
Conclusions
Ten men with T1DM and 11 healthy men who were active
in their leisure time participated in this study. They were
matched for age, BMI, body fat composition, and cardiorespiratory capacity. The pretest consisted of weight, height,
BMI, total fat, and body fat composition measurements as
well as filling out the International Physical Activity Questionnaire to show baseline activity level. The subjects were
also required to do a maximum oxygen uptake test to establish a baseline fitness level. A week later, the subjects performed an acute bout of exercise at 80% of their VO2max for
30 minutes. All subjects fasted overnight for the preceding 12
hours of the test. Blood samples were taken from subjects
before and after the exercise bout. Glucose-oxidase method
and quimioluminiscent method were used to detect serum
glucose and insulin levels, respectively. Serum proton nuclear
magnetic resonance (H-NMR) and gas chromatography-mass
spectrometry (GC-MS) were performed for the metabolite
analysis.
Both aerobic and resistance exercise reduce glucose exposure over the next 48 hours. However, there is a higher risk of
late-onset nocturnal hypoglycemia with aerobic exercise
compared with resistive exercise. This finding has important
implications for medication prescription and dietary recommendations to the diabetic population. Also, caution should
be taken when aerobic exercise is scheduled at times when
late-onset hypoglycemia is likely to occur during sleep.
Comment
Prescription of exercise to diabetic patients is a common
practice among health professionals. Physical activity
guidelines have been established for the diabetic population; however, there is a need for understanding the
effects of exercise in a nuanced way. This study sheds
light on the acute effects of exercise on glycemia in the
type 2 population. Acute aerobic exercise exhibits a
higher likelihood of causing late-onset hypoglycemia
than resistive exercise, similar to what has recently been
reported for patients with T1DM (6). This finding is vital
to exercise induced hypoglycemia prevention, especially
during nocturnal periods. Unfortunately, there is no indication that the aerobic exercise group and the resistive
exercise group performed an equivalent amount of exercise. Therefore, there is a potential for exercise volume
to be a confounding variable. Further research should be
done where comparisons of equivalent amounts of work
(energy expenditure) are performed. Moreover, studies
should investigate the intensity and duration of aerobic
exercise that is least likely to cause hypoglycemia.
Metabolomics approach for analyzing the effects
of exercise in subjects with type 1 diabetes mellitus
Brugnara L1,2, Vinaixa M 2,3, Murillo S 1,2, Samino S 3,4,
Rodriguez MA 2,3, Beltran A 3,4, Lerin C 1,2, Davison G 5,
Correig X 2–4, Novials A1,2
1
Department of Endocrinology, Institut d’Investigacions Biomèdiques
August Pi i Sunyer (IDIBAPS), Hospital Clı́nic de Barcelona, Barcelona, Spain; 2Spanish Biomedical Research Centre in Diabetes and
Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain;
3
Metabolomics Platform, Universitat Rovira i Virgili, Tarragona,
Spain; 4Institut d’Investigació Sanitària Pere Virgili (IISPV), Reus,
Spain; and 5Sport and Exercise Sciences Research Institute, University of Ulster, Newtownabbey, Northern Ireland, United Kingdom
PLoS One 2012; 7:e40600
Methods
Results
Before the exercise intervention, glucose, insulin, tricarboxylic acid (TCA) intermediates, and glycerol were higher
and lysine was lower in the diabetic group compared with the
control. After the exercise bout, glucose decreased and insulin
increased significantly in the diabetic group, whereas there
were no significant changes in the control. Gluconeogenic
precursors elevated in both groups; however, the elevation
was higher in the control. The same trend was observed with
TCA cycle intermediates. Significant increase in lipolytic
products was observed only in the control, with no significant
changes in the diabetic group. Branched chain amino acids
were significantly reduced in the control group only. Alphaketoisocaproic acid was significantly increased only in the
control group. Lysine was significantly increased only in diabetic group.
Conclusions
Overall, the metabolic response to high-intensity acute
exercise was similar in the T1DM group and the control.
However, the T1DM group showed a weaker response than
their control counterparts. Subjects in the T1DM group
showed an elevation in serum lactate, whereas the control
group showed an increase in lactate and pyruvate in response to exercise. This finding suggests that glycogenolysis and glycolysis are less activated after exercise in the
T1DM group than in the control. This may be explained by
the increased insulin in the T1DM group compared with the
control. The reduced pyruvate in T1DM patients in
S-96
response to exercise may be responsible for the reduced
TCA cycle replenishment. Lipolysis is also lower in the
T1DM group than in the control in response to exercise.
These findings may suggest an impaired oxidative aerobic
system in T1DM patients. Furthermore, data from this
study suggest that protein catabolism is also attenuated in
T1DM patients.
Comment
Although regular exercise is beneficial for most patients
with T1DM (7), metabolic disturbances may be caused by
acute exercise that may make glucose control challenging. In this study, although the patients with T1DM could
all do the exercise task (intense cycling for 30 minutes),
their fuel mobilization and utilization of energy differed
somewhat compared with the age-matched controls. In
general, it would appear from this study that at the onset
of strenuous exercise, patients with T1DM have a sluggish breakdown of stored liver and muscle glycogen, a
reduced energy flux through the TCA cycle, and reduced
rates of adipose mobilization. It may be that the failure to
lower circulating insulin levels at the onset of exercise
promotes these disturbances in fuel mobilization. Nonetheless, the job still can get done!
Short-term exercise training improves insulin sensitivity
but does not inhibit inflammatory pathway in immune
cells from insulin-resistant subjects
Reyna SM 1–3, Tantiwong P 2,3, Cersosimo E 2,3,
DeFronzo RA 2,3, Sriwijitkamol A 2, Musi N 2–4
1
Medical Research Division, Regional Academic Health Center,
Edinburg, TX; 2Diabetes Division, University of Texas Health
Science Center at San Antonio, San Antonio, TX; 3Texas Diabetes Institute, San Antonio, TX; and 4Geriatric, Research,
Education, and Clinical Center, Audie L. Murphy VA Hospital,
San Antonio, TX
J Diabetes Res 2013; 2013: 107805
Aim
To determine if exercise improves insulin sensitivity in insulin-resistant subjects by downregulating proinflammatory
signaling in immune cells.
Methods
The study included 17 lean, 8 obese nondiabetic, and 11
obese subjects with T2DM. Five T2DM subjects were diettreated, three T2DM subjects were newly diagnosed, and
one T2DM participant was diagnosed 2 months before the
study. Three months before the study, the subjects did not
exercise or only exercised once during the week, had a
stable body weight varying only by 1 kg for 3 months before
the study, and underwent an insulin clamp procedure
within 1–2 weeks after measuring subjects’ baseline VO2peak. The subjects participated in a supervised exercise
program within 1 week of the insulin clamp. The program
consisted of a 40-minute cycle ergometer exercise for 15
consecutive days. The subjects’ blood samples were collected before and after the pre- and post-exercise insulin
RIDDELL ET AL
clamps to isolate the peripheral blood mononuclear
cells (PMNC). Toll-like receptors 4 and 2 (TLR4 and TLR2)
activity were detected with primary and secondary antibodies using enhanced chemiluminescence reagents. Using
Western blotting, researchers measured extracellular
signal-regulated kinase (ERK) phosphorylation; C-Jun
amino-terminal kinase ( JNK) was measured as well. An
enzyme-linked immunosorbent assay (ELISA) kit measured nuclear factor-kappa-light-chain-enhancer of activated B cells (NFjB p65) binding, which plays a key role in
regulating the immune response to infection.
Results
Subjects with T2DM had the highest fasting glucose
levels, inflammatory, and endothelial markers. Obese and
subjects with T2DM had a higher fasting insulin level,
HbA1c, and non-esterified fatty acid (NEFA) concentration
than the control lean group. Based on the lower total glucose disposal using the insulin clamp, diabetic and obese
populations had more insulin resistance than the lean
population. The diabetic and obese groups did not significantly decrease BMI or weight with the increase in exercise.
Also, no change occurred in HbA1c, NEFA, glucose, and
plasma insulin levels. After exercise, insulin sensitivity increased by 11% in lean, 15% in obese, and 32% in T2DM
groups ( p < 0.05 in all groups). TLR4 protein (activates
immune system) levels in the PMNC subjects with diabetes
were 4.2-fold higher compared with the lean subjects
( p < 0.05). TLR4 was 2.7-fold ( p = 0.07) higher in the obese
than in the lean group. Neither exercise training nor insulin
therapy changed LR2 levels in the PMNC group. Diabetic
subjects also had higher baseline ERK phosphorylation, but
hyperinsulinemia during the insulin clamp did not significantly affect ERK phosphorylation. JNK phosphorylation
was not affected by insulin infusion or exercise. Neither
insulin nor exercise affected NFjB p65 DNA binding in the
lean, obese, and T2DM subjects.
Conclusions
PMNC cells were isolated because they fight infection
and adapt to intruders. These cells allowed the research to
conclude that diabetic patients have increased proinflammatory signaling, shown by increased TLR4 and ERK
phosphorylation. TLR4, TLR2 are important in the activation of the innate immune system, while ERK phosphorylation refers to a signaling pathway composed of proteins
and enzymes involved in cellular processes, mainly cell
survival and apoptosis. ERK deletion has been shown to
improve insulin sensitivity in skeletal muscle and reduce
liver fat content (8). While exercise improved insulin sensitivity in the lean, obese, and T2DM groups, it did not help
with the proinflammatory state, as measured by TLR content and ERK phosphorylation. Since proinflammatory
monocytes adhere more strongly to activated endothelial
cells and are precursors to the CD16 + macrophages distributed in atherosclerotic lesions, changes in TLR4 protein
content and ERK signaling may have affected the results.
Contrary to studies in mice that suggest that JNK plays an
important role in the pathogenesis of obesity and insulin
resistance (9), the JNK phosphorylation was not affected by
insulin infusion nor exercise.
S-97
28
Comment
This research shows that exercise is beneficial for insulin
sensitivity but not for downregulating proinflammatory
signaling in immune cells. It also suggests that insulin
sensitivity and inflammation are not tightly coupled. This
study is a stepping stone for further research in linking
the immune response with insulin resistance and exercise
not only because of the interesting results, but also because it references at least two studies that either supported or conflicted with each finding.
Cardiovascular effects of intensive lifestyle intervention
in type 2 diabetes
Look AHEAD Research Group, Wing RR 1, Bolin P 2,
Brancati FL 3, Bray GA 4, Clark JM 5, Coday M 6, Crow RS 7,
Curtis JM 8, Egan CM 9, Espeland MA10, Evans M11,
Foreyt JP12, Ghazarian S 13, Gregg EW14, Harrison B 15,
Hazuda HP 16, Hill JO17, Horton ES18, Hubbard VS19,
Jakicic JM 20, Jeffery RW 21, Johnson KC 22, Kahn SE 23,
Kitabchi AE 24, Knowler WC 25, Lewis CE 26,
Maschak-Carey BJ 27, Montez MG 28, Murillo A 29,
Nathan DM 30, Patricio J 31, Peters A 32, Pi-Sunyer X 33,
Pownall H 34, Reboussin D 35, Regensteiner JG 36,
Rickman AD 37, Ryan DH 38, Safford M 39, Wadden TA 40,
Wagenknecht LE 41, West DS 42, Williamson DF 43,
Yanovski SZ 44
1
Weight Control and Diabetes Research Center, Warren Alpert
Medical School of Brown University and Miriam Hospital, Providence, RI; 2National Institute of Diabetes and Digestive and
Kidney Diseases, National Institutes of Health, Bethesda, MD;
3
Johns Hopkins School of Medicine, Baltimore, MD; 4Pennington
Biomedical Research Center, Baton Rouge, LA; 5Johns Hopkins
School of Medicine, Baltimore, MD; 6Department of Preventive
Medicine, University of Tennessee Health Sciences Center,
Memphis, TN; 7Division of Epidemiology and Community Health,
University of Minnesota, Minneapolis, MN; 8NIH/NIDDK
Southwest American Indian Center; 9Weight Control and Diabetes
Research Center, Warren Alpert Medical School of Brown
University and Miriam Hospital, Providence, RI;10Department of
Biostatistical Sciences, Wake Forest University School of Medicine,
Winston-Salem, NC; 11NIH/NIDDK, Bethesda, MD; 12Department of Medicine, Baylor College of Medicine, Houston, TX;
13
Roybal Comprehensive Health Center, Los Angeles, CA; 14Centers for Disease Control and Prevention, Atlanta, GA; 15NIH/
NIDDK, Bethesda, MD; 16Department of Clinical Epidemiology,
University of Texas Health Science Center at San Antonio, San
Antonio, TX; 17Center for Human Nutrition, University of Colorado Health Sciences Center, Aurora, CO; 18Joslin Diabetes
Center, Boston, MA; 19NIH/NIDDK, Bethesda, MD; 20Department of Health and Physical Activity, University of Pittsburgh,
Pittsburgh, PA; 21Division of Epidemiology and Community
Health, University of Minnesota, Minneapolis, MN; 22Department
of Preventive Medicine, University of Tennessee Health Sciences
Center, Memphis, TN; 23Department of Medicine, University of
Washington, Seattle, WA; 24Department of Preventive Medicine,
University of Tennessee Health Sciences Center, Memphis, TN;
25
NIH/NIDDK Southwest American Indian Center, Phoenix, AZ;
26
Division of Preventive Medicine, University of Alabama
at Birmingham, Birmingham, AL; 27Weight and Eating Disorder Program, University of Pennsylvania, Philadelphia, PA;
Department of Clinical Epidemiology, University of Texas
Health Science Center at San Antonio, San Antonio, TX; 29Department of Medicine, University of Washington, Seattle, WA;
30
Diabetes Unit, Massachusetts General Hospital, Boston, MA;
31
Department of Medicine, St. Luke’s–Roosevelt Hospital, New
York, NY; 32Roybal Comprehensive Health Center, Los Angeles,
CA; 33Department of Medicine, St. Luke’s–Roosevelt Hospital,
New York, NY; 34Department of Medicine, Baylor College of
Medicine, Houston, TX; 35Department of Biostatistical Sciences,
Wake Forest University School of Medicine, Winston-Salem, NC;
36
Center for Women’s Health Research, University of Colorado
Health Sciences Center, Aurora, CO; 37Department of Health and
Physical Activity, University of Pittsburgh, Pittsburgh, PA;
38
Pennington Biomedical Research Center, Baton Rouge, LA;
39
Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL; 40Weight and Eating Disorder Program, University of Pennsylvania, Philadelphia, PA; 41Division of
Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC; 42Department of Health Behavior and
Health Education, College of Public Health, University of Arkansas
for Medical Sciences, Little Rock, AR; 43Centers for Disease Control and Prevention, Atlanta, GA; 44NIH/NIDDK, Bethesda, MD
N Engl J Med 2013; 369: 145–54
To determine whether a long-term intensive lifestyle intervention for weight loss decreases cardiovascular morbidity
and mortality for overweight or obese patients with T2DM.
Methods
The study followed 5,145 overweight or obese T2DM patients for up to 13.5 years. Each patient was randomly assigned to an intervention (targeting a 7% loss in body weight)
or control group. The intervention group emphasized weight
loss through decreased caloric intake and increased physical
activity, while the control group emphasized diabetes support
and education.
Results
The intervention group had greater weight loss than the
control group (8.6% vs. 0.7% at 1 year, 6.0% vs. 3.5% at study
end). Additionally, the intervention group reduced glycated
hemoglobin and initially improved fitness and all cardiovascular risk factors, besides low-density-lipoprotein cholesterol
levels, more so than the control group. The primary outcome
(composite of death from cardiovascular causes, nonfatal
myocardial infarction, nonfatal stroke, or hospitalization for
angina) occurred in 403 intervention patients and in 418
control patients. The trial was stopped early (after a follow-up
of *9 years) when interim analyses suggested that the intervention was having a neutral effect on the primary outcome.
Conclusions
The long-term intensive lifestyle intervention focusing on
weight loss failed to reduce the rate of cardiovascular events
in overweight or obese adults with T2DM. However, the intervention group had greater weight loss, reductions in glycated hemoglobin, and greater initial improvements in fitness
and cardiovascular risk factors than the control group.
S-98
Comment
These findings appear to suggest that lifestyle interventions
do not effectively reduce the rate of cardiovascular events in
patients with T2DM. This is surprising since a plethora of
studies support the recommendation for overweight or
obese patients to improve health status by losing weight
with diet and exercise. A short-term 16-week study indicated that a very-low-calorie diet improved the cardiovascular risk profile (metabolic profile, heart function, and
triglyceride stores in nonadipose tissues) in adults with
T2DM (10). This also counters observational studies that
have been reported that greater fitness is associated with
reduced risk of developing T2DM (11,12). The long followup period implemented in this study may have been the
key factor in achieving such a different result. This study
employed an interesting angle by educating the support
group. Overall, the cardiovascular events were relatively
low in both groups (all patients were aggressively treated
with cardioprotective drugs) and thus detecting differences
between the two intervention groups may have been difficult in the period studied.
Correlations of non-exercise activity thermogenesis
to metabolic parameters in Japanese patients
with type 2 diabetes
Hamasaki H 1,2, Yanai H1, Mishima S 1, Mineyama T 1,
Yamamoto-Honda R 3,4, Kakei M 2,5, Ezaki O 3,6, Noda M 3,4
1
Department of Internal Medicine, National Center for Global
Health and Medicine Kohnodai Hospital, Chiba, Japan; 2General
Internal Medicine, Community Healthcare Studies, Jichi Medical
University Graduate School, Tochigi, Japan; 3Department of Diabetes and Metabolic Medicine, Center Hospital, National Center
for Global Health and Medicine, Tokyo, Japan; 4Department of
Diabetes Research, Diabetes Research Center, National, Center for
Global Health and Medicine, Tokyo, Japan; 5First Department of
Comprehensive Medicine, Saitama Medical Center, Jichi Medical
University School of Medicine, Saitama, Japan; and 6Department
of Human Health and Design, Faculty of Human Life and Environmental Sciences, Showa Women’s University, Tokyo, Japan
Diabetol Metab Syndr 2013; 5: 26
RIDDELL ET AL
the study. As outlined by Ainsworth and colleagues’ guidelines
(13), each questionnaire item was given a score of 1–3 points in
order of levels of habitual physical activity, and then the scores
were added to determine the overall NEAT score. This score was
then compared with the subjects’ body weight, waist circumference, blood pressure, glucose and lipid metabolism, and arterial stiffness using Pearson’s correlation coefficients.
Results
The NEAT score was negatively correlated with serum
insulin levels (all subjects) and was negatively correlated with
waist circumference and positively correlated with highdensity lipoprotein cholesterol levels in women. The NEAT
score was negatively associated with serum insulin levels and
systolic and diastolic blood pressure in patients with abdominal obesity.
Conclusion
A high NEAT score is associated with benefiting insulin
sensitivity, waist circumference, high-density lipoprotein
cholesterol, blood pressure, and atherosclerosis in patients
with T2DM. Obese patients with both T2DM and hypertension had a significantly lower likelihood of adopting physical
activity to control their weight compared with patients with
neither condition (6% vs. 12%, p < 0.01) (14). This implies that
NEAT is more crucial for controlling body weight in obese
patients with T2DM in comparison to those without T2DM.
Comment
This is a cross-sectional study limiting inferences of
causality and its direction. The small sample size limited
the study as well. For instance, the significant correlation
between NEAT and serum insulin may have been highly
influenced by three subjects with very high insulin and
low NEAT. The primary drawback of this study was the
subjective questionnaire, rather than using more objective measures of energy expenditure. Moreover, selfreports do not account for other potentially contributing
factors, such as genetics or aerobic capacity, underlying
both the increased NEAT scores and health variables
measured. Particularly interesting to us was why only the
female patients’ NEAT score was negatively associated
with waist circumference and positively associated with
high-density lipoprotein cholesterol levels. Is it truly a
sex-related phenomenon?
To determine how non-exercise activity thermogenesis
(NEAT) is associated with cardiovascular risk factors in patients with T2DM. The NEAT score is the energy expenditure
due to physical activities other than planned exercise (i.e.,
sports, planned exercise) in daily life. Examples include
commuting to work, attending school, singing, dancing,
washing clothes, and cleaning.
Determinants of the changes in glycemic control with
exercise training in type 2 diabetes: a randomized trial
Methods
Pennington Biomedical Research Center and Louisiana State
University, Baton Rouge, LA
The researchers questioned 45 subjects about their physical
activity patterns using an original NEAT questionnaire that
evaluated physical activity habits. The subjects consisted of 22
women and 23 men with T2DM, aged between 20 and 90 years,
who did not take any hypoglycemic, antihypertensive, or
cholesterol-lowering agents. Subjects who engaged in active
sports-like exercise and resistance training were excluded from
Johannsen NM, Sparks LM, Zhang Z, Earnest CP, Smith SR,
Church TS, Ravussin E
PLoS One 2013; 8: e62973
To examine the effects of chronic exercise training on total
serum adiponectin, free fatty acid (FFA) concentrations, and
skeletal muscle peroxisome proliferator-activated receptor-c
coactivator-1a (PGC-1a) protein content and their relationship
to changes in glycemic control (HbA1c) in T2DM.
S-99
Methods
A subcohort of 35 patients (mean age 57.0 – 7.7 years, 48%
men, 74% Caucasian) from the Health Benefits of Aerobic and
Resistance Training in Type 2 Diabetes study was analyzed.
Participants were randomized to 9 months of aerobic training,
resistance training, combination of both, or a nonexercise group.
Muscle biopsies and serology were collected pre- and postintervention.
Results
Changes in HbA1c were inversely associated with changes in
serum adiponectin levels (r = - 0.45, p = 0.007). Participants diagnosed with T2DM for a longer duration had the largest increase in PGC-1a (r = 0.44, p = 0.008). Statistical modeling
examining changes in HbA1c suggested that male sex ( p = 0.05),
non-Caucasian ethnicity ( p = 0.02), duration of T2DM (r = 0.40;
p < 0.002), and changes in FFA (r = 0.36; p < 0.004), adiponectin
(r = - 0.26; p < 0.03), and PGC-1a (r = - 0.28; p = 0.02) levels explained 65% of the variability in the changes in HbA1c.
Conclusion
Changes in HbA1c after 9 months of exercise were independently associated with the duration of T2DM and changes
in serum FFA and negatively associated with changes in serum adiponectin and skeletal muscle PGC-1a.
Comment
T2DM is as much a disease of disordered lipid metabolism
as a disease of abnormal glucose metabolism. Individuals
with T2DM have an elevation in serum FFA and a reduction
in plasma adiponectin and PGC-1a expression in skeletal
muscle. PGC-1a is a key regulator of mitochondrial biogenesis and oxidative metabolism, which is critical in helping maintain muscle insulin sensitivity and efficient
metabolism. Decreases in HbA1c after 9 months of exercise
were associated with shorter duration of diabetes, lowering
of serum FFA concentrations, increasing serum adiponectin
concentrations, and increasing skeletal muscle PGC-1a
protein expression. A program of combined aerobic and
resistance training has the greatest effect on HbA1c. Resistance training alone may potentiate a greater change in
PGC-1a and, therefore, HbA1c. Based on this study, individuals who start an exercise program soon after diagnosis
of diabetes may see a larger effect on HbA1c levels. A prescription for exercise training programs for T2DM should be
aimed at improving plasma substrate availability, endocrine function, and skeletal muscle factors shown to improve glycemic outcomes.
References
1. Yardley JE, Stapleton JM, Sigal RJ, Kenny GP. Do heat events
pose a greater health risk for individuals with type 2 diabetes? Diabetes Technol Ther 2013; 15: 520–29.
2. Fang ZY, Sharman J, Prins JB, Marwick TH. Determinants of
exercise capacity in patients with type 2 diabetes. Diabetes
Care 2005; 28: 1643–48.
3. Grelier SF, Serresse OF, Boudreau-Lariviere CF, Zory R.
Effects of a three-month combined training program on
the cardiopulmonary and muscle strength capacities of
type 2 diabetic subjects. J Sports Med Phys Fitness 2013; 53:
56–64.
4. O’Hagan C, De Vito G, Boreham CA. Exercise prescription
in the treatment of type 2 diabetes mellitus: Current practices, existing guidelines and future directions. Sports Med
2013; 43: 39–49.
5. Copeland KC, Silverstein J, Moore KR, et al. Management of
newly diagnosed type 2 diabetes mellitus (T2DM) in children and adolescents. Pediatrics 2013; 131: 364.
6. Yardley JE, Kenny GP, Perkins BA, et al. Resistance versus
aerobic exercise: acute effects on glycemia in type 1 diabetes.
Diabetes Care 2013; 36: 537–42.
7. Chimen M, Kennedy A, Nirantharakumar K, et al. What
are the health benefits of physical activity in type 1 diabetes mellitus? A literature review. Diabetologia 2012; 55:
542–51.
8. Jager J, Corcelle V, Grémeaux T, et al. Deficiency in the extracellular signal-regulated kinase 1 (ERK1) protects leptindeficient mice from insulin resistance without affecting
obesity. Diabetologia 2011; 54: 180–89.
9. Hirosumi J, Tuncman G, Chang L, et al. A central role for
JNK in obesity and insulin resistance. Nature 2002; 420:
333–36.
10. Snel M, Jonker JT, Hammer S, et al. Long-term beneficial
effect of a 16-week very low calorie diet on pericardial fat in
obese type 2 diabetes mellitus patients. Obesity (Silver
Spring) 2012; 20: 1572–76.
11. Sui X, Hooker SP, Lee IM, et al. A prospective study of
cardiorespiratory fitness and risk of type 2 diabetes in women. Diabetes Care 2008; 31: 550–55.
12. Tudor-Locke C, Bell RC, Myers AM, et al. Controlled outcome evaluation of the First Step Program: A daily physical
activity intervention for individuals with type II diabetes. Int
J Obes Relat Metab Disord 2004; 28: 113–19.
13. Ainsworth BE, Haskell WL, Herrmann SD, et al. Compendium of physical activities: A second update of codes and
MET values. Med Sci Sports Exerc 2011; 5: 1575–81.
14. Zhao G, Ford ES, Li C, Mokdad AH. Weight control
behaviors in overweight/obese U.S. adults with diagnosed hypertension and diabetes. Cardiovasc Diabetol
2009; 5: 13.
DOI: 10.1089/dia.2014.1512
ORIGINAL ARTICLE
Diabetes Technology and Therapy
in the Pediatric Age Group
Shlomit Shalitin1 and H. Peter Chase 2
Introduction
T
ype 1 diabetes (T1D) is one of the most common chronic
childhood diseases, and its incidence appears to be rising
(1). The intensive treatment regimen for T1D is complex and
demanding, requiring multiple daily doses of insulin (administered by injections or pump), frequent monitoring of
blood glucose levels, accounting for carbohydrate intake,
and making adjustments to insulin intake based on changes in
diet and activity. As children reach adolescence, metabolic
control often deteriorates because of the hormonal changes of
puberty associated with insulin resistance (2) and because of
increasing self-management autonomy leading to lower adherence to the treatment regimen (3). Thus, there are unique
challenges in caring for children and adolescents with T1D
that differentiate pediatric from adult care.
Current standards for diabetes management reflect the
need to maintain blood glucose levels as near to normal as
safely as possible. Substantial evidence demonstrated the
relationship between glucose control and diabetic complications (4). Yet, special consideration must be given to the unique risks of hypoglycemia, especially in young children.
Nighttime is a time of considerable concern because of nocturnal hypoglycemia. Furthermore, it has been reported that
the most severe hypoglycemic events in children occur during
the night, accounting for 75% of all hypoglycemic seizures
(5). In addition, extensive evidence indicates that nearnormalization of blood glucose levels is seldom attainable in
children and adolescents after the remission period (6,7).
Therefore, the development of modern medical technologies
may help children and adolescents with T1D and their families to cope with the stress of modern diabetes management
and to live a normal life.
In the last year, the studies reviewed below evaluated the
implications and advantages of using the real-time continuous glucose monitoring (CGM) that provides 24-hour continuous glucose measurements, alone or as a part of the
sensor-augmented pump (SAP) therapy in pediatric patients.
However, it is still necessary to develop an artificial pancreas that could potentially solve the problem of hypoglycemia and hyperglycemia by taking over the decision-making
process and applying sophisticated computer algorithms to
decide how much insulin is needed at any given moment. In
the last year, there was a breakthrough in the development of
some prototypes of closed-loop (CL) systems. Results about
the safety and efficacy of these systems in the hospital, at
home, and at diabetes camp are reviewed below.
Our review of the literature included a Medline search for
articles dealing with the following topics: diabetes technology, insulin pump therapy (continuous subcutaneous insulin
infusion, CSII), CGM, CL systems, and new therapies in T1D
relating to the pediatric age group (0–18 years). We focused on
recent key articles that offer some insight into these issues that
have appeared between July 1, 2012, and June 30, 2013.
Most youth with type 1 diabetes in the T1D Exchange
Clinic registry do not meet American diabetes
association or international society for pediatric
and adolescent diabetes clinical guidelines
Wood JR 1, Miller KM 2, Maahs DM 3, Beck RW 1,
Dimeglio LA 4, Libman IM 5, Quinn M 6, Tamborlane WV 7,
Woerner SE 4, for the EXCHANGE Clinic Network
1
Children’s Hospital Los Angeles, Los Angeles, CA; 2Jaeb Center
for Health Research, Tampa, FL; 3Barbara Davis Center for
Childhood Diabetes, Aurora, CO; 4Indiana University School of
Medicine, Indianapolis IN; 5Children’s Hospital of Pittsburgh,
Pittsburgh, PA; 6Children’s Hospital of Boston, Boston, MA; and
7
Yale University, New Haven, CT
Diabetes Care 2013; 36: 2035–37
Background
The Diabetes Control and Complications Trial and the
Epidemiology of Diabetes Interventions and Complications
1
Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children’s
Medical Center of Israel, Petah Tikva, Israel.
2
Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, CO.
S-100
DIABETES TECHNOLOGY AND THERAPY IN THE PEDIATRIC AGE GROUP
studies have demonstrated in adolescents with T1D that intensive diabetes management significantly reduces the risk of
vascular complications. Both the American Diabetes Association (ADA) and the International Society for Pediatric and
Adolescent Diabetes (ISPAD) have established targets for
HbA1c levels, blood pressure (BP), lipids, and body mass
index (BMI) for youth with T1D. The aim of this study was to
assess the proportion of youth with T1D under the care of
pediatric endocrinologists in the United States who are
meeting targets for HbA1c, BP, BMI, and lipids.
number of youth with diabetes already have additional vascular disease risk factors at a young age.
Comment
Significant advances in diabetes management have occurred, including newer and more physiologic insulin analogs, sophisticated blood glucose monitoring, and insulin
delivery technologies such as CSII and CGM. However,
despite advances in technologies and strategies for care,
achieving HbA1c targets remains a significant challenge for
the majority of youth in the T1D Exchange Clinic registry.
Similarly, the SEARCH for Diabetes in Youth Study documented a relatively high percentage of pediatric patients
with diabetes who do not achieve the glycemic targets (7).
These data emphasize the importance of finding better
therapies for youth with diabetes to prevent future
complications and stress the need for additional work in
identifying the barriers to care, especially in adolescents.
Methods
The T1D Exchange Clinic Network includes 67 U.S.-based
pediatric or adult endocrinology practices. This report includes
13,316 participants enrolled through August 2012, who were
younger than 20 years at enrollment with T1D for > 1 year.
Data were collected for the registry’s database from the participant’s medical record and by a questionnaire completed by
the participant or parent. HbA1c measurement taken within 6
months before enrollment was available for 99% of participants. Data for BP and BMI were available for 95% and 98% of
participants, respectively. Data were categorized according to
the following ADA and ISPAD targets: HbA1c ADA < 8.5% for
those younger than 6 years, < 8.0% for those 6–13 years of age,
and < 7.5% for those 13–20 years of age; ISPAD £ 7.5% for all
ages; BP < 90th percentile for age, sex, and height; BMI < 85th
percentile for age and sex; LDL < 100 mg/dL ( < 2.6 mmol/L);
HDL (ADA > 35 mg/dL; ISPAD > 1.1 mmol/L); and triglycerides < 150 mg/dL ( < 1.7 mmol/L).
Results
Among the pediatric participants, 5% were younger than 6
years, 40% were 6–13 years of age, and 55% were 13–20 years of
age (mean age, 12.7 years; mean diabetes duration, 5.6 years;
48% female; 78% non-Hispanic white). An insulin pump was
used by 55% of participants and a CGM was used by 3%. The
median number of self-reported self-blood glucose monitoring
(SBGM) per day was 5. The age-specific ADA HbA1c target
was met by 32% of participants and the ISPAD HbA1c target
was met by 25% of participants. The percentage meeting ADA
and ISPAD HbA1c targets was higher in the younger age
groups compared with the group aged 13–20 years ( p < 0.001).
Among pump users 1–6 years old, the proportions of participants meeting the ADA and ISPAD HbA1c targets were 79%
and 37% compared with 50% and 17% among injection users
( p < 0.001, adjusted for diabetes duration, race/ethnicity,
household income, insurance, and SBGM per day). In those
aged 6–13 years, 50% and 32% of insulin pump users met the
ADA and ISPAD HbA1c targets compared with 34% and 20%
of injection users ( p < 0.001). In the group aged 13–20 years,
there was no significant difference in the percentage meeting
HbA1c targets between insulin pump users and injection users.
Only 14% of non-Hispanic black participants met the ADA
HbA1c target compared with 34% and 28% in non-Hispanic
white and Hispanic participants (adjusted p < 0.001). The majority of participants met targets for BP and lipids, and twothirds met the BMI goal of < 85th percentile.
Conclusions
Only approximately one-third of participants met the agespecific ADA and ISPAD targets for HbA1c. Moreover, a large
S-101
The use and efficacy of continuous glucose
monitoring in type 1 diabetes treated with insulin
pump therapy: a randomized controlled trial
Battelino T1, Conget I 2, Olsen B 3, Schütz-Fuhrmann I 4,
Hommel E 5, Hoogma R 6, Schierloh U 7, Sulli N 8, Bolinder J 9,
the SWITCH Study Group
1
UMC—University Children’s Hospital, Faculty of Medicine,
University of Ljubljana, Ljubljana, Slovenia; 2Diabetes Unit,
ICMDM Hospital Clı́nici Universitari, Barcelona, Spain;
3
Glostrup Hospital, Glostrup, Denmark; 4Hospital Hietzing,
Vienna, Austria; 5Steno Diabetes Center, Gentofte, Denmark;
6
Groene Hart Ziekenhuis, Gouda, The Netherlands; 7Clinique Pediatrique, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg; 8Clinica Pediatrica, Servizio Diabetologia, Policlinico
Umberto I, Rome, Italy; and 9Department of Medicine, Karolinska
University Hospital Huddinge, Karolinska Institute, Stockholm,
Sweden
Background
SAP, combining CSII and CGM, has been shown to significantly decrease HbA1c without an increase in hypoglycemia in adults and children, as compared with multiple daily
injections (MDI) (8). However, studies investigating whether
SAP can further improve glycemic control in patients with
T1D using CSII alone have yielded conflicting results. The aim
of the study was to determine whether patients with poorly
controlled T1D treated with CSII can achieve improved metabolic control with the addition of personal CGM, and to
evaluate associated changes in insulin treatment patterns
while using SAP.
Methods
In this randomized, controlled, crossover study, children
and adults (n = 153) on CSII with HbA1c 7.5–9.5% (58.5–
80.3 mmol/mol) were randomized to a ‘‘Sensor On’’ or ‘‘Sensor
Off’’ arm for 6 months. After 4 months’ washout, participants
crossed over to the other arm for 6 months. The primary outcome was the difference in HbA1c levels between arms after 6
S-102
months, adjusting for baseline levels. Secondary endpoints
included changes in glycemic patterns, as expressed by mean
24-hour glucose and 24-hour AUC values, and changes in
the time spent in hypoglycemia ( < 70 mg/dL [ < 3.9 mmol/L]),
in hyperglycemia ( > 180 mg/dL [ > 10 mmol/L]), and in euglycemia (70–180 mg/dL [3.9–10 mmol/L]).
Results
Participants were randomized to the ‘‘On’’/‘‘Off’’ sequence
(n = 77; 37 children of mean age 12 – 3.6 years) and to the
‘‘Off’’/‘‘On’’ sequence (n = 76; 35 children of mean age 12 – 3.2
years). The mean difference in HbA1c for the cohort was
- 0.43% ( - 4.74 mmol/mol) in favor of the ‘‘Sensor On’’ arm
(8.04% [64.34 mmol/mol] vs. 8.47% [69.08 mmol/mol];
p < 0.001). The mean difference was - 0.46% ( - 5.0 mmol/mol,
p < 0.001) in pediatric participants and - 0.41% ( - 4.4 mmol/
mol, p < 0.001) in adult participants. After cessation of glucose
sensing, HbA1c reverted to baseline levels. Less time was
spent with sensor glucose < 70 mg/dL [ < 3.9 mmol/L] during
the ‘‘Sensor On’’ arm than in the ‘‘Sensor Off’’ arm (19 vs.
31 min/day; p = 0.009). In the ‘‘Sensor On’’ arm, there was an
increase in the mean number of daily boluses (6.8 – 2.5 vs.
5.8 – 1.9, p < 0.0001), in the frequency of use of the temporary
basal rate (0.75 – 1.11 vs. 0.26 – 0.47, p < 0.0001), and in the
manual insulin suspend (0.91 – 1.25 vs. 0.70 – 0.75, p < 0.018)
functions. No significant difference was documented in the
number of severe hypoglycemic events between both arms.
Conclusions
This study demonstrated a decrease in HbA1c and a concurrent reduction in time spent in hypoglycemia through the addition of CGM to existing CSII for 6 months in patients with T1D.
Comment
Studies consistently showed that sufficient sensor use is
crucial to the success of CGM (8,9). In the present study,
72% of participants wore a sensor for more than 70% of the
required time. In the ‘‘On’’/‘‘Off’’ sequence, there was a
loss of effect after the removal of CGM during the washout
period and ‘‘Sensor Off’’ arm, whereas no change in the
HbA1c was observed during the washout period in the
‘‘Off’’/‘‘On’’ sequence. These findings again demonstrate
that the efficacy of CGM depends upon its continuous use.
Both pediatric and adult patients with T1D using CSII
therapy had a benefit from the addition of CGM with
improvement in HbA1c with a concomitant decrease in
time spent in hypoglycemia and hyperglycemia.
Factors that might contribute to lowering HbA1c levels
and reducing the time spent in hypoglycemia include the
following: with CGM, the participants used more frequent insulin bolus administration, more frequent temporary basal rates and manual basal suspend function,
and the bolus wizard calculator feature more frequently.
Hence, SAP was associated with more frequent selfadjustments of the insulin therapy.
It will be interesting to evaluate the impact of SAP
therapy for a longer period and also in others such as
young patients with hypoglycemic unawareness and
those with fear of hypoglycemia.
SHALITIN AND CHASE
Sensor-augmented pump therapy in very young
children with type 1 diabetes: an efficacy
and feasibility observational study
Frontino G 1, Bonfanti
Meschi F1, Rigamonti
Bonura C1, Sicignano
Cerutti F3, Chiumello
R 1, Scaramuzza A2, Rabbone I 3,
A 1, Battaglino R 1, Favalli V 1,
S 3, Gioia E 3, Vincenzo Zuccotti G 2,
G1
1
Endocrine Unit, Department of Pediatrics, Scientific Institute
Hospital San Raffaele, Vita-Salute University, Milan, Italy; 2Department of Pediatrics, University of Milan, Ospedale Luigi Sacco,
Milan, Italy; and 3Department of Pediatrics, University of Turin,
Turin, Italy
Background
There have been a number of reports on the efficacy and
safety of SAP therapy in older children and adults, but few
studies in very young children.
Methods
The SAP data were analyzed from 28 children (15 boys)
younger than 7 years (range, 3–7 years) with TID. The
DexCom Seven Plus CGM and Animas (model TR1200
or 2020) insulin pump were used. Efficacy and feasibility
were evaluated using a rating scale (with 3 being most
positive). Initial and final ( > 6 months) HbA1c values were
also analyzed.
Results
The SAP was used for at least 6 months by 85% of patients,
with an overall good satisfaction (92%). The greatest perceived benefit was the reduced fear of hypoglycemia (score of
3, 81%). HbA1c values significantly improved ( - 0.9%) only in
patients with baseline HbA1c > 7.5% ( p = 0.026).
Conclusions
The SAP was considered effective and feasible in this retrospective multicenter study. The significant drop in HbA1c
levels in the subgroup with baseline HbA1c levels > 7.5% was
the only statistically evaluated parameter reported.
Comment
When all subjects in this study were considered, the decrease in HbA1c ( - 0.2%) was not statistically significant.
Some of the reasons for discontinuation of the sensor use
are
difficult child compliance (n = 4)
skin reactions (n = 2)
sensor malfunctions (n = 3)
While this report shows that SAP therapy is feasible in
children aged £ 7 years, and is particularly beneficial
when HbA1c is > 7.5%, there are still areas that need
work. It will be important in future studies to evaluate
the potential to reduce severe lows (data not provided in
this report), which could be advantageous to neurologic
development in this young age group.
Effects of sensor-augmented pump therapy
on glycemic variability in well-controlled type 1
diabetes in the STAR 3 study
with T2D and has included subjects with cardiovascular
disease. Both of the latter groups were excluded in STAR 3
subjects, which may explain the negative findings in this
study. Further studies of CD40L may still be of interest in
patients with T1D and various diabetic complications.
Buse JB 1, Kudva YC 2, Battelino T 3, Davis SN 4, Shin J 5,
Welsh JB 5
1
University of North Carolina School of Medicine, Chapel Hill,
NC; 2Mayo Clinic, Rochester, MN; 3University Children’s Hospital, Ljubljana, Slovenia; 4University of Maryland School of
Medicine, Baltimore, MD; and 5Medtronic, Inc., Northridge, CA
Background
Glycemic variability has been suggested to contribute to the
risk of diabetic complications through induction of inflammation and oxidative stress. The STAR 3 trial (8) randomized
children and adults to receive either SAP therapy (n = 247) or
MDI therapy (n = 248) for 1 year.
Methods
Data from week-long CGM studies at baseline and at 1 year
from subjects in the STAR-3 trial were used to evaluate glycemic variability. In addition, soluble CD40 ligand (CD40L), a
biomarker of inflammation and thrombocyte function, was
measured at baseline and 1 year. Subject data were analyzed
by treatment group and HbA1c levels at 1 year.
Results
At 1 year, sensor glucose standard deviation (SD) and
coefficient of variation (CV) values were lower at HbA1c
levels < 8% among SAP than among MDI subjects; the overall
between-group difference was significant for both SD
( p < 0.01) and CV ( p = 0.01). The overall mean amplitude of
glycemic excursion was similar in the MDI and SAP groups
( p = 0.23). CD40L levels fell over the course of the study in
both groups, but the between-group difference was not significant ( p = 0.18). CD40L concentrations were unrelated to
HbA1c, change in HbA1c from baseline, or glycemic variability.
Conclusions
At comparable HbA1c levels of < 8% (but not above 8%),
SAP therapy reduced glycemic variability as measured by
CGM glucose SD and CV compared with MDI therapy. Mean
CD40L levels were not correlated with BMI, HbA1c, hypoglycemia, or CGM glucose SD.
Comment
SAP therapy may provide beneficial reductions in the
number and severity of glycemic excursions in comparison with MDI therapy in subjects with HbA1c levels
< 8%. It is unknown why a similar effect was not found
for subjects with an HbA1c value ‡ 8.0%. Possibly, glycemic variability was excessive in both the SAP and MDI
groups with the higher HbA1c values.
The CD40L biomarker did not appear related to
HbA1c levels or to glycemic variability. Much of the
previous research related to CD40L has been in patients
S-103
A prototype of a new noninvasive device to detect
nocturnal hypoglycemia in adolescents with type 1
diabetes—a pilot study
Schechter A 1, Eyal O 2,3, Zuckerman-Levin N 4,
Amihai-Ben-Yaacov V 1, Weintrob N 2,3, Shehadeh N 4,5
1
Gili Medical Ltd., Migdal HaEmek, Israel; 2Pediatric Endocrinology and Diabetes Unit, Dana Children’s Hospital, The Tel
Aviv Sourasky Medical Center, Tel Aviv, Israel; 3Sackler Faculty
of Medicine, Tel Aviv University, Tel Aviv, Israel; 4Department of
Pediatrics A and the Pediatric Diabetes Unit, Rambam Medical
Center, Meyer Children’s Hospital of Haifa, Haifa, Israel; and
5
Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
Background
CGM systems (CGMSs) were introduced to minimize the
risk of hypoglycemia in patients with diabetes. However, the
present CGMSs are invasive. Therefore, there is a need for a
noninvasive, convenient, reliable, and inexpensive device to
detect hypoglycemia. The Gili Medical hypoglycemia noninvasive monitoring system (GMHNIMS) has been currently
developed for these purposes. The aim of this study was to
test the newly developed device and to evaluate the ability of
the first prototype to reliably detect nocturnal hypoglycemic
events, and to test the correlation between the new algorithm
and the results of the CGMS.
Methods
The GMHNIMS consists of a monitor used to record in real
time several physiological parameters received from different
sensors, and a transmitter designed to evaluate the glucose
level, from which the hypoglycemia condition can be detected. The four sensors (heart rate, perspiration, skin temperature, and tremor) of the system detect physiologic
changes during hypoglycemia. The data collected are stored
in the monitoring system and transmitted to the Gili Medical
computer and analyzed by a built-in algorithm, and provide
an alarm if an event is detected. Patients with T1D (n = 10)
aged 14–18 years with diabetes duration for at least 1 year
participated in this pilot study. The GMHNIMS was connected to the study subjects during three consecutive nights in
an inpatient setting while they received their usual insulin
regimen (MDI or CSII). In addition, each patient was connected to a real-time CGMS for 3 nights. When a hypoglycemic event was suspected clinically by the patient, a bedside
capillary glucose was checked by a glucometer.
Results
The device was found to be well tolerated. The sensitivity of
the GMHNIMS for detection of true hypoglycemic events was
100% with specificity of 85.7%.
S-104
Conclusions
The GMHNIMS showed high detection rates of nocturnal
hypoglycemic events with an acceptable degree of falsepositive readings in young patients with T1D. The device
was found to be safe and convenient.
Comment
Severe hypoglycemic events often cause physical and
psychosocial morbidity and sometimes even mortality.
Fear of hypoglycemia hinders the successful implementation of intensive insulin therapy and demands a
huge effort filled with tension and anxiety. Nocturnal
hypoglycemia is reported in 13–56% of adolescents with
T1D. So far, no noninvasive method for detecting
asymptomatic nocturnal hypoglycemia has been proven
successful. Previous devices (e.g., HypoMon, GlucoWatch Biographer) have some limitations, including
relatively high incidence of false-positive alarms, calibration failure (especially with significant changes in skin
temperature or excessive sweating), and skin irritation.
Comparing the results obtained from the GMHNIMS
with hypoglycemic events suspected by the patient and
confirmed by the glucometer revealed extremely high
detection rates (100%) of the system with relative low
(14.3%) false-positive rates. These results imply that the
GMHNIMS can activate an alarm in order to try to wake
up the patient before severe nocturnal hypoglycemic
events and thus prevent deleterious effects, and also be of
aid during mild nocturnal hypoglycemic events.
The uniqueness of the device is the monitoring of
several physiological effects concurrently, along with an
algorithm for detecting an imminent hypoglycemic event
based on these physiological effects. These features may
improve the detection of hypoglycemia, and being
noninvasive may improve compliance with using the
device. Future research should include a larger sample
size and especially tightly controlled patients.
SHALITIN AND CHASE
of this study was to investigate the safety and efficacy of a
portable CL system used during the night.
Methods
Eight subjects with T1D were admitted to the Clinical Research Center for two nights (9 pm to 7 am) for CL control. The
Medtronic Portable Glucose Control System (PGCS), which
included a BlackBerry Storm smart phone platform, was used
with Bluetooth radiofrequency transmission.
Results
The mean overnight plasma glucose level was at
6.4 – 1.7 mmol/L (115 – 31 mg/dL) for the overnight studies.
Plasma glucose levels were maintained between 3.9 and
8 mmol/L (70–144 mg/dL) for 78% of the time, with 7% below
and 15% above this range. Plasma glucose levels below
3.3 mmol/L ( < 60 mg/dL) occurred in 3 of the 16 study nights.
There were no severe hypoglycemic events. Investigator intervention, most commonly for calibration of the sensor, was
required for 7 of the 16 nights.
Conclusions
The PGCS was safe and effective in achieving overnight
glucose control. The finding of 78% of glucose values in the
desired range was very positive.
Comment
Overnight CL glucose control will likely be the third
component approved for the CL pancreas (following
pump shut-off for hypoglycemia and then for predicted
hypoglycemia). This study used fault detection settings
regarding (a) correlation of sensor signals; (b) deviation
of sensor glucose (SG1 and SG2) from the mean (SG); (c)
mutual difference in rate of glucose change (direction of
trend); (d) loss of sensor signal, RF, or Bluetooth connectivity; and (e) insulin delivery limits. This is a first step
in improving safety with the PGCS. It is likely that further
fault detection methods will become available in the future. As glucose sensors continue to become more accurate and more reliable, overnight glucose control will be a
major advance in the treatment of people with T1D.
The use of an automated, portable glucose
control system for overnight glucose control
in adolescents and young adults with type 1 diabetes
O’Grady MJ 1,2, Retterath AJ 2, Keenan DB 3, Kurtz N 3,
Cantwell M 3, Spital G 3, Kremliovsky MN 3, Roy A 3,
Davis EA 1,2,4, Jones TW 1,2,4, Ly TT 1,2,4
1
Department of Endocrinology and Diabetes, Princess Margaret
Hospital for Children, Perth, Western Australia, Australia;
2
Telethon Institute for Child Health Research, Centre for Child
Health Research, The University of Western Australia, Perth,
Western Australia, Australia; 3Medtronic Minimed, Northridge,
CA; and 4School of Paediatrics and Child Health, The University of
Western Australia, Perth, Western Australia, Australia
Diabetes Care 2012; 35: 2182–87
Background
Management of T1D in the future will likely involve the CL
artificial pancreas. Achieving overnight glucose control using
a CL system will be easier than attaining daytime glucose
control when meals, stress, and exercise are present. The aim
Closed-loop basal insulin delivery over 36 hours
in adolescents with type 1 diabetes
Elleri D 1,2, Allen JM 1,2, Kumareswaran K2, Leelarathna L2,
Nodale M 2, Caldwell K 2, Cheng P 3, Kollman C 3, Haidar A 2,
Murphy HR 2, Wilinska ME 1,2, Acerini CL 1, Dunger DB1,2,
Hovorka R 1,2
1
Department of Paediatrics, University of Cambridge, Cambridge,
United Kingdom; 2Metabolic Research Laboratories, Institute of
Metabolic Science, Cambridge, United Kingdom; and 3Jaeb Center
for Health Research, Tampa, FL
Background
The CL insulin delivery system will likely be the preferred treatment of T1D in the future. Studies usually
begin with adults (10) and then, as in this and the following study, progress to adolescents and then to younger
children.
Methods
Twelve adolescents with T1D were studied on two occasions in a clinical research facility with either CL control
or conventional pump therapy (CPT) in random order.
The sensor used was the DexCom SEVEN PLUS and
the pump was the Animas 2020 from Johnson and Johnson. The safety and efficacy of CL insulin delivery were
evaluated during sleep and after regular meals and unannounced periods of exercise. Meal boluses were administered 10 minutes before meals except if finger-stick
glucose values were £ 72 mg/dL, when they were given
with the meal.
S-105
Background
An ambulatory, portable, automated CL system for overnight CL glucose control in young people with T1D was
evaluated. Previous descriptions of CL control had not simulated possible use in a home setting and had not compared
early versus late initiation of the overnight CL system.
Methods
A randomized, crossover study of CL glucose control over
two admissions to the clinical research facility involved eight
young patients (mean age 14.3 years) with T1D. Automated
CL control was initiated at 18:00 or 21:00 hours and ran until
08:00 hours the next day. The Abbott Florence CL system
employing the Navigator Combined controller was used for
CL management.
Results
Results
The primary outcome of the median time in target range
(71–180 mg/dL) increased from 49% on CPT to 84% on CL
therapy ( p = 0.02). Similarly, mean plasma glucose levels
fell from 165 mg/dL on CPT to 128 mg/dL on CL therapy
( p = 0.02). Glucose levels were within the target range
100% of the time during 17 of the 24 nights using the CL
therapy. Hypoglycemia ( < 55 mg/dL) was frequent for
both control (10 occasions) and CL (9 occasions) admissions.
Conclusions
Day and night CL basal insulin delivery can improve glucose control in adolescents. However, unannounced moderate-intensity exercise and excessive prandial boluses pose
challenges to hypoglycemia-free CL basal insulin delivery.
Overnight plasma glucose levels (between 21:00 and 08:00
hours) were within the target range (71–145 mg/dL) for 82
(59–98)% of time when CL was started at 18:00 hours and 64
(48–70)% when CL was started at 21:00 hours [median (interquartile range), p = 0.036]. All other parameters were similar
comparing the early versus the late initiation of the CL system.
Conclusions
Overnight glucose control was safe and similar when the
CL system was initiated at 18:00 or 21:00 hours. Glucose levels
were in the target range 84% of the time with the earlier initiation, compared with 64% of the time with the later initiation, suggesting that the earlier time of CL initiation may be
advantageous.
Comment
This study was unique in using a single sensor and nonintervention by staff with a portable system as might be
utilized in the home setting. As there were few differences
between initiation at 18:00 versus 21:00 hours, either could
be used in future home studies. Others have been concerned that insulin on board from the dinner meal, unknown to the CL system, might make initiation at the later
time more troublesome. Surprisingly, this was not found,
and if anything, the earlier starting time was advantageous. This study showed safety and a prelude to the use of
the CL system in young people in a home setting.
Comment
The CL system can clearly improve glucose control in
adolescents with T1D, particularly during the night.
There were no hypoglycemic episodes during the night
with CL management (vs. one episode with CPT). In
contrast, during CL therapy, four hypoglycemia events
occurred within 2.5 hours of breakfast or dinner and five
episodes occurred after exercise.
Although the success with overnight CL control was
obvious, the future challenge is to determine whether CL
insulin delivery can maintain glycemic control after
meals, physical exercise, and snacks.
Evaluation of a portable ambulatory prototype
for automated overnight closed-loop insulin delivery
in young people with type 1 diabetes
Elleri D 1,2, Allen J 1,2, Biagioni M 1, Kumareswaran K 1,
Leelarathna L 1, Caldwell K 1, Nodale M 1, Wilinska ME 1,2,
Acerini C 2, Dunger DB 1,2, Hovorka R 1,2
1
Metabolic Research Laboratories, Institute of Metabolic Science,
Cambridge, United Kingdom; and 2Department of Pediatrics,
University of Cambridge, Cambridge, United Kingdom
Closed-loop insulin therapy improves glycemic control
in children aged <7 years: a randomized controlled trial
Dauber A 1, Corcia L 2, Safer J 1, Agus MSD 1,3, Einis S 4,
Steil GM 3
1
Division of Endocrinology, 2Department of Medicine, 3Medicine
Critical Care Program, and 4Department of Nursing, Boston
Children’s Hospital, Boston, MA
Background
There have been many efforts to improve glycemic control
with the goal of developing an automated artificial pancreas,
S-106
SHALITIN AND CHASE
that is, CL insulin therapy, which involves the integration of
CGM with CSII via a computer-driven algorithm that calculates insulin dosage. In adults and older children, CL therapy
has been shown to improve glycemic control while decreasing
rates of hypoglycemia. However, only little data are available
regarding CL insulin therapy in very young children who are
particularly vulnerable to frequent episodes of hypoglycemia.
The aim of the study was to assess the option of improving
nocturnal glycemic control and meal glycemic response using
CL therapy in children aged < 7 years with T1D.
Methods
In a randomized, controlled, crossover trial conducted in an
inpatient clinical research center, CL therapy was compared
with standard open-loop CSII in children. Eligibility criteria
included children with T1D, age < 7 years, duration of diabetes > 6 months, and use of CSII > 6 weeks. Both modes of
treatment were compared from 10:00 P.M. to 12:00 P.M. on 2
consecutive days. The primary outcome was plasma glucose
time in range (110–200 mg/dL [6.11–11.11 mmol/L]) during
the night (10:00 P.M.–8:00 A.M.). Secondary outcomes included peak postprandial glucose levels, incidence of hypoglycemia, degree of hyperglycemia, and prelunch glucose
levels.
Results
Ten patients were included in the study [mean age 5.1 years
(range 2–6 years), mean duration of diabetes 2.1 years]. Seven
subjects had HbA1c values < 8.5%. For the primary nocturnal
outcome, a trend toward a higher mean time for plasma
glucose within target range (110–200 mg/dL [6.11–
11.11 mmol/L]) was noted for closed- versus open-loop
therapy (5.3 vs. 3.2 hours, respectively), although this difference did not achieve statistical significance. CL therapy significantly reduced time spent > 300 mg/dL [16.66 mmol/L]
(0.18 vs. 1.3 hours, p = 0.035) and the total area under the curve
of glucose > 200 mg/dL [11.11 mmol/L] ( p = 0.049). During
open-loop therapy, five subjects received an additional correction dose of insulin overnight because of persistent hyperglycemia. There were no differences in peak postprandial
glucose or number of hypoglycemic episodes. During CL
therapy, there was a more rapid rise in postprandial plasma
glucose as a result of the delayed delivery of insulin. There
was significant improvement in the prelunch blood glucose
on CL therapy (189 vs. 273 mg/dL [10.5 vs. 15.17 mmol/L]
versus open-loop, p = 0.009).
Conclusions
CL therapy in young children with T1D decreased nocturnal hyperglycemia without increasing the incidence of
hypoglycemia and improved prelunch blood glucose.
Comment
Management of T1D in very young children is especially
difficult because of unpredictable eating patterns, erratic
activity level, and increased susceptibility to severe hypoglycemia. Young children have increased risk of longterm neurocognitive dysfunction, which may be related
to episodes of severe hypoglycemia. While there have
been substantial technological advances with the advent
of CSII and CGM, a recent trial of CGM use in young
children showed no benefit in glycemic control or decrease in rates of hypoglycemia (11). Novel strategies for
treating these young children are desperately needed.
This study showed that CL therapy has the potential to
improve young children’s diabetes care.
The ‘‘Glucositter’’ overnight automated closed loop
system for type 1 diabetes: a randomized crossover trial
Nimri R1, Danne T 2, Kordonouri O 2, Atlas E 1, Bratina N 3,
Biester T 2, Avbelj M 3, Miller S 1, Muller I 1, Phillip M 1,4,
Battelino T 3
1
Jesse Z and Sara Lea Shafer Institute for Endocrinology and
Children’s Medical Center of Israel, Petah Tikva, Israel; 2Diabetes
Centre for Children and Adolescents, Auf der Bult, Kinder- und
Jugendkrankenhaus, Hannover, Germany; 3Department of Pediatric Endocrinology, Diabetes and Metabolism, Faculty of Medicine,
University Medical Centre–University Children’s Hospital, University of Ljubljana, Ljubljana, Slovenia; and 4Department of Pediatrics, Sackler Faculty of Medicine, Tel Aviv University, Tel
Aviv, Israel
Background
CL systems have provided an innovative therapeutic approach to maintain blood glucose levels within the desired range
while reducing the risk of both hypoglycemia and hyperglycemia. The aim of this study was to assess the safety and efficacy of
the CL MD-Logic Artificial Pancreas (MDLAP), which provides
a personalized treatment approach with real-time learning
ability and safety alerts warning for impending hypoglycemic
and hyperglycemic events, in controlling nocturnal glucose
levels in patients with T1D therapy in an inpatient setting. The
primary outcome was the number of hypoglycemic events
(glucose level below 63 mg/dL [3.5 mmol/L]).
Methods
A prospective randomized, multicenter, multinational,
crossover trial was conducted in Slovenia, Germany, and Israel. Patients with T1D (n = 12, age 23.8 – 15.6 years, duration
of diabetes 13.5 – 11.9 years, HbA1c 8.1 – 0.8%) were randomly assigned to participate in two sequential overnight
sessions: one using CSII and the other, CL insulin delivery by
MDLAP. At each inpatient overnight session, at around 19:00,
subjects received their dinner. Patients/parents were asked to
estimate the carbohydrate content of the meal and to give
an insulin bolus 5–10 min before based on their insulin-tocarbohydrate ratio and the capillary blood glucose level. Patients’ standard insulin pump settings were applied. On the
overnight CL session, the MDLAP controller was started simultaneously with mealtime. From this point forth, fully
automated control of all insulin delivery was carried out via
the CL MDLAP system. Endpoints analyses were based on
sensor glucose readings.
Results
Three events of nocturnal hypoglycemia occurred during
CSII and none during the CL control ( p = 0.18). The percentage
of time spent in the near-normal range of 63–140 mg/dL (3.5–
7.78 mmol/L) was significantly higher in the overnight CL
sessions [76% (54–85)] than during CSII therapy [29% (11–44)]
[p = 0.02, median (interquartile range)]. The mean overnight
glucose level was reduced by 36 mg/dL (2 mmol/L) with CL
insulin delivery ( p = 0.02) with significantly less glucose variability when compared with the CSII nights ( p < 0.001).
Conclusion
The MDLAP was able to safely improve overnight glucose
control without increased risk of hypoglycemia in patients
with T1D.
Comment
This trial showed the advantage of the MDLAP system
over CSII therapy in controlling the overnight glucose
levels in patients with T1D, and it was found to be feasible
and safe. The MDLAP has several means for responding
to hypoglycemia: it modifies or suspends insulin delivery
according to the predicted risk of hypoglycemia, and
when this is not sufficient to prevent hypoglycemia, it
activates an alert to warn the patient to consume carbohydrates. Another safety layer is the real-time learning
algorithm that can adjust insulin delivery in response to
impending hypoglycemia or hyperglycemia. These features can lead to reduction in the hypoglycemia risks and
to improvement of glycemic control. Furthermore, the
MDLAP system demonstrated significantly reduced glucose variability, as indicated by the significant reduction
in the sensor glucose level range overnight. Another advantage of the MDLAP control over the CSII was the
significantly better morning fasting blood glucose, which
may also improve daytime glucose control.
The difference in insulin therapy between the MDLAP
and the CSII open-loop nights was probably in a better
control of the MDLAP in insulin dosing, number of
correction boluses, and insulin delivery timing.
Testing of the MDLAP system in three different clinical
centers with diverse ethnicity of patients and possible
differences in diabetes management permitted a better
assessment of its effectiveness. However, this study
examined the MDLAP system in a small number of
motivated patients for one CL overnight. Further larger
studies are needed to test the system over a longer period.
Technological improvements are still needed, including
automated calibration as well as the means to detect
sensing errors, before the CL can be tested at home.
Nocturnal glucose control with an artificial
pancreas at a diabetes camp
Phillip M 1,2, Battelino T 3, Atlas E1, Kordonouri O 4, Bratina
N 3, Miller S1, Biester T 4, Stefanija MA 3, Muller I 1, Nimri R 1,
Danne T 4
1
S-107
Children’s Medical Center of Israel, Petah Tikva; 2Sackler Faculty
of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Department of
Pediatric Endocrinology, Diabetes and Metabolism, University
Medical Center–University Children’s Hospital, and Faculty of
Medicine, University of Ljubljana, Ljubljana, Slovenia; and 4Diabetes Center for Children and Adolescents, Auf der Bult, Kinderund Jugendkrankenhaus, Hannover, Germany
N Engl J Med 2013; 368: 824–33
Background
Since most cases of severe hypoglycemia occur at night,
maintenance of nocturnal euglycemia is important. Recent
studies that have been carried out in hospitals have shown that
fully automated artificial-pancreas systems can improve glucose control and reduce the risk of nocturnal hypoglycemia.
However, it is not known whether such results can be replicated in settings outside the hospital. The aim of this study was
to evaluate the safety and efficacy of the artificial-pancreas
system in young patients with T1D in a youth-camp setting,
with the aim of achieving a substantial reduction in nocturnal
hypoglycemia with near-normal overnight glucose control.
Methods
In this prospective, multicenter, multinational (Israel, Slovenia, and Germany), randomized crossover trial, the short-term
safety and efficacy of an artificial pancreas system for control of
nocturnal glucose levels was assessed in patients with T1D aged
10–18 years at a diabetes camp. Each of the camp periods lasted
for 3 days. In two consecutive overnight sessions, patients
(n = 56) were randomly assigned to receive treatment with an
artificial pancreas on the first night and with SAP (control) on
the second night or to the reverse order of therapies on the first
and second nights. The primary end points were the number of
hypoglycemic events (sensor glucose value of < 63 mg/dL
[3.5 mmol/L] for at least 10 consecutive minutes), the time spent
with glucose levels below 60 mg/dL (3.3 mmol/L), and the
mean overnight glucose level for individual patients.
Results
On nights when the artificial pancreas was used, as compared with nights when the SAP was used, there were fewer
episodes of nighttime glucose levels below 63 mg/dL (7 vs.
22) and significantly shorter periods when glucose levels were
below 60 mg/dL ( p = 0.003 and p = 0.02, respectively). There
were no significant between-treatment differences in the median overnight glucose levels, which were 126.4 mg/dL (IR,
115.7–139.1 [7.0 mmol/L; IR, 6.4–7.7]) with the artificial pancreas and 140.4 mg/dL (IR, 105.7–167.4 [7.8 mmol/L; IR, 5.9–
9.3]) with SAP. Glucose levels were significantly more stable
over time with the artificial pancreas than with the SAP. More
bolus injections of insulin were delivered during the nights
when the artificial pancreas was used than during the nights
when the SAP was used. No significant between-treatment
differences were found in the number of hypoglycemia
alarms or subsequent carbohydrate interventions. No serious
adverse events were reported.
Conclusions
Pediatric patients at a diabetes camp who were treated with
an artificial pancreas system had less nocturnal hypoglycemia
S-108
and tighter glucose control than when they were treated with
SAP.
Comment
In this study, the artificial pancreas system was able to
maintain better blood glucose levels and helped prevent
dangerous overnight drops in blood glucose levels
compared with SAP therapy. The significant improvement in patients’ overnight glucose control and the reduction in the number of events and duration of
hypoglycemia appeared to be related to the combined
effect of better control of the amount of insulin provided
and better control of the timing of insulin delivery, together with the presence of an alarm module, in the
artificial pancreas. However, we have to remember that
each treatment was evaluated in only one-night sessions, and the challenges of a CL system for glucose and
insulin control may be different in a design of a few
nights.
Diabetes camps offer a great place to test the artificial
pancreas. It represents a transitional phase between a
hospital clinical research center and the child’s home, and
at the camp the children are often far more active than
usual, which leaves them prone to hypoglycemia
throughout the night. The camp provides the elements
of a real-life setting in a place where healthcare needs can
still be met by the research team.
If this CL system proves to be reliable also for the longterm at home, it will allow patients and families to cope
better with the never-ceasing challenge of achieving
better glycemic control without the fear of severe
hypoglycemia.
SHALITIN AND CHASE
Results
The use of pramlintide with the CL system did not result in
large changes in 24-hour mean blood glucose ( - 4 mg/dL) or
CGM glucose ( - 9 mg/dL) levels. However, the time from
meal start to peak blood glucose was delayed by *1 hour
(2.5 – 0.9 vs. 1.5 – 0.5 hour, p = 0.0001). The magnitude of glycemic excursion was also reduced (88 – 42 vs. 113 – 32 mg/dL,
p = 0.0006).
Conclusions
Pramlintide usage with the CL resulted in a delay in the
time to peak postprandial glucose levels as well as in a reduction of prandial glucose excursions.
Comment
This research showed the benefit of CLP compared with
CL alone. As previously described in adolescents (14),
pramlintide delayed the time to peak postprandial glucose levels as well as the magnitude of glucose excursions. As the authors note, the manual injection of
pramlintide at meal times distracts from the convenience
of a CL system and is not likely to be accepted on a longterm basis. They suggest that strategies to incorporate
pramlintide into a CL system with dual-pump delivery,
coformulation, or with use of a delayed-release preparation might prove to be both practical and beneficial.
Unfortunately, in spite of the current success, these
opinions are unlikely to be feasible for adolescents in the
near future. Hopefully, the development of more rapidacting insulins will obviate the need for the CLP system.
Effect of pramlintide on prandial glycemic excursions
during closed-loop control in adolescents and young
adults with type 1 diabetes
S.S. has no competing financial interests. H.P.C. has received a research grant from Dexcom.
Weinzimer SA 1, Sherr JL 1, Cengiz E 1, Kim G 1, Ruiz J 1,
Carria L 1, Voskanyan G 2, Roy A 2, Tamborlane WV 1
References
1
Department of Pediatrics, Yale University School of Medicine,
New Haven, CT; and 2Medtronic Diabetes, Northridge, CA
Diabetes Care 2012; 35: 1994–99
Background
Although the artificial pancreas is one of the most promising technologies for care of people with T1D, mealtime
control has been challenging. This is in part due to a delay in
insulin activity and high blood glucose levels (12,13), and a
secondary tendency toward hypoglycemia in the late postprandial period.
Methods
Eight subjects (4 female, age 15–28 years: A1c 7.5 – 0.7%)
were studied for 48 hours on a CL insulin delivery system
with a proportioned integral derivative algorithm with 24hour CL control alone and 24-hour CL control plus 30 lg
premeal injections of pramlintide (CLP). Timing and contents
of meals were identical on both study days.
1. Cizza G, Brown RJ, Rother KI. Rising incidence and challenges of childhood diabetes. A mini review. J Endocrinol
Invest 2012; 35: 541–46.
2. Amiel SA, Sherwin RS, Simonson DC, Lauritano AA, Tamborlane WV. Impaired insulin action in puberty. A contributing factor to poor glycemic control in adolescents with
diabetes. N Engl J Med 1986; 315: 215–19.
3. Rausch JR, Hood KK, Delamater A, Shroff Pendley J,
Rohan JM, Reeves G, Dolan L, Drotar D. Changes in
treatment adherence and glycemic control during the
transition to adolescence in type 1 diabetes. Diabetes Care
2012; 35: 1219–24.
4. The Diabetes Control and Complications Trial Research
Group. The effect of intensive treatment of diabetes on the
development and progression of long-term complications in
insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:
977–86.
5. Davis E, Keating B, Byrne G, Russell M, Jones T. Hypoglycemia: Incidence and clinical predictors in a large population-based sample of children and adolescents with IDDM.
Diabetes Care 1997; 20: 22–25.
6. Holl RW, Swift PG, Mortensen HB, Lynggaard H, Hougaard
P, Aanstoot HJ, Chiarelli F, Daneman D, Danne T, Dorchy H,
7.
8.
9.
10.
Garandeau P, Greene S, Hoey HM, Kaprio EA, Kocova M,
Martul P, Matsuura N, Robertson KJ, Schoenle EJ, Sovik O,
Tsou RM, Vanelli M, Aman J. Insulin injection regimens and
metabolic control in an international survey of adolescents
with type 1 diabetes over 3 years: results from the Hvidore
study group. Eur J Pediatr 2003; 162: 22–29.
Pihoker C, Badaru A, Anderson A, Morgan T, Dolan L,
Dabelea D, Imperatore G, Linder B, Marcovina S, MayerDavis E, Reynolds K, Klingensmith GJ; SEARCH for Diabetes in Youth Study Group. Insulin regimens and clinical
outcomes in a type 1 diabetes cohort: The search for diabetes
in youth study. Diabetes Care 2013; 36: 27–33.
Bergenstal RM, Tamborlane WV, Ahmann A, et al. Effectiveness of sensor-augmented insulin-pump therapy in type
1 diabetes. N Engl J Med 2010; 363: 311–20.
Juvenile Diabetes Research Foundation Continuous Glucose
Monitoring Study Group, Tamborlane WV, Beck RW, et al.
Continuous glucose monitoring and intensive treatment of
type 1 diabetes. N Engl J Med 2008; 359: 1464–76.
Hovorka R, Kumareswaran K, Harris J, et al. Overnight
closed loop insulin delivery (artificial pancreas) in adults
11.
12.
13.
14.
S-109
with type 1 diabetes: Crossover randomised controlled
studies. Br Med J 2011; 342: d1855.
Mauras N, Beck R, Xing D, et al., Diabetes Research in Children
Network (DirecNet) Study Group. A randomized clinical trial
to assess the efficacy and safety of real-time continuous glucose
monitoring in the management of type 1 diabetes in young
children aged 4 to < 10 years. Diabetes Care 2012; 35: 204–10.
Weinzimer SA, Steil GM, Swan KL, Dziura J, Kurtz N,
Tamborlane WV. Fully automated closed-loop insulin delivery versus semi automated hybrid control in pediatric
patients with type 1 diabetes using an artificial pancreas.
Diabetes Care 2008; 31: 934–39.
Cobry E, McFann K, Messer L, Gage V, VanderWel B,
Horton L, Chase HP. Timing of meal insulin boulses to
achieve optimal postprandial glycemic control in patients
with type 1 diabetes. Diabetes Tech Ther 2009; 12: 173–77.
Chase HP, Lutz K, Pencek R, Zhang B, Porter L. Pramlintide
lowered glucose excursions and was well-tolerated in adolescents with type 1 diabetes: results from a randomized,
single-blind, placebo-controlled, crossover study. J Pediatr
2009; 155: 369–73.
DOI: 10.1089/dia.2014.1513
ORIGINAL ARTICLE
Diabetes Technology and the Human Factor
Alon Liberman1, Bruce Buckingham 2, and Moshe Phillip1
Treatment satisfaction in the sensor-augmented
pump therapy for A1C reduction 3 (STAR 3) trial
Introduction
T
he impressive progress achieved in recent years in
diabetes technologies has made diabetes technological
devices such as continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) a
significant part of diabetes treatment. Many studies conducted in recent years emphasized the advantages of
using these technologies.
The concept of the ‘‘human factor’’ in diabetes technologies as discussed in this chapter has several different
aspects. First, it can refer to the way patients are satisfied
with the use of the device and whether it is perceived
convenient or inconvenient. For example, is the device
perceived as ‘‘user friendly’’ (easy to learn and to operate,
comfortable, does not cause many hassles). Second, there is
the issue of effectiveness of the technology as it relates to
their day-to-day diabetes management. For example, there
is an improvement in glycemic control when one diabetes
treatment regimen is compared to another (i.e., CSII vs.
multiple daily injections (MDI)).
Those two fundamental aspects may have different meanings for different groups. For example, different age groups
(toddlers, children, adolescents, young adults, adults, and
older people) can see different advantages and disadvantages
in technological devices. The feasibility and utility of technological devices also need to fit the environments in which
they will be used, such as school, the work place, and/or
home. Specific subgroups such as diabetic youth with eating
disorders can have unique interactions with diabetes
technologies.
In addition, diabetes technologies can be used as a measurement device, providing more rich and accurate data
about patients’ self-care that can contribute to our understanding of concepts such as adherence and satisfaction, and
they can provide measurement tools to assess how glycemic
control can effect cognition and intelligence. The present
chapter will review articles published in the last year that
have studied some of these issues.
Peyrot M 1, Rubin RR 2; STAR 3 Study Group
1
Department of Sociology, Loyola University Maryland, Baltimore, MD; and 2Behavioral Health Consulting, Baltimore, MD
Diabetes Med 2013; 30: 464–67
Aim
To identify insulin delivery system perceptions that contributed to improvements in general satisfaction with insulin
therapy (treatment satisfaction) that were more significant in
subjects using sensor-augmented pump therapy than those
using multiple daily injections with self-monitoring of blood
glucose.
Methods
The sensor-augmented pump therapy for A1C Reduction
3 (STAR 3) trial was a randomized 12-month clinical trial
that compared sensor-augmented pump therapy to multiple daily injections + self-monitoring of blood glucose in
both adults and children. The Insulin Delivery System
Rating Questionnaire measured perceptions of convenience, problems, interference with daily activities, blood
glucose monitoring burden, social burden, clinical efficacy,
diabetes worries and psychological well-being, as well as
treatment satisfaction. The authors conducted different
multiple regression analyses for the 334 adult patients and
147 pediatric patients and their caregivers to evaluate the
independent correlations ( p < 0.05) between change from
baseline to follow-up in user perceptions and treatment
satisfaction.
Results
Increased convenience was correlated with better treatment satisfaction in all user groups. Reduced interference
with daily activities (caregivers), reduced social burden
1
Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children’s
Medical Center of Israel, Petah Tikva, Israel.
2
Stanford Medical Center, Stanford, CA.
S-110
DIABETES TECHNOLOGY AND THE HUMAN FACTOR
(adults), and increased efficacy (both) also were correlated
with better treatment satisfaction.
Conclusions
Convenience was found to be the major factor in treatment satisfaction among children, while perceived clinical
efficacy was also a primary determinant among adults, reflecting different emphases on the treatment process itself
versus treatment results. Among adult patients and caregivers, improved treatment satisfaction was also a function
of reductions in social burden and interference with daily
activities (respectively), reflecting concern with the wider
psychosocial influence of sensor-augmented pump therapy
on their lives.
The pump was a saviour for me. Patients’ experiences
of insulin pump therapy
1,2
3
Garmo A , Hörnsten Å , Leksell J
1,4
1
School of Health and Social Studies, Dalarna University,
Dalarna, Sweden; 2Clinic of Internal Medicine, Falun Hospital,
Dalarna County Council, Sweden; 3Department of Nursing,
Umeå University, Umeå, Sweden; and 4Department of Medical
Sciences, Uppsala University, Uppsala, Sweden
Diabetes Med 2013; 30: 717–23
Aims
The present study was part of a larger study investigating
the potential long-term effects of glycemic control and treatment satisfaction in people with type 1 diabetes mellitus who
changed their insulin regimen from multiple daily insulin
injections to insulin pump therapy. A total of 46 participants
who made the transition between May 1999 and February
2004 participated. The aim of the study was to describe experiences of the effect of insulin pump therapy in adults with
type 1 diabetes mellitus after > 5 years’ use of an insulin
pump.
Methods
During spring 2009, 16 of the individuals were interviewed
through a narrative approach on the influence of insulin
pump therapy on daily life. The interviews were analyzed
using content analysis.
Results
Insulin pump therapy was experienced as both a
shackle and a lifeline. Six subthemes emerged: subjected
versus empowered; dependent versus autonomous; vulnerable versus strengthened; routinized versus flexible; burdened versus relieved; and stigmatized versus
normalized.
Conclusions
Users of insulin pump therapy have different perspectives
about using the technical equipment over years. Both positive
and negative views emerged. However, it was difficult to
identify any general trends that covered all views and can
predict which individuals will be able to optimally manage
pump therapy. Even so, the subthemes that emerged could be
S-111
used by physicians and diabetes specialist nurses when
counseling and planning educational programs aimed at
supporting self-management among people using insulin
pump therapy.
What are the quality of life-related benefits
and losses associated with real-time continuous
glucose monitoring? A survey of current users
Polonsky WH 1,2, Hessler D3
1
University of California–San Diego, San Diego, CA; 2Behavioral
Diabetes Institute, San Diego, CA; and 3University of California–
San Francisco, San Francisco, CA
Aims
The authors examined the possible effect of real-time (RT)
continuous glucose monitoring (CGM) on quality of life
(QOL). Different types and frequencies of diabetes-specific
QOL changes resulting from RT-CGM were explored as reported by current users and investigated what patientreported factors predict these changes.
Online questionnaires were completed by users of the
Dexcom-7 sensor (n = 877) investigating their perceived QOL
benefits since RT-CGM initiation and RT-CGM attitudes and
behavior. Exploratory factor analysis (EFA) tested the 16 QOL
benefit items to identify underlying factors. Regression analyses examined correlations between demographics and RTCGM attitudes and behavior with the QOL factors derived
from the EFA.
Results
The analysis identified three major QOL factors: Perceived
Control over Diabetes, Hypoglycemic Safety, and Interpersonal Support. Improvement in QOL measures was found
more in Perceived Control over Diabetes and Hypoglycemic
Safety (86% and 85% of respondents, respectively), and less in
Interpersonal Support (37%). Consistent independent predictors of perceived benefits were greater confidence in using
RT-CGM data ( p < 0.001), satisfaction with device accuracy
( p £ 0.05) and usability ( p < 0.01), older age ( p < 0.01), more
frequent receiver screen views ( p < 0.05), and use of multiple
daily injections (Hypoglycemic Safety and Interpersonal
Support, p £ 0.05).
Conclusions
Diabetes-specific QOL benefits resulting from RT-CGM
were frequently found. Major predictors of QOL benefits were satisfaction with device accuracy and usability
and confidence in one’s ability to use RT-CGM data,
implying that perceived efficacy, for both device and
self, are important QOL factors. Psychoeducational strategies to boost confidence in using RT-CGM data and
provide reasonable device expectations might empower
QOL benefits.
S-112
Comment
The subjective experience of patients concerning the use
of diabetes technology has a significant effect on both
patients’ quality of life and adherence to diabetes regimen. The studies cited above provide complementary
aspects of this important issue. As one can see, the
question of what makes a device satisfactory relies
heavily on the patient’s expectations, values, and developmental stage.
Children preferred significantly the convenience in
wearing the device and were not concerned with effectiveness as compared to adults. This finding is understandable based on our knowledge of how adolescents
have a problem in appreciating the significance of future
diabetes complications. It also reflects the difficulty of
children and youth to tolerate inconveniences and to
have deferred gratification (1,2).
Patients may also have different views about using the
same device. While some patients feel that a certain
technology improves their quality of life significantly,
others may feel that the same technology is causing a
burden. Good or bad experiences can influence the
patients’ motivation and emotional well-being. The
knowledge obtained from patients’ subjective experience
can help the diabetes team to develop a psychoeducational protocol that answers issues that are relevant to the
patient and help to prevent diabetes technology dropouts. As we move to in-home, in-school, and in-work
closed-loop systems, it will be critical to do user evaluation studies to assess the perceived hassles of using the
device as compared to the perceived benefits. What a
team of engineers considers easy to use and successful
may not be perceived by children, adolescents, and
adults as user friendly and beneficial. Perceived benefits
are best accepted if they are immediate, not delayed.
Less, not more hassles in insulin dose decisions, fewer
user inputs to determine a dose, fewer immediate
concerns about daytime and overnight hypoglycemia,
and immediate, significant and visually observed differences in postprandial glucose levels and markedly
decreased glucose excursions will be immediately perceived by a CGM user as beneficial. A 0.3% decrease in
A1C levels or a 5% improvement in the percent of
readings in range may be statistically valid, but will not
have an immediate perceived benefit to the adolescent. It
will be critical that any burden of using and wearing
more devices with communications issues between
devices is offset by immediate benefits to the user in
observed CGM readings.
Insulin regimens and clinical outcomes in a type 1
diabetes cohort: the SEARCH for Diabetes
in Youth study
Pihoker C1, Badaru A 1, Anderson A2, Morgan T 2, Dolan L3,
Dabelea D4, Imperatore G5, Linder B6, Marcovina S7,
Mayer-Davis E8, Reynolds K9, Klingensmith GJ 10;
SEARCH for Diabetes in Youth Study Group
1
Department of Pediatrics, University of Washington, Seattle,
WA; 2Department of Biostatistics, Wake Forest University School
LIEBERMAN ET AL
of Medicine, Winston-Salem, NC; 3Department of Pediatrics,
Cincinnati Children’s Hospital, University of Cincinnati College
of Medicine, Cincinnati, OH; 4Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver,
Aurora, CO; 5Division of Diabetes Translation, Centers for Diseases Control and Prevention, Atlanta, GA; 6National Institute
of Diabetes and Digestive and Kidney Diseases, National Institutes
of Health, Bethesda, MD; 7Department of Medicine, University of
Washington, Seattle, WA; 8Departments of Nutrition and
Medicine, University of North Carolina, Chapel Hill, NC;
9
Department of Research and Evaluation, Kaiser Permanente
Southern California, Pasadena, CA; and 10Barbara Davis Center
and Department of Pediatrics, University of Colorado Denver,
School of Medicine, Aurora, CO
Aims
To study the patterns and correlations of insulin regimens
and change in regimens with clinical outcomes in a heterogeneous population of children with newly diagnosed type 1
diabetes.
The study sample consisted of adolescents with type 1 diabetes who completed a baseline SEARCH for Diabetes in
Youth study visit, which occurred generally between 4 and
16 months postdiagnosis of diabetes, and at least one followup visit. Demographic, diabetes self-management, physical,
and laboratory measures were collected at study visits, with
follow-up visits at 2–3 years postdiagnosis. Insulin regimens
and change in regimen compared with the initial visit were
categorized as more intensive (MI), no change (NC), or less
intensive (LI). The authors investigated associations between
insulin regimens, change in regimen, and outcomes including
A1C and fasting C-peptide.
Results
About 51.7% out of the 1,606 subjects (with a mean followup of 36 months) changed to an MI regimen, 44.7% had NC,
and 3.6% changed to an LI regimen. Subjects who were
younger, non-Hispanic white, and from families of higher
income and parental education and who had private health
insurance were more likely to be in MI or NC groups. Those
in MI and NC groups had lower baseline A1C ( p = 0.028)
and smaller increase in A1C over time than LI ( p < 0.01).
Younger age, continuous subcutaneous insulin pump therapy, and change to MI were associated with higher probability of achieving target A1C levels.
Conclusions
Insulin regimens were intensified over time in more
than half of the subjects but varied by sociodemographic
domains. As more intensive regimens were correlated with
better outcomes, early intensification of management may
help to achieve better outcomes in all children with diabetes.
Although intensification of the insulin regimen is preferred,
the choice of an insulin regimen should be tailored according
to the child and family’s ability to adhere with the prescribed
regimen.
Comment
This study emphasizes that changing to more intense
insulin regimens, including diabetes technologies (i.e.,
CSII and CGM), is correlated with certain socioeconomic
and sociodemographic characters such as ethnicity,
families with higher income, higher parental education,
and private health insurance. It is also associated with
better glycemic control and lower HbA1c levels. These
findings are consistent with several studies indicating
that social support and socioeconomic status (3) (and not
only the patient’s personal or subjective experience) have
a major influence on the adherence potential both in diabetes in general and in diabetes technology regimens.
S-113
Division of Pediatric Endocrinology and Diabetes, Stanford
University School of Medicine, Stanford, CA
Aims
Children with type 1 diabetes (T1D) spend 4–7 hours/day
in school with minimal supervision of their diabetes management. The use of real-time continuous glucose monitoring
(RT-CGM) may provide an increased level of supervision of
the child’s diabetes management. Because there is no published information on the impact of using RT-CGM in the
classroom/school environment, the authors sought to make
this assessment.
Sensor-augmented pump therapy in very young
children with type 1 diabetes: an efficacy and feasibility
observational study
Frontino G1, Bonfanti R1, Scaramuzza A2, Rabbone I 3, Meschi F1,
Rigamonti A1, Battaglino R1, Favalli V1, Bonura C1, Sicignano S3,
Gioia E3, Zuccotti GV 2, Cerutti F 3, Chiumello G1
1
Department of Pediatrics, Endocrine Unit, Scientific Institute
Hospital San Raffaele, Vita-Salute University, Milan, Italy;
2
Department of Pediatrics, University of Milan, Ospedale Luigi
Sacco, Milan, Italy; and 3Department of Pediatrics, University of
Turin, Turin, Italy
Children with T1D using RT-CGM, their caregivers, and
teachers completed a questionnaire about RT-CGM in the
classroom/school environment.
Results
The RT-CGM was well tolerated in the classroom/school
environment. Seventy percent of parents, 75% of students,
and 51% of teachers found RT-CGM useful in the classroom/school environment. The students found the device
to be more bothering than did the adults (both parents and
teachers). However, all three groups thought that RT-CGM
improved their comfort with diabetes management at
school.
Aims
The purpose of this study was to assess the efficacy and
feasibility of sensor-augmented pump (SAP) therapy in very
young children with type 1 diabetes (T1D).
SAP (Dexcom [San Diego, CA] Seven Plus usage combined
with insulin pump) therapy was retrospectively evaluated in
28 children (15 boys) younger than 7 years (mean age, 5.8 – 1.2
years; range, 3–7 years), with T1D. Glycosylated hemoglobin
(HbA1c) was evaluated at baseline and at the end of the study,
as were efficacy and feasibility of the system, using a rating
scale (with 3 being the most positive).
Results
SAP was used for at least 6 months by 85% of patients, with
a generally good satisfaction (92%). The greatest perceived
benefit was the reduced fear of hypoglycemia (score of 3,
81%). HbA1c was significantly better only in subjects with
baseline HbA1c > 7.5% ( p = 0.026).
Conclusions
The authors conclude that SAP therapy is feasible in preschool children with T1D, and in patients with a HbA1c > at
baseline, it provides a 0.9% decrease.
Real-time continuous glucose monitoring systems
in the classroom/school environment
Benassi K, Drobny J, Aye T
Conclusions
The authors conclude that RT-CGM is useful and not
perceived as a significant hassle in the classroom/school environment. An improvement in the education materials provided to teachers could further increase RT-CGM acceptance
in the classroom/school environment.
Comment
Parents and caregivers of children with diabetes experience a heavy burden as a result of the demands of
the diabetes regimen requirements and the anxiety
about their child’s health and even life. The efforts are
endless and deal with unexpected eating patterns, extreme glucose variability, and inconsistencies in insulin
sensitivity. The anxiety caused by the possible consequences of severe hypoglycemic or hyperglycemic
events to the young child can affect both the parents’
quality of life and daily functioning. Another challenging situation is sending the child to school without
the parents’ direct supervision and often without a
professional team or even a person who knows how to
manage diabetes.
These two interesting studies suggest that increasing
the use of diabetes technologies among children and even
young children can help ease this burden. The studies
indicate that using technological devices is both safe and
feasible. These findings are concordant with previous
studies that showed the potential of using diabetes
technologies in children (4).
S-114
Continuous glucose monitoring and cognitive
performance in type 2 diabetes
Pearce KL1–3, Noakes M 2, Wilson C 1,4, Clifton PM 1,5
1
Commonwealth Scientific and Industrial Research Organization,
Human Nutrition, Adelaide, South Australia, Australia; 2School
of Pharmacy and Medical Sciences, University of South Australia,
South Australia, Australia; 3Department of Physiology, University
of Adelaide, South Australia, Australia; 4Flinders Centre for
Cancer Prevention and Control, Flinders University, Adelaide,
South Australia, Australia; and 5Baker IDI, Adelaide, South
Australia, Australia
Aims
Type 2 diabetes is correlated with reductions in cognitive
function that are in turn correlated with glycated hemoglobin (HbA1c) levels, but there are no data on whether changes
in cognition is associated with postmeal glucose spikes. The
authors investigated the correlations between cognition and
glucose levels measured by a continuous glucose monitoring
system (CGMS) both before and after a weight loss diet.
A total of 44 white participants with type 2 diabetes
(59.0 – 6.2 years old; body–mass index, 32.8 – 4.2 kg/m2; HbA1c,
6.9 –1.0%) completed an 8-week energy-restricted (*6–7 MJ,
30% deficit) diet. Cognitive functioning (short-term memory,
working memory, speed of processing [inspection time], psychomotor speed, and executive function) was evaluated during
four practice sessions, baseline, and week 8. Parallel glucose
levels were collected using the CGMS in 27 participants. Results were evaluated by fasting blood glucose (FBG), postprandial peak glucose (Gmax), time spent >12 mmol/L (T >12),
and 24-hour area under the glucose curve (AUC24).
Results
Although there was a fall in FBG of 0.65 mmol/L after
8 weeks, digits backward outcome was associated with FBG
at both week 0 and week 8 (r = - 0.43, p < 0.01 and r = - 0.32,
p < 0.01, respectively). Digits forward outcome was associated
with FBG (r = - 0.39, p < 0.01), Gmax (r = - 0.46, p < 0.05), and
AUC24 (r = - 0.50, p < 0.01) at week 0 and FBG (r = - 0.59,
p < 0.001), Gmax (r = 0.37, p = 0.01), AUC24 (r = - 0.41, p < 0.01),
and percentage weight loss (r = 0.31, p < 0.01) at week 8.
Cognitive function was not changed by weight loss, sex,
baseline lipid levels, or premorbid intelligence levels (National Adult Reading Test).
Conclusions
FBG, Gmax, and AUC24 were associated with cognitive
function, and an energy-restricted diet for 8 weeks did not
change this relationship.
Outpatient assessment of determinants of glucose
excursions in adolescents with type 1 diabetes:
proof of concept
Maahs DM 1, Mayer-Davis E 2, Bishop FK 1, Wang L 2,
Mangan M 2, McMurray RG 2
LIEBERMAN ET AL
1
Barbara Davis Center for Childhood Diabetes, University of
Colorado Denver, Aurora, CO; and 2Departments of Nutrition
and Medicine, University of North Carolina at Chapel Hill, Chapel
Hill, NC
Aims
Although controlled inpatient studies on the effects of food,
physical activity (PA), and insulin dosing on glucose excursions exist, the information is quite limited. The authors report
in this study the use of continuous glucose monitors (CGM),
accelerometers, insulin dose data from both insulin pumps
and memory pens, and meal information from logs and
photos over 5 days in 30 youth with type 1 diabetes (T1D) as a
proof-of-principle pilot study.
There were a total of 30 participants (20 on insulin pumps,
10 receiving multiple daily injections; 15 – 2 years old; diabetes duration, 8 – 4 years; hemoglobin A1c, 8.1 – 1.0%).
Participants continued their existing insulin regimens, and
time-stamped insulin dosing data were obtained from insulin
pump downloads or insulin pen digital logs. Time-stamped
cell phone photographs of food pre- and postconsumption
and food logs were used to augment 24-hour dietary recalls
for days 1 and 3. These variables were incorporated into regression models to predict glucose excursions at 1–4 hours
postbreakfast.
Results
CGM information on both days 1 and 3 were obtained in
57 of the possible 60 participant-days with an average of
125 daily CGM readings (out of a possible 144). PA and dietary recall data were obtained in 100% and 93% of subjects on
day 1 and 90% and 100% of subjects on day 3, respectively. All
of these variables affected glucose excursions at 1–4 hours
after waking, and 56 of the 60 subject-days contributed to the
modeling analysis.
Conclusions
Outpatient high-resolution time-stamped data on the main
inputs of glucose variability in youth with T1D are feasible
and can be modeled. Future applications include using these
data for in silico modeling and for monitoring outpatient iterations of closed-loop studies, as well as to enhance clinical
advice regarding insulin dosing to match diet and PA
behaviors.
Frequency of mealtime insulin boluses as a proxy
measure of adherence for children and youths
Patton SR 1, Clements MA2, Fridlington A2, Cohoon C2,
Turpin AL2, Delurgio SA3
1
Department of Pediatrics, University of Kansas Medical Center,
Kansas City, Kansas, MO; and 2Section of Endocrinology and
3
Center for Health Outcomes and Health Services Research,
Children’s Mercy Hospital, Kansas City, MO
S-115
Background
importance of not missing meal boluses (6–8), and this
study again confirms this finding and shows that a
missed meal bolus is of even greater significance in
predicting A1c levels when compared to the frequency of
blood glucose testing. These findings again provide
additional evidence for the value of a hybrid or full
closed-loop system to overcome issues with a missed
meal bolus, particularly in adolescents.
Electronic measures of adherence can be better than patient
report. In type 1 diabetes, frequency of blood glucose monitoring (BGM), as measured by patients’ home blood glucose
meters, has already been identified as a valid proxy of adherence. The authors present methodology to calculate adherence using insulin pump data and assess the reliability and
validity of this methodology.
Blood glucose meter records, insulin pump data, and corresponding hemoglobin A1c (HbA1c) levels were randomly
obtained from clinical and research databases for 100 children
and adolescents (referred to hereafter as youths) with type 1
diabetes (mean – SD age, 12.7 – 4.6 years). Youths’ mean frequency of daily BGM was calculated. In addition, the authors
calculated a mean mealtime insulin bolus score (BOLUS):
youths received 1 point each for a bolus between 0600 and
1000 hours, 1100 and 1500 hours, and 1600 and 2200 hours
(maximum of 1 point/meal or 3 points/day).
Results
Simple associations between youths’ HbA1c level, age,
frequency of BGM, and insulin BOLUS scores were found to
be significant. Partial associations and multiple regression
analyses revealed that insulin BOLUS scores better explain
variations in HbA1c levels than the electronically data frequency of daily blood glucose measures.
Conclusions
The authors concluded that their procedures for calculating
insulin BOLUS scores using insulin pump records were better
than the frequency of BGM in predicting youths’ HbA1c levels.
Comment
Psychological evaluations and tests are usually based on
a subjective foundation whether it may be observations,
subjects’ self-reports (i.e., questionnaires), or even psychometric evaluations. There is no objective way (i.e.,
blood test or MRI) to study concepts such as cognition or
adherence. Obtaining dates about bolus omission or
glucose excursions in adolescents with diabetes may be
used to measure adherence in a way that is beyond the
patient’s self-report or the impression of his or her parent.
This, of course, does not mean that the objective measures
will entirely replace the subjective ones; rather, they will
be complementary. The subjective measures will provide
the personal experience of the subject as well as theoretical concepts that will enrich the objective methods (e.g.,
the concept of executive functioning that enables us to
define different factors concerning our ability to concentrate and make plans) (5).
Another interesting possibility derived from these
articles is to build personal tailor-made programs for
patients. The patient and the diabetes team will be able to
specifically point out what exactly are the problems and
barriers that cause poor glycemic control. There have
been a number of other studies that have pointed out the
Disordered eating behaviors in youth with type 1
diabetes: prospective pilot assessment following
initiation of insulin pump therapy
Markowitz JT 1, Alleyn CA 1, Phillips R 1, Muir A2,
Young-Hyman D3, Laffel LM 1
1
Pediatric, Adolescent, & Adult Section, Section on Genetics &
Epidemiology, Joslin Diabetes Center, Boston, MA; 2Department
of Pediatrics, Emory University, Atlanta, GA; and 3Georgia
Prevention Institute, Georgia Health Sciences University,
Augusta, GA
Aims
Type 1 diabetes patients are at risk for developing disordered
eating behaviors, especially related to insulin manipulation.
Implementation of insulin pump therapy may enhance either
normalization of eating behaviors or a greater focus on food
intake due to renewed emphasis on carbohydrate counting.
Prospective studies are needed to evaluate disordered eating
behaviors at the time of implementation of pump therapy using
diabetes-specific measurement instruments.
A total of 43 adolescents with type 1 diabetes, 10–17 years
of age, participated in a multicenter pilot study, and were
evaluated before pump initiation and after 1 and 6 months of
pump therapy. Adolescents completed the Diabetes-specific
Eating Problems Survey-Revised (DEPS-R), a validated
questionnaire of risk for both diabetes-specific and general
disordered eating behaviors.
Results
Adolescents (45% female), 13.3 years old with diabetes
for 2.1 years, had a mean hemoglobin A1c of 8.3% – 1.3%
(68 – 14.5 mmol/mol) at baseline. DEPS-R scores decreased over
time ( p = 0.01). Overall rate of high risk for eating disorders was
low. Overweight/obese adolescents endorsed more disordered
eating behaviors than normal-weight subjects. DEPS-R scores
were associated with z-score for body–mass index at all three
time points and with hemoglobin A1c levels after 1 and 6
months. There was no significant difference in hemoglobin A1c
over the 6 months; however, it was higher in overweight/obese
participants than in normal-weight participants.
Conclusions
Initiation of insulin pump therapy was correlated with diminished endorsement of disordered eating behaviors in adolescents with type 1 diabetes. Longer follow-up studies are
S-116
needed to evaluate the influence of insulin pump therapy on
glycemic control, weight status, and disordered eating behaviors in this vulnerable population.
Comment
This study is a great example of ‘‘thinking outside the
box.’’ Some clinicians have been concerned that using
more intense insulin management in children with potential eating disorders could worsen their eating disorder, giving them an additional tool to manipulate their
eating behavior. This article is encouraging in that the
exact opposite was seen. The great meal flexibility with
pump therapy decreased tendencies toward disordered
eating behaviors. Adolescents with disordered eating
behaviors and diabetes should be treated and understood
differently than general eating disorders. The authors
emphasize that the demands of conventional insulin
regimens might encourage disordered eating; thus, instead of only talking with the patients about their eating
disorders and body image issues, more flexible eating
patterns enabled by insulin pump therapy improved
some of the disordered eating. A specific questionnaire
was developed emphasizing the importance of having a
diabetes-oriented eating disorder questionnaire (9). This
approach indicates that psychological treatment for patients with diabetes demands profound understanding of
the disease and the challenges as well as the different
regimens and the way they affect the patient’s life.
LIEBERMAN ET AL
Results
There was good internal consistency for both the youth and
caregiver reports and strong agreement between the caregiver
and youth reports. Higher ADQ scores, indicating better adherence, were related with better self-efficacy, more parental
support, less diabetes-related conflict, and less experience
with treatment barriers. Factor analysis supported maintaining the one-factor structure of the ADQ. Higher ADQ scores
were correlated with lower HbA(1c) levels.
Conclusions
The ADQ showed good psychometric properties. The ADQ
appears to be a valuable questionnaire for evaluating adherence in families with children and adolescents with type 1
diabetes in both clinical and research settings, although the
test–retest reliability and sensitivity to change of the instrument still needs to be established.
Comment
Adherence is a significant issue in diabetes treatment, and
there are several potential advantages of using this new
questionnaire. First of all, it was simplified to allow the
patients and their caregivers to answer the questions online
without the need for a trained professional to be with them
to administer the questionnaire. This allows for the possibility of doing large Internet-based surveys. In addition, it
has different versions for patients using either conventional
injections or insulin pump therapy, making it more sensitive to the unique aspects of adherence with these two
modes of therapy. The authors sought to identify the specific components of adherence to different aspects of the
diabetes regimen (insulin administration, blood glucose
measurements, carbohydrate counting, physical activity,
and CSII management). The questionnaire was built on
both patients’ interviews and diabetes experts’ reviews.
This method represents a very balanced approach that
takes into consideration the patients’ point of view about
their diabetes in order to improve their functioning.
Psychometric evaluation of the adherence
in diabetes questionnaire
Kristensen LJ 1, Thastum M 1, Mose AH 2, Birkebaek NH 2;
Danish Society for Diabetes in Childhood and Adolescence
1
Department of Psychology and Behavioural Sciences, Aarhus
University, Aarhus, Denmark; and 2Department of Pediatrics,
Aarhus University Hospital, Aarhus N, Denmark
Diabetes Care 2012; 35: 2161–66
Aims
The purpose of this study was to evaluate the psychometric
properties of a short, new, self-administered questionnaire
(17–19 items) for evaluating the adherence behavior of children and adolescents with type 1 diabetes and their parents.
This questionnaire has different versions depending on the
method of insulin administration: continuous subcutaneous
insulin infusion (Adherence in Diabetes Questionnaire
[ADQ]-I) or conventional insulin injection (ADQ-C).
In this trial, 1,028 caregivers and 766 children and adolescents 2–17 years old were assigned through the Danish Registry of Childhood Diabetes and completed the national web
survey. The survey included the ADQ and psychosocial
measures of self-efficacy, parental support, family conflict,
and aspects of diabetes-related quality of life. HbA(1c) was
measured in a central laboratory. The psychometric properties of the ADQ were evaluated, and the correlation with
glycemic control was assessed.
A profile of self-care behaviors in emerging adults
with type 1 diabetes
Hendricks M1, Monaghan M 2, Soutor S1, Chen R3, Holmes CS1,3
1
Virginia Commonwealth University, Richmond, VA; 2Children’s
National Medical Center, Washington, DC; and 3Georgetown
University, Washington, DC
Diabetes Educ 2013; 39: 195–203
Aims
The target of this study was to characterize everyday diabetes self-care behaviors and to assess correlations among
self-care behaviors, psychosocial adjustment, and glycemic
control in an understudied sample of emerging adults with
type 1 diabetes.
Methods
A total of 49 emerging adults (65% women; age 18–26
years) completed two diabetes interviews to evaluate
self-care behaviors and self-report measures of psychosocial
adjustment. Glycemic control was evaluated through hemoglobin A1C.
Results
Diabetes self-care behaviors varied widely and were mostly
suboptimal; only a small percentage of subjects showed selfcare behaviors consistent with national and international recommendations. Psychosocial adjustment was within normal
limits and was not related to frequency of self-care behaviors
in this sample. Mean glycemic control (8.3%) was higher
than the recommended A1C level ( < 7.0%) for this age group.
Use of intensive (e.g., multiple daily injections or pump) insulin
regimens was associated with better glycemic control.
S-117
endocrinologist to an adult care physician (n = 19). Nine youth
saw no physician between time 1 and time 2. There were
group differences in demographic and parent relationship
variables and self-care behavior and glycemic control related
to the transition of care. Patients who stayed in the pediatric
healthcare system had the best self-care and did not show a
decline in glycemic control through the study period.
Conclusions
Early transition from the pediatric healthcare system to the
adult healthcare system is correlated with psychosocial variables and poor glycemic control. Future study should identify
factors that determine optimal timing and strategies to avoid
worsening of care and control during this transition.
Conclusions
Comment
Most of the participants in this study did not engage in
optimal daily diabetes self-care. Intensive insulin therapy was
correlated with better glycemic control without corresponding psychosocial distress. Diabetes care behaviors could be
improved in this age group, and emerging adults may benefit from targeted education and behavioral support to improve diabetes self-management and to achieve better health
outcomes.
Emerging adulthood is a relatively new concept referring
to the age period from the late teens to the mid to late 20s
(age 18–25). It has been referred to as, ‘‘A new term to a
new phenomenon,’’ describing the sociological phenomenon in industrialized countries where persons at
this age group feel that they are ‘‘no longer adolescents
and not yet adults.’’ They are not dependent on their
parents like in their youth, but they cannot be completely
independent like adults (10). This group may also have
issues in obtaining good health benefits if they are not in a
country with socialized healthcare; that is, they may be in
school or working part time in a job that does not provide
healthcare benefits. In addition, a position statement
published by the American Diabetes Association in 2011
emphasized potential risk at this age group for poor
glycemic control and associated problems in adherence
to their diabetes treatment (11).
This complicated age group is also challenging when
considering the use of diabetes technology. For some
emerging adults, using insulin pump therapy has caused
them distress. It is encouraging to know that using
intensive insulin therapy has been positive for most
patients. The pediatric diabetes team should carefully
assess its late adolescents/young adults to be sure that
they are mature enough to make the transition to an adult
clinic, which is, generally speaking, less supportive than
the pediatric diabetes clinic.
Characterizing the transition from paediatric to adult
care among emerging adults with type 1 diabetes
Helgeson VS 1, Reynolds KA2, Snyder PR 1, Palladino DK 1,
Becker DJ3, Siminerio L4, Escobar O3
1
Psychology Department, Carnegie Mellon University, Pittsburgh, PA; 2The Rand Corporation, Pittsburgh, PA; 3Department
of Pediatric Endocrinology, University of Pittsburgh and Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA; and
4
University of Pittsburgh School of Medicine and University of
Pittsburgh Diabetes Institute, Quantum One, Pittsburgh, PA
Diabetes Med 2013; 30: 610–15
Aims
The purpose of this study was to describe the transition of
adolescents with type 1 diabetes from childhood to adult
healthcare services, study the connection of this transition
with self-care and glycemic control, and distinguish adolescents who received medical treatment from different physicians in terms of demographic and parent relationship
variables.
A total of 118 adolescents with type 1 diabetes participated
in a prospective study that examined the transition from the
pediatric to adult healthcare systems and were assessed
during their senior year of high school (time 1) and 1 year later
(time 2). Data on self-care, glycemic control, and parent relationship were collected.
A.L. has no competing financial interests. B.B. is on the
medical advisory boards for Medtronic Diabetes, Sanofi
Aventis, Glysense, and Roche. He has received research
support from Medtronic Diabetes. M.P. is a member of advisory boards for AstraZeneca, Sanofi, Medtronic, and Eli Lilly.
He is a consultant to Bristol Myers-Squibb, AstraZeneca, and
Andromeda. He is on the speaker’s bureau of Johnson and
Johnson, Sanofi, Medtronic, Novo Nordisk, and Roche. He is a
shareholder of CGM-3.
Results
References
Methods
Most of the adolescents saw a pediatric endocrinologist at
both evaluations (n = 64); others saw an adult care physician
at both evaluations (n = 26) or transitioned from a pediatric
1. Aanstoot H-J, Anderson BJ, Daneman D, et al. The global
burden of youth diabetes: Perspectives and potential: A
charter paper. Pediatr Diabetes 2007; 8 (Suppl. 8): 4–40.
S-118
2. de Vries L, Grushka Y, Lebenthal Y, Shalitin S, Phillip M.
Factors associated with increased risk of insulin pump
discontinuation in pediatric patients with type 1 diabetes.
Pediatr Diabetes 2011; 12: 506–12.
3. Reading R. A clinical trial to maintain glycemic control in
youth with type 2 diabetes. Child Care Health Dev 2012; 38:
607–8.
4. Tsalikian E, Fox L, Weinzimer S, Buckingham B, White NH,
Beck R, Kollman C, Xing D, Ruedy K; Diabetes, Research in
Children Network Study Group. Feasibility of prolonged
continuous glucose monitoring in toddlers with type 1 diabetes. Pediatr Diabetes 2011; 13: 301–7.
5. McNally K, Rohan J, Pendley JS, Delamater A, Drotar D.
Executive functioning, treatment adherence, and glycemic
control in children with type 1 diabetes. Diabetes Care 2010;
33: 1159–62.
6. Burdick J, Chase HP, Slover RH, et al. Missed insulin meal
boluses and elevated hemoglobin A1c levels in children
LIEBERMAN ET AL
7.
8.
9.
10.
11.
receiving insulin pump therapy. Pediatrics 2004; 113:
e221–24.
O’Connell MA, Donath S, Cameron FJ. Poor adherence to
integral daily tasks limits the efficacy of CSII in youth. Pediatr Diabetes 2011; 12: 556–59.
Olinder AL, Nyhlin KT, Smide B. Reasons for missed mealtime insulin boluses from the perspective of adolescents using
insulin pumps: ‘‘Lost focus.’’ Pediatr Diabetes 2011; 12: 402–9.
Powers MA, Richter S, Ackard D, Critchley S, Meier M,
Criego A. Determining the influence of type 1 diabetes on
two common eating disorder questionnaires. Diabetes Educ
2013; 39: 387–96.
Arnett JJ. Emerging adulthood: A theory of development
from the late teens through the twenties. Am Psychol 2000;
55: 469–80.
Peters A, Laffel L. Diabetes care for emerging adults: Recommendations for transition from pediatric to adult diabetes care systems. Diabetes Care 2011; 34: 2477–85.
DOI: 10.1089/dia.2014.1514
ORIGINAL ARTICLE
Newer Therapies for Diabetes Management
Satish K. Garg and Viral N. Shah
Introduction
W
ith the increasing global epidemic of diabetes, especially type 2 diabetes, all major pharmaceutical
companies are focusing on new molecules for the treatment of
diabetes and obesity. With the better management of diabetes
(improved HbA1c values), the microvascular complications
have significantly reduced over the past two decades. This has
been achieved without increasing hypoglycemia especially
with newer technological advances (discussed at length in
chapters 12 and 13 in this yearbook).
We review here the abstracts related to the newer molecules
that are being investigated in the management of diabetes. We
searched more than 400 articles on newer agents published
from July 2012 to June 2013, of which the best 19 abstracts are
discussed. Also, we briefly mention newer insulin analogs
and alternate insulin delivery methods, as this topic is discussed at length by colleagues in chapter 5 of this yearbook.
in the European Union. This article summarizes the milestones
in the development of canagliflozin, leading to its first approval
for use in adults with type 2 diabetes.
Canagliflozin, a new sodium-glucose cotransporter 2
inhibitor, in the treatment of diabetes
Nisly SA1, Kolanczyk DM 2, Walton AM 3
1
Department of Pharmacy Practice, College of Pharmacy and
Health Sciences (COPHS), Butler University, and Internal
Medicine, Indiana University Health, Methodist Hospital, Indianapolis, IN; 2Cardiology, Department of Pharmaceutical Services, University of Chicago Medical Center, Chicago, IL; and
3
Department of Pharmacy Practice, COPHS, Butler University,
and Ambulatory Care, St. Vincent Health, Indianapolis, IN
Am J Health Syst Pharm 2013; 70: 311–19
Purpose
Canagliflozin: first global approval
The published evidence on the pharmacology, pharmacodynamics, pharmacokinetics, safety, and efficacy of a promising investigational agent for managing type 2 diabetes is
evaluated.
Elkinson S, Scott LJ
Summary
Adis R&D Insight, North Shore Auckland, New Zealand
Canagliflozin belongs to a class of agents—the sodium–
glucose co-transporter 2 (SGLT2) inhibitors—whose novel
mechanism of action offers potential advantages over other
antihyperglycemic agents, including a relatively low hypoglycemia risk and weight-loss-promoting effects. Canagliflozin has dose-dependent pharmacokinetics, and research in
laboratory animals demonstrated high oral bioavailability
(85%) and rapid effects in lowering glycosylated hemoglobin
(HbA1c) values. In four early-stage clinical trials involving a
total of over 500 patients, the use of canagliflozin for varying
periods was associated with significant mean reductions in
HbA1c (absolute reductions of 0.45–0.92%) and fasting plasma glucose (decreases ranged from 16.2% to 42.4%) and
weight loss ranging from 0.7 to 3.5 kg. More than a dozen
phase II or III clinical trials of canagliflozin in adults are ongoing or have been recently completed, but the final results of
SODIUM–GLUCOSE CO-TRANSPORTER
(SGLT-1 And 2) INHIBITORS
Drugs 2013; 73: 979–88
Canagliflozin (Invokana), an oral selective sodium–glucose
co-transporter 2 (SGLT2) inhibitor, is under global development with Mitsubishi Tanabe Pharma and Janssen Pharmaceuticals, a subsidiary of Johnson and Johnson, for the
treatment of type 2 diabetes mellitus. SGLT2 are mainly located
in the proximal tubule of the kidney and are involved in the
reabsorption of filtered glucose from the glomeruli into the
body. Inhibition of SGLT2 lowers blood glucose in an insulinindependent manner as a consequence of blocking reabsorption of filtered glucose in the glomeruli, thereby increasing
urinary excretion of glucose and, in turn, potentially reducing
body weight. Canagliflozin is the first SGLT2 inhibitor to be
approved in the United States and is under regulatory review
Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver Health Sciences Center, Aurora, CO.
S-119
S-120
most of those studies have not been published. Adverse effects reported in clinical trials of canagliflozin include urinary
tract and genital infections, occurring in about 10% of patients. Additional and larger phase III clinical trials to delineate the potential role of canagliflozin and other SGLT2
inhibitors in the management of diabetes (including studies
involving the elderly, children, and patients with renal or
hepatic dysfunction) are planned or currently under way.
Conclusion
Canagliflozin and other investigational SGLT2 inhibitors have a novel mechanism of action that may offer a future
alternative treatment pathway for managing type 2 diabetes.
Ipragliflozin and other sodium-glucose cotransporter-2
(SGLT2) inhibitors in the treatment of type 2 diabetes:
preclinical and clinical data
Kurosaki E1, Ogasawara H 2
1
Astellas Pharma, Inc., Ibaraki, Japan; and 2Astellas Pharma
Global Development, Tokyo, Japan
Pharmacol Ther 2013; 139: 51–59
Sodium–glucose co-transporter-2 (SGLT2) is expressed in
the proximal tubules of the kidneys and plays a key role in
renal glucose reabsorption. A novel class of antidiabetic
medications, SGLT2-selective inhibitors, attempts to improve
glycemic control in diabetics by preventing glucose from being reabsorbed through SGLT2 and reentering circulation.
Ipragliflozin is an SGLT2 inhibitor in phase 3 clinical development for the treatment of type 2 diabetes mellitus (T2DM).
In this review, we summarize recent animal and human
studies on ipragliflozin and other SGLT2 inhibitors, including
dapagliflozin, canagliflozin, empagliflozin, tofogliflozin, and
luseogliflozin. These agents all show potent and selective
SGLT2 inhibition in vitro and reduce blood glucose levels and
HbA1c in both diabetic animal models and patients with
T2DM. SGLT2 inhibitors offer several advantages over other
classes of hypoglycemic agents. Because of their insulinindependent mode of action, SGLT2 inhibitors provide steady
glucose control without major risk for hypoglycemia and may
also reverse b-cell dysfunction and insulin resistance. Other
favorable effects of SGLT2 inhibitors include a reduction in
both body weight and blood pressure. SGLT2 inhibitors are
safe and well tolerated and can easily be combined with other
classes of antidiabetic medications to achieve tighter glycemic
control. The long-term safety and efficacy of these agents are
under evaluation.
Dapagliflozin a glucose-regulating drug with diuretic
properties in subjects with type 2 diabetes
Lambers Heerspink HJ1, de Zeeuw D1, Wie L 3, Leslie B 2,
List J 2
1
Department of Clinical Pharmacology, University Medical
Center Groningen, University of Groningen, Groningen, The
Netherlands; 2Global Clinical Research, Bristol-Meyer-Squibb,
Princeton, NJ; and 3Global Biometric Sciences, Bristol-MeyerSquibb, Hopewell, NJ
Diabetes Obes Metab 2013 May 13; DOI: 10.1111/dom.12127
GARG AND SHAH
Aims
Sodium–glucose co-transporter 2 (SGLT2) reabsorbs glucose
and sodium in the renal proximal tubule. Dapagliflozin, an
SGLT2 inhibitor, targets hyperglycemia in type 2 diabetes by
increasing renal glucose excretion. To investigate whether the
parallel-occurring sodium loss would have diuretic-like physiologic effects, we compared dapagliflozin and hydrochlorothiazide (HCTZ) effects on 24-hour blood pressure (BP), body
weight, plasma volume, and glomerular filtration rate (GFR).
Methods
In this randomized, placebo-controlled, double-blind trial,
75 subjects with type 2 diabetes were assigned placebo, dapagliflozin 10 mg/day, or HCTZ 25 mg/day. Changes from
baseline BP, body weight, plasma volume, and GFR were
assessed after 12 weeks of treatment.
Results
Subjects’ mean age was 56 years, type 2 diabetes mellitus
(T2DM) duration 6.3 years, and hemoglobin A1c (HbA1c)
7.5%. Treatment with placebo, dapagliflozin, or HCTZ resulted in changes from baseline in 24-hour ambulatory
mean systolic blood pressure (SBP) of - 0.9 (95% CI - 4.2,
+ 2.4), - 3.3 (95% CI - 6.8, + 0.2), and - 6.6 (95% CI - 9.9,
- 3.2) mmHg, respectively, at week 12, adjusted for baseline
SBP. Body weight decreased with dapagliflozin and HCTZ.
In a substudy, plasma volume appeared to decrease with
dapagliflozin but did not change with placebo or HCTZ
treatment. Dapagliflozin induced a greater reduction in GFR
( - 10.8%; 95% CI - 14.6, - 6.7) relative to placebo ( - 2.9%;
95% CI - 6.9, + 1.2) or HCTZ ( - 3.4%; 95% CI - 7.3, + 0.6).
Conclusions
Dapagliflozin-induced SGLT2 inhibition for 12 weeks is
associated with reductions in 24-hour BP, body weight, GFR,
and possibly plasma volume. Cumulatively, these effects
suggest that dapagliflozin may have a diuretic-like capacity to
lower BP in addition to beneficial effects on glycemic control.
Dapagliflozin, an SGLT2 inhibitor for the treatment
of type 2 diabetes
Demaris KM, White JR
Washington State University, Spokane, WA
Drugs Today (Barc) 2013; 49: 289–301
Dapagliflozin is a selective, competitive inhibitor of
sodium–glucose cotransporter 2 (SGLT2) acting to block reabsorption of filtered glucose in the kidney. Independent of
pancreatic b-cell function or the modulation of insulin sensitivity, this novel treatment strategy promotes glucosuria and
direct lowering of plasma glucose concentrations. Dapagliflozin has been approved for the treatment of type 2 diabetes
in the European Union; however, the U.S. Food and Drug
Administration rejected the approval of dapagliflozin based
on lack of clinical data to effectively assess the benefit-to-risk
profile. This article will highlight the physiology of renal
glucose regulation and reabsorption, briefly outline the
pharmacology of dapagliflozin, and discuss the results of
completed clinical trials as well as the status of the drug.
NEWER THERAPIES FOR DIABETES MANAGEMENT
S-121
Safety, pharmacokinetics and pharmacodynamics
of remogliflozin etabonate, a novel SGLT2 inhibitor,
and metformin when co-administered in subjects
Comment
SGLTs are a family of glucose transporters. There are
many SGLTs of which SGLT1 and SGLT2 are well characterized. SGLT2 is localized mainly in proximal convoluted tubules of kidney and involved in glucose
reabsorption. Blocking SGLT2 transporter will result in
increased urinary glucose excretion, loss of weight, and
improvement in glucose control. In addition, SGLT1 inhibition further reduces glucose reabsorption from the
distal tubules of the kidney. We chose five abstracts in
this category as there is increased activity in this class of
molecules by major pharmaceutical companies.
Canagliflozin was the first SGLT2 inhibitor approved
by the U.S. Food and Drug Administration (FDA) in the
United States, and it is under regulatory review by
European Medicines Agency. The first article summarizes
the development of canagliflozin and its clinical data. The
second article describes the clinical effects of canagliflozin
in phase 2 and phases 3 studies in patients with type 2
diabetes. Ipragliflozin is another SGLT2 inhibitor; the third
article summarizes the preclinical and clinical data of this
agent in the management of type 2 diabetes.
Two more SGLT2 inhibitors are under clinical trials:
dapagliflozin and remoglifozin. The last three abstracts
present clinical efficacy data of these two SGLT2 inhibitors in patients with type 2 diabetes.
Overall, all four agents showed promise in the management of type 2 diabetes. They do have similar HbA1c
reduction by 0.5–0.9% with significant weight and blood
pressure reduction compared with the placebo. However, these agents are associated with higher urinary and
genital tract infections, especially in women. Earlier
studies on dapagliflozin had insignificant imbalance
toward bladder and breast cancer. Since the SGLT are
ubiquitous, long-term safety is unknown. The combined
SGLT1 and 2 inhibitors are currently being investigated
in addition to their role in management of type 1 diabetes.
Hussey EK1, Kapur A1, O’Connor-Semmes R1, Tao W1,
Rafferty B1, Polli JW1, James CD Jr2, Dobbins RL1
1
GlaxoSmithKline, Research Triangle Park, NC;
and 2Tandem Labs, Durham, NC
BMC Pharmacol Toxicol 2013; 14: 25
Background
The sodium-dependent glucose co-transporter-2 (SGLT2)
is expressed in absorptive epithelia of the renal tubules.
Remogliflozin etabonate (RE) is the prodrug of remogliflozin, the active entity that inhibits SGLT2. An inhibitor
of this pathway would enhance urinary glucose excretion (UGE), and potentially improve plasma glucose concentrations in diabetic patients. RE is intended for use for
the treatment of type 2 diabetes mellitus (T2DM) as monotherapy and in combination with existing therapies.
Metformin, a dimethylbiguanide, is an effective oral antihyperglycemic agent widely used for the treatment of
T2DM.
Methods
This was a randomized, open-label, repeat-dose, twosequence, crossover study in 13 subjects with T2DM. Subjects were randomized to one of two treatment sequences in
which they received either metformin alone, RE alone, or
both over three 3-day treatment periods separated by two
nontreatment intervals of variable duration. On the evening before each treatment period, subjects were admitted
and confined to the clinical site for the duration of the 3-day
treatment period. Pharmacokinetic, pharmacodynamic
(urine glucose and fasting plasma glucose), and safety
(adverse events, vital signs, ECG, clinical laboratory parameters, including lactic acid) assessments were performed at check-in and throughout the treatment periods.
Pharmacokinetic sampling occurred on day 3 of each
treatment period.
GLUCAGON-LIKE PEPTIDE-1 (GLP-1) ANALOGS
Clinical potential of lixisenatide once daily treatment
for type 2 diabetes mellitus
Results
Petersen AB1, Christensen M1,2
This study demonstrated the lack of effect of RE on
steady-state metformin pharmacokinetics. Metformin did
not affect the area under the curve of RE, remogliflozin, or
its active metabolite, GSK279782, although Cmax values
were slightly lower for remogliflozin and its metabolite
after coadministration with metformin compared with
administration of RE alone. Metformin did not alter the
pharmacodynamic effects (UGE) of RE. Concomitant administration of metformin and RE was well tolerated with
minimal hypoglycemia, with no serious adverse events and
no increase in lactic acid.
1
Conclusions
Coadministration of metformin and RE was well-tolerated
in this study. The results support continued development of
RE as a treatment for T2DM.
Department of Clinical Pharmacology, Bispebjerg Hospital,
Copenhagen, Denmark; and 2Diabetes Research Division, Department of Internal Medicine, Gentofte Hospital, Copenhagen,
Denmark
Diabetes Metab Syndr Obes 2013; 6: 217–31
The glucagon-like peptide (GLP)-1 receptor agonist lixisenatide (Lyxumia) was approved for marketing by the European Medicines Agency in February 2013 and has been
evaluated in a clinical study program called GetGoal. Lixisenatide activates the GLP-1 receptor and thereby exercises
the range of physiological effects generated by GLP-1, which
consist of increased insulin secretion, inhibition of glucagon
secretion, and decreased gastrointestinal motility alongside
the promotion of satiety. In the GetGoal study program, lixisenatide demonstrated significant reductions in glycated
S-122
hemoglobin (HbA1c), and fasting and postprandial plasma
glucose compared with placebo. The effect on glycemia was
evident, with both monotherapy and in combination with
insulin and various oral antidiabetic agents. Furthermore, a
general trend toward reduced body weight was reported. In
head-to-head trials with the other GLP-1 receptor agonists
(exenatide and liraglutide) on the market, lixisenatide demonstrated a superior effect with respect to reduction in postprandial plasma glucose and had a tendency toward fewer
adverse events. However, lixisenatide seemed to be less efficient or, at best, equivalent to exenatide and liraglutide in
reducing HbA1c, fasting plasma glucose, and body weight.
The combination of a substantial effect on postprandial plasma glucose and labeling with once-daily administration separates lixisenatide from the other GLP-1 receptor agonists.
The combination of basal insulin, having a lowering effect on
fasting plasma glucose, and lixisenatide, curtailing the postprandial glucose excursions, makes sense from a clinical point
of view. Not surprisingly, lixisenatide is undergoing clinical
development as a combination product with insulin glargine
(Lantus). At present the main place in therapy of lixisenatide
seems to be in combination with basal insulin. A large multicenter study will determine the future potential of lixisenatide in preventing cardiovascular events and mortality, in
patients with type 2 diabetes and recent acute coronary syndrome.
Lixisenatide: first global approval
Elkinson S1, Keating GM 2
1
Adis R&D Insight, North Shore, Auckland, New Zealand; and
Adis, Auckland, New Zealand
2
Drugs 2013; 73: 383–91
The selective once-daily prandial glucagon-like peptide-1
(GLP-1) receptor agonist lixisenatide (Lyxumia) is under
development with Sanofi for the treatment of type 2 diabetes mellitus. Lixisenatide belongs to a class of GLP-1
compounds designed to mimic the endogenous hormone
GLP-1. Native GLP-1 stimulates insulin secretion in a glucosedependent manner, as well as suppressing glucagon production and slowing gastric emptying. A once-daily subcutaneous
formulation of lixisenatide has been approved in the European
Union, Iceland, Liechtenstein, Norway, and Mexico for the
treatment of type 2 diabetes and is under regulatory review in
the United States, Switzerland, Brazil, Canada, Ukraine, South
Africa, Japan, and Australia. This article summarizes the
milestones in the development of lixisenatide, leading to this
first approval for use in adults with type 2 diabetes.
Once weekly exenatide: efficacy, tolerability
and place in therapy
Wysham C1, Grimm M 2, Chen S 2
1
Department of Medicine, University of Washington School of
Medicine, Seattle, WA; and 2Amylin Pharmaceuticals, LLC,
San Diego, CA
Diabetes Obes Metab 2013; 15: 871–881
Exenatide once weekly is the first glucose-lowering agent
available to patients with type 2 diabetes mellitus (T2DM).
GARG AND SHAH
This long-acting formulation contains the same active ingredient as exenatide twice daily, except that the exenatide
is encapsulated in dissolvable microspheres. After subcutaneous injection, exenatide once weekly microspheres remain in place under the skin and slowly degrade, releasing
active exenatide continuously into circulation. In randomized clinical trials, exenatide once weekly was associated
with significant glycemic improvement and moderate
weight loss in patients with T2DM when administered as
monotherapy or in combination with a variety of oral antidiabetic agents. Exenatide once weekly also lowered
blood glucose more effectively than titrated basal insulin in
patients on metformin or metformin plus sulphonylurea
background therapy. Gastrointestinal side effects (nausea,
vomiting, and diarrhea) were the most common tolerability
issues associated with exenatide once weekly administration, but they occurred at lower rates than in patients on
other glucagon-like peptide receptor agonists (i.e., exenatide twice daily or liraglutide). Issues regarding the place of
exenatide once weekly in T2DM pharmacotherapy are
discussed.
Comment
The first GLP-1 analog, exenatide, was approved by
the FDA in 2005 followed by approval of liraglutide in
2010. GLP-1 analogs have shown promise in the management of type 2 diabetes. Lixisenatide, a recently approved GLP-1 analog, demonstrated a modest reduction
in postprandial plasma glucose and had a tendency toward fewer adverse events than other GLP-1 analogs.
However, overall reduction in HbA1c and weight loss
is similar to exenatide and liraglutide. Furthermore,
lixisenatide is undergoing clinical development as a
combination product with insulin glargine. Similarly,
Liraglutide, a once-daily GLP-1 analog, is also being investigated with insulin detemir so that fasting plasma
glucose (FPG) and postprandial plasma glucose (PPG)
reductions can be achieved with basal insulin and GLP-1
analog, respectively.
Another development is prolonging the duration
of exenatide once weekly so that patient compliance can be enhanced. The last article described the
efficacy and tolerability of once-weekly exenatide
preparation.
Most of the earlier GLP analogs (exenatide) were
short-acting and reduce prandial glucose excursion
when given before meals. However, newer analogs are
longer acting and have a significant effect on FPG.
There is preferential efficacy of this class of drug in
Asians, probably because of higher carbohydrate
intake. Long-term safety of these drugs has been
recently questioned, especially in relation to pancreatitis and pancreatic cancer. Many long-term studies are
ongoing to investigate their safety as it relates to
cardiovascular outcome and cancers. As of July 2013,
European Medicines Agency’s Committee for Medicinal Products for Human Use concluded that presently
available data for incretin-based therapy do not adequately support concerns about pancreatic adverse
events.
DIPEPTIDYL PEPTIDASE-IV (DPP IV) INHIBITORS
Effect of sitagliptin on post-prandial glucagon
and GLP-1 levels in patients with type 1 diabetes:
investigator-initiated, double-blind, randomized,
placebo-controlled trial
Garg SK1–3, Moser EG1,4, Bode BW 5, Klaff LJ 6, Hiatt WR 7,
Beatson C1, Snell-Bergeon JK1
1
Barbara Davis Center for Diabetes, University of Colorado
Anschutz Medical Center, Aurora, CO; 2Diabetes Technology
and Therapeutics and 3University of Colorado Anschutz
Medical Campus, Aurora, CO; 4School of Medicine, University of
Colorado Anschutz Medical Campus, Aurora, CO; 5Atlanta Diabetes Associates, Atlanta, GA; 6Rainier Clinical Research Center,
Renton, WA; and 7CPC Clinical Research and Department of
Medicine/Cardiology, University of Colorado School of Medicine,
Aurora, CO
Endocr Pract 2013; 19: 19–28
Objective
Peripheral insulin resistance in type 1 diabetes may be related to a paradoxical postprandial glucagon increase. This
study evaluated the effects of sitagliptin (dipeptidyl peptidase-IV [DPP-IV] inhibitor, approved for patients with type 2
diabetes) in adults with type 1 diabetes to improve glycemic
control through decreasing postprandial glucagon.
Methods
This investigator-initiated, double-blind, randomized,
parallel, 20-week study enrolled 141 subjects. Subjects received sitagliptin 100 mg/day or placebo for 16 weeks. A
subset of 85 patients wore blinded continuous glucose monitors (CGM) for five separate 7-day periods. The primary
outcome was postmeal (Boost) reduction in 4-hour glucagon
area under the curve (AUC). Secondary endpoints included
changes in glycated hemoglobin (A1c), CGM data, insulin
dose, glucagon-like peptide-1 (GLP-1), glucose-dependent
insulinotropic peptide (GIP), and C-peptide levels.
Results
There were no differences at screening between groups;
however, after a 4-week run-in phase, A1c was significantly
lower in the sitagliptin versus the placebo group. Postmeal
GLP-1 levels were higher ( p < 0.001) and GIP levels lower
( p = 0.03) with glucagon suppression at 30 minutes (LS means
23.2 – 1.9 vs. 16.0 – 1.8; p = 0.006) in the sitagliptin group at
16 weeks. There were no differences between the groups
in change in A1c, insulin dose, weight, or C-peptide after
16 weeks of treatment. However, C-peptide-positive patients
randomized to sitagliptlin had a nonsignificant trend toward decrease in A1c, mean glucose, and time spent in
hyperglycemia.
Conclusion
Sitagliptin use in type 1 diabetes did not change glucagon
AUC, A1c, insulin dose, or weight despite postmeal rise in
GLP-1 levels. C-peptide-positive subjects treated with si-
S-123
tagliptin had a nonsignificant trend in decreasing hyperglycemia, which needs further evaluation.
Comment
The DPP IVs are oral incretins that increase the native
GLP-1 levels. Different DPP IV inhibitors approved for
use in the United States and Europe are sitagliptin, vildagliptin, saxagliptin, alogliptin, and Linagliptin. These
agents have similar mechanisms of actions to GLP-1 analogs (except that reduction in A1c is modest [0.5–0.8%])
and are weight- and lipid-neutral. The effect of this class
of drugs in patients with type 1 diabetes is not known. It
is known that patients with type 1 diabetes do have
postprandial paradoxical rise in glucagon (though small
as compared with type 2 diabetes). Few small studies
have reported improvement in A1c, loss of weight, and
significant reduction in insulin dose in type 1 diabetes.
This article described the effect of sitagliptin, a DPP IV
inhibitor, on postprandial glucagon and GLP-1 levels in
patients with type 1 diabetes. In this randomized study,
there was a significant rise in GLP-1 levels as expected in
patients with type 1 diabetes receiving sitagliptin but was
not associated with improvement in metabolic effects or
insulin dosages. This is in contrast to the previous pilot
study (Ellis SL, et al. Diabet. Med 2011; 28: 1176–81) by
the same investigators, where there was a small reduction in A1c (0.2%). The authors also described possible
roles of this class of drugs in C-peptide-positive patients
with type 1 diabetes. This area is being investigated further with the use of GLP-1 analogs in which the blood
levels of GLP achieved would be much higher.
NEWER INSULINS
Insulin degludec and insulin degludec/insulin aspart:
a review of their use in the management
of diabetes mellitus
Keating GM
Adis, North Shore, Auckland, New Zealand
Drugs 2013; 73: 575–93
Insulin degludec (Tresiba) is an ultra-long-acting insulin
analog that is also available as a coformulation with rapidacting insulin aspart (insulin degludec/insulin aspart) [Ryzodeg]. Insulin degludec has a flat, stable glucose-lowering
profile with a duration of action of > 42 hours and less withinpatient day-to-day variability in glucose-lowering effect than
the long-acting insulin analog insulin glargine. In clinical trials, insulin degludec achieved similar glycemic control to that
seen with insulin glargine in patients with type 1 or 2 diabetes
but with a lower risk of nocturnal hypoglycemia. In addition,
trials examining a flexible dosing regimen of insulin degludec
in patients with type 1 or 2 diabetes show the potential for
adjusting the injection time, without compromising glycemic
control or safety. A 200 U/mL formulation of insulin degludec
is also available for use in patients who require large volumes
of basal insulin. Insulin degludec/insulin aspart was noninferior to the long-acting insulin analog insulin detemir in
patients with type 1diabetes and has the potential to reduce
S-124
the number of daily injections. Trial results also indicate that
insulin degludec/insulin aspart may be an appropriate option
for initiating insulin therapy in patients with type 2 diabetes
inadequately controlled with oral antidiabetic drugs. Subcutaneous insulin degludec was generally well-tolerated in
patients with type 1 or 2 diabetes. In conclusion, insulin degludec and insulin degludec/insulin aspart represent a useful
advance in the treatment of type 1 or 2 diabetes.
Newer insulin analogs: advances in basal
insulin replacement
Zinman B
Samuel Lunenfeld Research Institute, Mount Sinai Hospital,
University of Toronto, Toronto, Ontario, Canada; and Leadership
Sinai Centre for Diabetes, Toronto, Ontario, Canada
Diabetes Obes Metab 2013; 15 Suppl 1: 6–10
Basal insulin analog therapy is the most common method
of introducing insulin replacement therapy for the majority of
patients with type 2 diabetes mellitus. Long-acting insulin
analogs provide relatively peakless and more physiologic
insulin replacement therapy than neutral protaminated Hagedorn insulin. Recently, two new basal insulin analogs have
been developed with superior pharmacokinetic and pharmacodynamics properties: insulin degludec and a pegylated
insulin lispro. These agents are generally well tolerated and
have been evaluated in both type 1 and type 2 diabetes. In this
article, we review the results of clinical trials assessing the
efficacy, safety, and tolerability of these newer longer-acting
insulin analogs. In general, rates of hypoglycemia in these
trials were low, glucose control was comparable to currently
available basal insulin analogs, and rates of nocturnal hypoglycemia were significantly and substantially lower. While
further study will be required, advances in basal insulin replacement may offer important advantages over existing options for starting insulin strategies.
A randomized, controlled study of once-daily
LY2605541, a novel long-acting basal insulin,
versus insulin glargine in basal insulin-treated
patients with type 2 diabetes
Bergenstal RM1, Rosenstock J 2, Arakaki RF 3, Prince MJ 4,
Qu Y 4, Sinha VP 4, Howey DC 4, Jacober SJ 4
1
International Diabetes Center at Park Nicollet, Minneapolis, MN;
Dallas Diabetes and Endocrine Center at Medical City, Dallas,
TX; 3University of Hawaii at Manoa, Honolulu, HI; and 4Eli Lilly
and Company, Indianapolis, IN
2
Diabetes Care 2012; 35: 2140–47
Objective
To evaluate whether LY2605541 results in lower fasting
blood glucose (FBG) versus insulin glargine (GL).
GARG AND SHAH
tients converted to morning insulin administration during
lead-in were randomized 2:1 from GL (n = 248) or NPH insulin
(n = 39) to LY2605541 (n = 195) or GL (n = 95) once daily in the
morning.
Results
At 12 weeks, FBG (mean – SE) was similar with LY2605541
and GL (118.2 – 2.0 mg/dL [6.6 – 0.1 mmol/L] vs. 116.9 –
2.7 mg/dL [6.5 – 0.2 mmol/L], p = 0.433) as was A1C (7.0 –
0.1% vs. 7.2 – 0.1%, p = 0.279). Intraday blood glucose variability was reduced with LY2605541 (34.4 vs. 39.1 mg/dL [1.9
vs. 2.2 mmol/L], p = 0.031). LY2605541 patients had weight
loss ( - 0.6 – 0.2 kg, p = 0.007), whereas GL patients gained
weight (0.3 – 0.2 kg, p = 0.662; treatment difference: - 0.8 kg,
p = 0.001). The incidence and rate of both total hypoglycemia
and nocturnal hypoglycemia were comparable between
LY2605541 and GL; however, LY2605541 had a 48% reduction
in nocturnal hypoglycemia after adjusting for baseline hypoglycemia ( p = 0.021). Adverse events were similar across
treatments. Alanine aminotransferase and aspartate aminotransferase remained within normal range but were significantly higher with LY2605541 ( p £ 0.001).
Conclusions
In patients with type 2 diabetes, LY2605541 and GL had
comparable glucose control and total hypoglycemia rates, but
LY2605541 showed reduced intraday variability, lower nocturnal hypoglycemia, and weight loss relative to GL.
Coverage of prandial insulin requirements by means
of an ultra-rapid-acting inhaled insulin
Boss AH1, Petrucci R1, Lorber D 2
1
MannKind Corporation, Valencia, CA; and 2Lang Center for
Research and Education, New York Hospital, Queens, NY
Barriers to the use of prandial insulin regimens include inadequate synchronization of insulin action to postprandial
plasma glucose excursions as well as a significant risk of
hypoglycemia and weight gain. Technosphere insulin (TI) is
inhaled as ultra-rapid-acting human insulin that is quickly
absorbed in the alveoli. With a time to maximum plasma
drug concentration of approximately 14 min and a time to
maximum effect of 35–40 min, TI more closely matches the
postprandial insulin concentrations seen in nondiabetic individuals. Studies have shown that long-term administration of
prandial TI in combination with long-acting basal insulin results in reductions in hemoglobin A1c comparable to conventional subcutaneously injected prandial insulins but with
improved control of early postprandial BG. Furthermore, TI
has been associated with less weight gain and a lower incidence
of hypoglycemia, which may enhance patient satisfaction and
acceptability of insulin therapy. This review discusses the
clinical properties of TI and proposes strategies for optimal use.
This 12-week, randomized, open-label, phase 2 study enrolled patients with type 2 diabetes (hemoglobin A(1c) [A1C]
£ 10.5%), taking metformin and/or sulfonylurea with GL or
neutral protamine hagedorn (NPH) insulin once daily. Pa-
Novel lyophilized hydrogel patches for convenient
and effective administration of microneedle-mediated
insulin delivery
Qiu Y1, Qin G1,2, Zhang SV1, Wu Y1,2, Xu B1, Gao Y1
S-125
1
Key Laboratory of Photochemical Conversion and Optoelectronic
Materials, Technical Institute of Physics and Chemistry, Chinese
Academy of Sciences, Beijing, China; and 2Graduate University
Chinese Academy of Sciences, Beijing, China
Another approach to rapid onset of insulin is to
deliver insulin in the intradermal space. The last article
in this section by Qiu et al. describes the lyophilized
hydrogel patch system, which is developed for microneedle-mediated insulin delivery. It was demonstrated
to be an appropriate drug reservoir for sustained
release of insulin with microneedle-mediated transdermal delivery.
Many of these currently available insulin analogs
(glargine and lispro) are going off patent in the next 1–2
years, and thus many biosimilars are expected to be
available.
Int J Pharm 2012; 437: 51–56
A lyophilized hydrogel patch system was developed for
microneedle-mediated insulin delivery. The matrix of crosslinked poly(acrylamide-co-acrylic acid) was synthesized by
precipitation polymerization. Recombinant human insulin
was loaded into the lyophilized polymer matrix, which can be
rehydrated by water. After the hydrated patch was applied to
the abdominal skin of diabetic rats after microneedle pretreatment, pharmacodynamics and pharmacokinetics evaluation was performed. The blood samples were collected to
monitor blood glucose and serum insulin levels for 12 hours.
Blood glucose was lowered in proportion to the concentration
of insulin loaded in lyophilized hydrogel patches (R(2) = 0.99),
with a longer duration of action compared to subcutaneous
injection. Stability study confirmed that more than 90% of
insulin activity was retained in lyophilized hydrogel after 6
months of storage at 4C. In conclusion, hydrogel patches
were demonstrated to be an appropriate drug reservoir for
sustained release of insulin with microneedle-mediated
transdermal delivery.
Comment
Currently available basal and prandial insulins do not
mimic the physiological release of insulin from a b-cell of
the pancreas. Insulin degludec is an ultra-long-acting
insulin analog. It is also available as a coformulation with
rapid-acting insulin aspart (degludec plus). Insulin degludec has a longer duration of action of > 42 hours with
a longer t½, and less within-patient day-to-day variability
in glucose-lowering effect than insulin glargine. Advantages of insulin degludec are at lower risk of nocturnal hypoglycemia and more flexibility in injection time.
However, it is not approved by the FDA because of cardiovascular concerns. The peripheral subcutaneous administration of currently available insulin analogs does
not mimic the twofold higher portal-versus-systemic
circulating insulin levels seen with endogenously secreted insulin. The newer insulin Ly2605541 is developed
to mimic physiology, that is, more hepatic insulin delivery. In a 12-week phase 2 trial in subjects with type 2
diabetes randomized to LY2605541 or glargine once a
day. At 12 weeks, reduction in FPG and HbA1c was
similar in both groups; however, the blood glucose variability was less and there was a 48% reduction in nocturnal hypoglycemia with LY2605541 group compared
with glargine with modest weight loss because of liverspecific effects (hepatic glucose studies are pending).
The currently available rapid-acting insulin analogs
are not that rapid, and these need to be given 15–30
minutes before meals, which are not optimal in real life.
The only inhaled insulin being investigated in phase 3
clinical trials is Technosphere insulin (TI), which is ultrarapid-acting human insulin that is quickly absorbed from
the lung alveoli.
GLUCOKINASE ACTIVATORS
Discovery of a novel phenylethyl benzamide
glucokinase activator for the treatment of type 2
diabetes mellitus
Park K, Lee BM, Kim YH, Han T, Yi W, Lee DH, Choi HH,
Chong W, Lee CH
Yuhan Research Institute, Yongin-si, Gyeonggi-do, Republic of
Korea
Bioorg Med Chem Lett 2013; 23: 537–42
Novel benzamide derivatives were synthesized and tested
at in vitro assay by measuring fold increase of glucokinase
activity at 5.0 mM glucose concentration. Among the prepared compounds, a benzamide glucokinase activator (YHGKA) was found to be an active glucokinase activator with
EC(50) of 70 nM. YH-GKA showed similar glucose AUC reduction of 29.6% (50 mg/kg) in an oral glucose tolerance test
(OGTT) study with C57BL/J6 mice compared to 29.9% for
metformin (300 mg/kg). Acute treatment of the compound in
C57BL/J6 and ob/ob mice elicited basal-glucose-lowering
activity. In subchronic study with ob/ob mice, YH-GKA
showed significant decrease in blood glucose levels and no
adverse effects on serum lipids or body weight. In addition,
YH-GKA exhibited high bioavailability and moderate elimination in preclinical species.
Small molecular glucokinase activators: has another
new anti-diabetic therapeutic lost favour?
Rees MG1,2, Gloyn AL1
1
Oxford Centre for Diabetes Endocrinology & Metabolism, University of Oxford, Oxford, United Kingdom; and 2National Human
Genome Research Institute, National Institutes of Health, Bethesda, MD
Br J Pharmacol 2013; 168: 335–38
Glucokinase activators (GKAs) represent one of the
leading hopes for the next generation of type 2 diabetes
(T2D) therapeutics, showing efficacy in reducing blood
glucose and HbA1c levels in animal models of T2D and
short-term human trials. While the hypoglycemic risks of
glucokinase activation in pancreatic beta cells have long
been appreciated, the hepatic effects of GKAs have generally
been perceived to be without significant side effect. In this
S-126
issue of the British Journal of Pharmacology, (Br. J Pharmacol
2013; 168: 339–53), De Ceuninck et al. report that acute and
chronic GKA treatment of normoglycemic and hyperglycemic rodent models results in significant accumulation of
triglycerides in the liver. This suggests that GKA-mediated
activation of hepatic glucose uptake and suppression of
endogenous glucose production may come at a significant
cost; namely, the development of hepatic steatosis. This
raises important questions regarding the safety of GKAs,
and emphasizes that both plasma and hepatic lipid profiles
should be carefully monitored in ongoing and future studies
of these molecules.
Comment
The enzyme glucokinase (GK) is a rate-limiting enzyme
for hepatic glucose clearance and glycogen synthesis,
both processes that are impaired in type 2 diabetes.
Therefore, it was identified as a possible target for diabetes management. The first article describes the discovery of a molecule ‘‘phenylethyl benzamide,’’ which
is a glucokinase activator, while the second article discusses the clinical effects and potential concerns with
the use of these molecules. These molecules are in early
phase of development, and we are not sure if they will
make it to the market in the near future because of safety
concerns.
GARG AND SHAH
38431055 (100 and 500 mg) or sitagliptin (100 mg) as a
single dose or JNJ-38431055 (500 mg) once daily for 14
consecutive days was tested. Effects on stimulated plasma
glucose, insulin, C-peptide, and incretin concentrations
were prespecified outcomes.
Results
JNJ-38431055 was well tolerated and not associated
with hypoglycemia. Plasma systemic exposure of JNJ38431055 increased as the dose increased, was approximately twofold greater after multiple-dose administration,
and attained steady state after approximately 8 days.
Compared with the placebo, single-dose administration of
oral JNJ-38431055 decreased glucose excursion during an
oral glucose tolerance test, but multiple-dose administration did not alter 24-hour weighted mean glucose. Multiple dosing of JNJ-38431055 increased postmeal total
glucagon-like peptide 1 and gastric insulinotropic peptide
concentrations compared to baseline.
Conclusions
These studies provide evidence of limited glucose lowering and incretin activity for JNJ-38431055 in subjects with
T2DM.
Comment
JNJ-38431055 is a novel GPR119 receptor agonist.
This molecule has been tried in patients with type 2
diabetes in this dose-finding study. It was found that
JNJ-38431055 was well tolerated and not associated
with hypoglycemia. However, phase 2 and phase 3
clinical trials are needed before any conclusions can
be made.
OTHER NEWER AGENTS FOR THE MANAGEMENT
OF DIABETES
Effects of JNJ-38431055, a novel GPR119 receptor
agonist, in randomized, double-blind, placebocontrolled studies in subjects with type 2 diabetes
Katz LB1, Gambale JJ1, Rothenberg PL1, Vanapalli SR 2, Vaccaro
N 2, Xi L 3, Sarich TC1, Stein PP1
Departments of 1Clinical Development and 2Clinical Pharmacology, Johnson & Johnson Pharmaceutical R&D, Raritan, NJ; and
3
Department of Biostatistics, Johnson & Johnson Pharmaceutical
R&D, Spring House, PA
Diabetes Obes Metab 2012; 14: 709–16
Targeting VEGF-B as a novel treatment for insulin
resistance and type 2 diabetes
Hagberg CE1,2, Mehlem A1, Falkevall A1,2, Muhl L1,2, Fam BC 3,
Ortsäter H 4, Scotney P 5, Nyqvist D1, Samén E 6,7, Lu L 6,
Stone-Elander S 6,7, Proietto J 3, Andrikopoulos S 3, Sjöholm A 4,
Nash A 5, Eriksson U1
1
Aim
G-protein-coupled receptor agonists are currently under
investigation for their potential utility in patients with type
2 diabetes mellitus (T2DM). The objective was to determine the pharmacokinetics, pharmacodynamics, safety, and
tolerability of GPR119 agonist, JNJ-38431055, in T2DM subjects.
Methods
This was a randomized, double-blind, placebo- and
positive-controlled, single-dose, crossover study and a
randomized, double-blind, placebo-controlled, multipledose, parallel design study. The study was conducted at
four U.S. research centers. Two different experiments involving 25 and 32 different subjects were performed in
male and female subjects, aged 25–60 years, mean body–
mass index between 22 and 39.9 kg/m2, who had T2DM
diagnosed 6 months to 10 years before screening. JNJ-
Tissue Biology Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; 2Ludwig Institute for Cancer
Research Ltd, Stockholm Branch, Karolinska Institute, Stockholm, Sweden; 3Department of Medicine (AH), University of
Melbourne, Heidelberg, Victoria, Australia; 4Diabetes Research
Unit, Department of Clinical Science and Education, Södersjukhuset, Karolinska Institute, Stockholm, Sweden; 5CSL
Limited, Parkville, Victoria, Australia; 6Karolinska University
Hospital, Neuroradiology Department and Karolinska Experimental Research and Imaging Center, Solna, Stockholm,
Sweden; and 7Clinical Neurosciences, Karolinska Institute,
Stockholm, Sweden
Nature 2012; 490: 426–30
The prevalence of type 2 diabetes is rapidly increasing,
with severe socioeconomic impacts. Excess lipid deposition
in peripheral tissues impairs insulin sensitivity and glucose
uptake, and has been proposed to contribute to the pathology
of type 2 diabetes. However, few treatment options exist that
directly target ectopic lipid accumulation. Recently, it was
found that vascular endothelial growth factor B (VEGF-B)
controls endothelial uptake and transport of fatty acids in
heart and skeletal muscle. Here we show that decreased
VEGF-B signaling in rodent models of type 2 diabetes restores
insulin sensitivity and improves glucose tolerance. Genetic
deletion of Vegfb in diabetic db/db mice prevented ectopic
lipid deposition, increased muscle glucose uptake, and
maintained normoglycemia. Pharmacological inhibition of
VEGF-B signaling by antibody administration to db/db mice
enhanced glucose tolerance, preserved pancreatic islet architecture, improved b-cell function, and ameliorated dyslipidemia, key elements of type 2 diabetes and the metabolic
syndrome. The potential use of VEGF-B neutralization in type
2 diabetes was further elucidated in rats fed a high-fat diet, in
which it normalized insulin sensitivity and increased glucose
uptake in skeletal muscle and heart. Our results demonstrate
that the vascular endothelium can function as an efficient
barrier to excess muscle lipid uptake even under conditions of
severe obesity and type 2 diabetes, and that this barrier can be
maintained by inhibition of VEGF-B signaling. We propose
VEGF-B antagonism as a novel pharmacological approach for
type 2 diabetes, targeting the lipid transport properties of the
endothelium to improve muscle insulin sensitivity and glucose disposal.
S-127
Comment
Type 2 diabetes is a combined defect of inadequate insulin
secretion from beta cells of the pancreas for the degree of
hyperglycemia and insulin resistance, which is the principal defect. This article describes the role of VEGF-B in
controlling the endothelial uptake and transport of fatty
acids in heart and skeletal muscle. Therefore, targeting this
receptor, we can expect reduction of insulin resistance by
these tissues. However, there is no clinical trial involving
human subjects, but the animal data are promising.
Conclusions
Many newer pharmaceutical agents may become available
in the near future to allow providers to individualize treatment
for patients with diabetes. Long-term safety of these agents,
especially related to cardiovascular outcomes and cancers, will
need to be evaluated over time. These agents will allow us to
better manage diabetes, reduce hypoglycemia, and be weight
neutral, thus reducing long-term complications of diabetes. At
the same time, several insulin analogs are going to be off-patent
in 2014 and 2015. Biosimilars will be available with a hope to
reduce the overall cost to the healthcare system.
ABSTRACTS
DOI: 10.1089/dia.2014.1515
ATTD 2014 ABSTRACTS
ATTD 2014 Oral Presentations
COMMODITY12 – project aiming at developing a system
O-1
providing COntinuous Multi-parametric and Multi-layered
analysis Of DIabetes TYpe 1 & 2
EMPOWER – project aiming at supporting the self-management of diabetes patients through a modular and standards-based Patient Empowerment Framework
GoCarb – project aiming at designing a computational
system which will support individuals with type 1 diabetes
in automatically estimating the grams of carbohydrate in a
meal in near real-time
7TH FRAMEWORK PROGRAM – FUNDED EHEALTH
SYSTEMS FOR DIABETES
P. Kardas1, P. Beck2, S. Bromuri3, F. Chiarugi4, M. Enzmann5,
B. Höll2, O. Keller6, S. Lane7, J. Mader8, O. Marchesini9,
S. Mougiakakou10, K. Neubauer8, T.R. Pieber2,8, M. Plößnig11,
S.G. Puricel12, L. Schaupp8, S. Spat2
1
Medical University of Lodz, Poland
JOANNEUM RESEARCH Forschungsgesellschaft mbH,
HEALTH – Institute for Biomedicine and Health Sciences,
Graz, Austria
3
Haute Ecole Specialisee de Suisse Occidentale
4
Foundation for Research and Technology - Hellas, Institute
of Computer Science, Computational Medicine Laboratory,
Heraklion, Greece
5
Fraunhofer Institute for Secure Information Technology (SIT),
Darmstadt, Germany
6
Deutsches Forschungszentrum für KünstlicheIintelligenz
GMBH, Saarbrucken, Germany
7
Triteq Ltd, Hungerford, United Kingdom
8
Medical University of Graz, Department of Internal
Medicine, Division of Endocrinology and Metabolism, Graz,
Austria
9
Portavita B.V., Amsterdam, The Netherlands
10
ARTORG Center for Biomedical Engineering Research,
University of Bern, Switzerland
11
Salzburg Research Forschungsgesellschaft, Salzburg,
Austria
12
Centre Hospitalier Universitaire Vaudois, Lausanne,
Switzerland
2
Diabetes is a condition of rising prevalence in Europe, which
treatment is not only costly, but also very laborious. Thus, it
creates major problems to European public health. In the era of
limited resources in healthcare – both in terms of workforce and
budget – there is an urgent need to redesign approaches to diabetes treatment. This might be possible with employment of
novel eHealth technologies to both prevention and treatment of
diabetes.
European Commission, being fully aware of this situation,
decided to facilitate research and technological development in
the field of diabetes. Thus, several RTD projects were funded
under the 7th Framework Program. Of these, five complementary
projects will be presented during this workshop:
AP@home (Artificial Pancreas at home) – project aiming
at developing a functional artificial pancreas
REACTION Project – project aiming at developing an
integrated ICT platform that supports improved long-term
management of diabetes
Due to its large spectrum, the workshop will be a perfect forum
to learn latest European eHealth initiatives for diabetes, and get in
touch with newest eHealth technologies. Both academia and
business are cordially invited to take part in this event.
O-2
DO WE NEED A REMOTE MONITORING SYSTEM
IN THE PRODUCT? REMOTE MONITORING - PRO
T. Danne1
1
Kinder - und Jugendkrankenhaus, Auf der Bult,
Hannover, Germany
During the initial outpatient pilot-trials of the DREAM project
the sessions are performed under the supervision of a diabetes
research team consisting of an onsite physician specialized in
diabetes treatment and technical supporter engineer. The patients
glucose levels (glucose sensor and SMBG), and technical alarms
were transferred from patient’s home via the internet and the
Remote safety and control diabetes management system
(MDRS) to the command and control center within the clinic and
externally to the other team members at other remote sites. Optionally, the study team can provide the patient’s caregivers with
a PC which will be connected to the MDRS system and will show
only the information and alarms relating to that specific patient.
This allows the patient’s caregiver to view glucose levels and
insulin delivery from the own bedside. If required, support will
be provided over the phone by the study team. The MDRS system
is composed from two modules, the Remote diabetes monitoring
(RDM) module and the Safety Module for patient alerts. This
software is based on the ZONTM Control Software Package of
Galooli Ltd. It is designed to transfer all the data from the patient
to a remote control & command center which is capable of
controlling tens of patients simultaneously.
Thus, the remote monitoring enables the supervising personnel
to alert the patient and intervene in cases of impending hypoglycemia, long standing hyperglycemia and technical faults of any
component of the AP system and provides an added benefit of the
whole closed loop system.
A-1
A-2
ATTD 2014 ORAL PRESENTATIONS
O-3
Results: Overnight hypoglycemia with at least one CGM
value £ 60 mg/dl occurred in 196 of 942 (21%) intervention
nights versus 322 of 970 (33%) control nights (odds ratio 0.52,
95% confidence interval 0.43 to 0.64, P < 0.001). Median hypoglycemia area under the curve was reduced by 81% and hypoglycemia lasting > 2 hours was reduced by 78%. Median
morning blood glucose was 129 mg/dl after control nights and
144 mg/dl after intervention nights (P < 0.001). In each arm, 6%
of nights had morning blood glucose > 250 mg/dl and morning
ketosis was present < 1% of the time.
Conclusion: Use of a nocturnal PLGS system can substantially reduce overnight hypoglycemia, with only a slight increase
in morning hyperglycemia and no increase in ketosis.
KEYNOTE SPEAKER: GLUCOSE
MONITORING - AND BEYOND?
R. Weitgasser1,2
1
Dept of Internal Medicine, Diakonissen Hospital Salzburg,
Salzburg, Austria
2
1st Dept of Internal Medicine, Paracelsus Medical University,
Salzburg, Austria
Back in the 1980s when first programmes for patient education
were established and validated monitoring glucose control became recognized as being a valuable part of diabetes care.
Technical improvement in BG monitoring like the development
of more accurate, small und fast acting devices led to a broad use
of SMBG. Besides technical improvement SMBG was focused to
structured measurements providing information on daily glucose
variability. This challenge got support by the development of
CGMS. New systems became a treatment complement predominantly used in patients on intensive insulin treatment regimens.
Glucose sensor augmented insulin pump treatment meanwhile
approaches the long aimed-for closed-loop system. Additional
steps like the low glucose suspend to prevent hypoglycaemic
reactions as well as the development of self-learning algorithms
will probably further enhance glycaemic control. Beyond these
technical device oriented steps into the future measures to improve patient empowerment and compliance need to be enforced.
According to ongoing research the near future will probably
provide each diabetic patient with some kind of a CGMS replacing currently used conventional structured SMBG. The use of
smart phones or related e-health technology providing easy and
time-sparing measures for physical activity (e.g. kind of, duration, intensity), nutrition (e.g. carbohydrate content/counting,
fat content) and stress (illness, accident, psychological stress)
combined with SMBG/CGM as well as information on blood
pressure, lipids, body weight, smoking habits, etc. could help to
improve treatment quality when embedded into a continuous
feedback loop between patients and caring medical personal.
O-4
A RANDOMIZED TRIAL OF A HOME SYSTEM
TO REDUCE NOCTURNAL HYPOGLYCEMIA
IN TYPE 1 DIABETES
H.P. Chase1
1
Pediatrics, University of Colorado Anschutz Medical Campus,
Aurora, USA
H. Peter Chase, MD, for the In-Home Closed Loop Study Group
University of Colorado Anschutz Medical Campus
Background: Overnight hypoglycemia is common in individuals with type 1 diabetes (T1D) and has many ramifications,
including being a major barrier for optimal glycemic control. It is
likely the predicted low-glucose suspend (PLGS) feature will be
the second component of the artificial pancreas (AP).
Methods: Following in-hospital safety studies, we have participated in an in-home randomized trial to determine whether
nocturnal hypoglycemia could be safely reduced by temporarily
suspending insulin pump delivery when hypoglycemia was
predicted by an algorithm based on continuous glucose monitor
(CGM) glucose levels. Following an initial run-in phase, 45 individuals with T1D (age 15–45 years) participated in a 42-night
trial (total 1,912 nights) of randomized PLGS vs. control nights.
O-5
PREDICTIVE LOW GLUCOSE MANAGEMENT
WITH SENSOR AUGMENTED CSII IN RESPONSE
TO EXERCISE
T. Danne1
1
Diabetes Centre for Children and Adolescents, Kinder- und
Jugendkrankenhaus AUF DER BULT, Hannover, Germany
Background: Predictive Low Glucose Management (PLGM)
may help prevent hypoglycemia by stopping insulin pump delivery based on predicted sensor glucose (SG) values.
Methods: Hypoglycemic challenges were simulated using the
FDA-accepted glucose simulator with 100 virtual patients.
PLGM was then tested with a system composed of a Paradigm
insulin pump, an Enlite glucose sensor, and a Blackberry-based
controller. Subjects (n = 22) on CSII [5f, 17m; age 15 (14–20)
years, diabetes duration 7 (2–14) years; HbA1c 8.0 (6.7–10.4)%,
(median(range)) exercised until the PLGM system suspended
insulin delivery or until the reference blood glucose value (HemoCue) reached the predictive suspension threshold setting.
Results: PLGM reduced hypoglycemia ( < 70 mg/dL) in silico
by 26.7% compared to no insulin suspension, as opposed to a
5.3% reduction in hypoglycemia with use of LGS. The median
duration of hypoglycemia (time spent < 70 mg/dL) with PLGM
was significantly less than with LGS (58 min vs 101 min, respectively, p < 0.001). In the clinical trial the hypoglycemic
threshold during exercise was reached in 73% of the patients and
hypoglycemia was prevented in 80% of the successful experiments. The mean ( – SD) sensor glucose at predictive suspension
was 92 – 7 mg/dL resulting in a post suspension nadir (HemoCue) of 77 – 22 mg/dL. The suspension lasted for 90 – 35
(range: 30 to 120) min resulting in a sensor glucose at insulin
resumption of 97 – 19 mg/dL.
Conclusions: In silico modeling and early feasibility data
demonstrate that PLGM may further reduce the severity of hypoglycemia beyond that already established for algorithms that
use a threshold-based suspension.
O-6
SAFE CONTROL ALGORITHMS TO PERSONALIZE
THE OUTPATIENT ARTIFICIAL PANCREAS
F. Doyle1
1
Chemical Engineering, UC Santa Barbara, Santa Barbara, USA
Model-based control algorithms for the artificial pancreas
have been demonstrated in numerous clinical trials as effective
A-3
methods to manage overnight periods, postprandial excursions,
and even some forms of physical exertion (mild to moderate
exercise). However, the requirements for patient safety are
somewhat reduced in the in-clinic setting where medical professionals (and often engineers) are hovering over the patient for
the duration of the trial.
As we move to the outpatient testing for the artificial pancreas,
patient safety is a paramount concern. Our experience points
strongly to personalization as a key component of an algorithm
for effective and safe feedback control. The overall approach
in our studies includes three main elements: MPC with timevarying zones, a Health Monitoring System (HMS) overlay, and
customization in the form of subject specific attributes (e.g.,
insulin sensitivity). Our zone MPC has been extended to deal
with (personalized) varying safety concerns over diurnal cycles,
and allows the design of safe strategies for the overnight window.
Our Health Monitoring System (HMS) incorporates hypoglycemic alarming as well as meal detection, signaling to the subject
for possible interventions (snack ingestion, missed bolus, etc.).
Finally, we have explored a number of approaches for personalization, from the model parameters used in MPC to adaptation
that takes place over hours or days to ‘‘learn’’ patient attributes.
All of these elements enhance the safety of a closed-loop artificial pancreas. Clinical data from pilot outpatient studies will be
discussed along with algorithmic details.
Diabetic foot (DF) is recognized as one of the most serious
complications of diabetic disease. About 5% off all patients with
diabetes type II will develop an arterial diabetic foot problem. Up to
70% of all lower-leg amputations are performed in patients with
diabetes and up to 85% of all amputations are preceded by an ulcer.
Ulcer prevention is therefore recognized to be the best way to prevent amputation. However when an ulcer is present, the primary
need is to achieve fast ulcer healing. If there is also concomitant
infection the ulcer healing is often more difficult. Optimal wound
care, antibiotics, off loading and other techniques should all be
applied in daily practise to achieve ulcer healing. Active revascularisation plays a crucial role in achieving ulcer healing. Nonsurgical revascularisation options for DF have expanded over the
last decade and have become a prominent tool to prevent amputation
The radiologist plays in important role in the management of the
diabetic foot. Both imaging and treatment are closely related. The
definition and diagnosis of diabetic foot syndrome is not the same
as CLI, and new diagnostic parameters can play an important role.
Traditional imaging with duplex, CTA or MRA will guide the
endovascular treatment options. Both open and endo treatment
have the same outcome regarding limb salvage. Decision on all
available treatment options is best done in a Multidisciplinary team.
O-9
CURRENT STRATEGIES FOR THE TREATMENT
OF THE SEVERELY INSULIN RESISTANT PATIENT
O-7
21ST CENTURY TECHNOLOGY AND ITS USE
IN DIABETIC FOOT CARE
1
1
D.G. Armstrong , N. Giovinco , B. Najafi
I. Hirsch1
1
School of Medicine, University of Washington, Seattle, USA
1
1
Surgery / Southern Arizona Limb Salvage Alliance (SALSA),
University of Arizona College of Medicine, Tucson, USA
As Auguste Comte said two centuries ago, ‘‘Demography is
destiny’’. Even he, however, couldn’t foresee the massive
changes occurring at breakneck speed in our world.
Over the past generation, significant advances in care have led
to incremental improvements in healing worldwide. However, it
may be argued that the most potent advances in healing have
been in organization of care. Technologies are now emerging
that may allow further enhancements of organization and integration of care while also bringing in much needed bedside,
chairside, and in-home diagnostics to identify key points in
healing and potential early warning signs for recurrence. This
symposium reviews what are believed to be several key areas of
change over the next generation all yielding specific advances in
wound diagnostics. The authors believe that devices will be organized into personal health servers in cloud-synchronized devices already existing in the home (eg, a scale), the clinic, and on
(or in) the patient. This talk will explore the intersection of
consumer technology with medical devices and their collision–
or perhaps synergy – with our aging species.
Historically, the most severely insulin resistant patients had
high levels of insulin antibodies from animal insulins. This resulted in the development of U-500 regular insulin in the early
1950s. Over time, this was also used for the more insulin resistant
patients with type 2 diabetes. More recently, the use of U500
insulin has become extremely common due to the explosion of the
severely insulin resistant patient. Many don’t appreciate that our
currently available U100 insulin glargine has minimal effect with
doses greater than 1 u/kg. As a way to improve absorption, we are
learning that splitting the large depot into more than one site can
improve glycemia, but robust trials examining this strategy are
lacking. Since the main rationale for using insulin analogues is to
reduce hypoglycemia risk, it is reasonable and perhaps preferable
to use NPH as the basal insulin for these patients. As for mealtime
insulins, there are few studies comparing human insulin to a rapidacting analogue for these patients, but the fast-acting insulins will
have a prolonged activity with higher doses. The other strategy
that often helps is adding a GLP-1 agonist to these patients. Small
trials have shown improvements in glycemia and weight.
For patients who still require high-doses of insulin, we currently utilize U-500 regular insulin that has a longer duration of
action than U-100 regular insulin, and thus we use it both as a
basal and a prandial insulin. Indeed, many use it in an insulin
pump with good success.
O-8
THE ROLE OF THE INTERVENTIONAL
RADIOLOGIST IN DIABETIC FOOT MANAGEMENT
J. Reekers
1
1
Interventional Radiology, AMC, Amsterdam, Netherlands
The role of the radiologist in diabetic foot management.
O-10
PATIENT NARRATIVES ON THEIR EXPERIENCES
OF CGM
J. Pickup1
1
Guy’s Hospital, King’s College London School of Medicine,
London, United Kingdom
A-4
Relatively little is known about the patient experience of realtime continuous glucose monitoring (CGM) in type 1 diabetes
when used in everyday practice and when described in patients’
own words. We therefore conducted an online survey of patient
narratives about continuous CGM, with analysis of the first 100
responses by qualitative framework analysis. There were 50
adults and 50 children, median CGM use 1.9 years, with 87%
using it in conjunction with CSII. We identified 6 themes, with
various subthemes: metabolic control, life on CGM, GGM procedures, technical issues, financial issues and attitudes to CGM.
Most patients had an overwhelmingly positive experience with
reduced HbA1c and hypoglycaemia and improved quality of life.
Patients tended to recognize and accept limitations such as sensor
inaccuracies. Some healthcare professionals were reported to
have a very negative attitude to the technology. Many patients
said that CGM was life-changing.
O-11
PROMOTING DIABETES SELF CARE:
WHAT WORKS AND WHAT DOESN’T
J.J. Seley1
1
Division of Endocrinology, New York Presbyterian Hospital/
Weill Cornell Medical Center, New York, USA
Living with diabetes can be very challenging. We ask patients
to perform multiple tasks day after day including monitoring blood
glucose at frequent intervals, planning meals, calculating insulin
doses based on current blood glucose and carbohydrate intake and
balancing meals and medication with physical activity to achieve
and maintain glycemic targets. It is no wonder that many patients
have difficulty doing all that they are asked to do on a daily basis.
Research has shown that knowledge is not enough to promote
diabetes self-care and behavior change. A number of behavioral
change theories offer the clinician guidance in preparing, motivating and supporting patients in diabetes self-care. These include patient empowerment, health belief model, transtheoretical
model and motivational interviewing. The patient empowerment
model puts the patient in control of their self-care and promotes
informed decision-making. In the health belief model, benefits
and barriers to performing self-care behaviors are identified and
potential strategies to reduce barriers are generated. The transtheoretical model views behavior change as an ongoing process
of stages ranging from precontemplation where the patient is
unaware of a problem to maintenance where the patient has the
ability to perform self-care over time. Motivational interviewing
is an approach where the clinician uses active listening and encourages and supports self-efficacy. With the availability of more
and more technological tools to manage diabetes, it is more
important than ever to provide comprehensive education and
support to our patients in order for them to succeed in controlling
their diabetes without compromising quality of life.
O-12
HOW TO SAFELY AND EFFECTIVELY TRAIN
PATIENTS TO USE INSULIN PUMPS AND STAY
ON THE DEVICE
H. Rogers1
1
Diabetes, King’s College Hospital NHS Foundation Trust,
How to Assist Patients to use an Insulin Pump Safely and
Effectively and to Stay on the Device
People with diabetes wish to be able to self-manage their
diabetes in order to achieve biomedical outcomes within target
and they also desire to have the burden of self-management
reduced to the extent that their quality of life is improved. Insulin
Pump therapy can assist, but this is not always the case. A certain
approach needs to be in place in order to ensure that Insulin Pump
therapy is not just another treatment given to patients with an
expectation that they will both master it and achieve improved
outcomes. Education is the key to ensuring improvements in
biomedical outcomes, in self-management and in burden reduction. And not just any education programme - structured
education that is underpinned by facets that lead to mastery and
maintenance is required. Health Care Professionals (HCPs) are
accustomed to providing education that includes knowledge and
self-management skills, however HCPs are beginning to recognise that these alone are not enough. If the twin goals of selfmanagement and reduced burden are to be achieved then the
structured education also needs to incorporate ways to improve
confidence, participation in goal setting and decision making,
coping skills, and self-efficacy.
Insulin pump pathway
Choice of pump
Trial using saline
Education - bite-sized chunks
Availability of HCPs and Pump Expertise
We will examine the attributes above to establish how the
knowledge and skills needed for Insulin Pump therapy can be
best presented by HCPs.
O-13
HOW TO SAFELY AND EFFECTIVELY TRAIN
PATIENTS TO USE CGM AND STAY ON THE DEVICE
A. Gianini1
1
Department of Endocrinology Diabetes and Metabolic
Diseases, Children’s Hospital, Ljubljana, Slovenia
Education and the use of continous glucose monitoring
Ana Gianini
Modern technology entered diabetes treatment with continuous subcutaneous insulin infusion (CSII) and was frequently
leading to improved matabolic control. In the last 10 years next to
CSII, systems for continuous glucose monitoring (CGM) gave
new information about glucose excursions in different situations.
According to different databases such as Type 1 Diabetes Exchange more than 10% of adults are using CGM routinely, next
to them 3% in pediatric cohorts.
In Slovenia children and adolescents use CSII in more than
80% (530 from 660). The use of sensors was reimbursed for
children in February 2010 and since then the number of young
patients that continuously use CGM is increasing steadily,
reaching 10% of pump users in 2013.
Structured education for patients, families and often professional caregivers about the sensor use is of extreme importance at
the CGM introduction. In the first month patients can be confused
by the number of informations and alarms from CGMS leading
frequently to disappointment and discontinuation of CGM use.
Topics discussed at CGM introduction are
Proper insertion of the sensor
Importance of good calibration
Alarms, troubleshooting
ISIG signal
Practical use of CGM (profiles, correction boluses, food
boluses, sport activity, sick days, school or kindergarten
regimen . )
Sometimes parents are advised to shut down the alarms for the
first sensor or even for the first month of sensor use. In this case
they simply follow CGM curve and values on the screen.
24/7 telephone support can help to support the patient.
O-14
THE SWEET-PROJECT - USE OF TECHNOLOGY
FOR LONGITUDINAL BENCHMARKING
OF INTERNATIONAL PEDIATRIC DIABETES
CENTRES 2006 TO 2013: DATA ANALYSIS
FROM 122.853 VISITS FROM 10.767 PATIENTS
M. Witsch1, Z. Sumnı́k2, H. Veeze3, C. de Beaufort1,
J.J. Robert5, G. Forsander6, A. Szypowska7, J. Allgrove8,
S. Waldron9, M. Rosu10, A. Gerasimidou-Vazeou11, K. Lange12,
O. Kordonouri4, C. Maffeis13, J.F. Raposo14, E. Pankowska15,
L. Madacsy16, K. Klee4, B. Aschemeier4, T. Danne4,
for the SWEET Group
1
DCCP- Clinique pédiatrique de Luxembourg, Luxembourg,
Luxembourg
2
University Hospital Motol, Department of Paediatrics, Prague,
Czech Republic
3
Stichting Diabetes, Rotterdam, Netherlands
4
Kinderkrankenhaus auf der Bult, Hannover, Germany
5
Hopital des Enfants-Malades, Department Diabete de l’enfant,
Paris, France
6
Sahlgrenska University Hospital, Gothenburg, Sweden
7
The Medical University of Warsaw, Department of Pediatric
Diabetology, Neonatology and Birth Defects, Warsaw, Poland
8
Royal London Hospital, Whitechapel, Barts and the London
NHS Trust, London, United Kingdom
9
Dorset County Hospital, Dietetic Department, Dorset,
United Kingdom
10
Clinical Medical Center ‘‘Cristian Serban’’ for the
Evaluation and Rehabilitation of Children and Adolescents
Buzias, Buzias, Romania
11
Panagioti and Aglalia Kyriakou Children’s Hospital,
Department of Pediatrics and Diabetes Center, Athens, Greece
12
Hannover Medical School Medical School, Department of
Medical Psychology, Hannover, Germany
13
University of Verona, Pediatric Diabetes Unit, Verona, Italy
14
Associação Protectora dos Diabéticos de Portugal, Lisboa,
Portugal
15
Instytut Matki I Dziecka, Warsaw, Poland
16
Semmelweis University, Budapest, Hungary
Objectives: ‘‘SWEET’’ is an acronym derived from ‘‘Better
control in Pediatric and Adolescent diabeteS: Working to crEate
cEnTers of Reference’’ and is based on a partnership of established national and European diabetes organizations (www
.sweet-project.eu) led by ISPAD. Data in participating centres
were directly extracted from 2006 ongoing from local electronic
health records.
Methods: The SWEET Online platform allows presently
nineteen centres from fifteen countries to connect to one unified
anonymized diabetes database. Aggregate data are de-identified
and exported for longitudinal health and economic data analysis.
Results: The number of patients and patient visits increased
from 2006 (n = 921) to 2012 (n = 7633), currently including
A-5
10,767 patients and 122,853 patient-visits overall. For example,
patients with a valid HbA1c in the database rose from 744 (mean H
bA1c: 8,1%) in 2006, to 1161 (8,1%) in 2007, 1412 (8,2%) in 2008,
1972 (8,2%) in 2009, 3320 (8,0%) in 2010, 5952 (7,9%) in 2011 and
6372 (7,9%) in 2012. The percent of patients within the target
HbA1c range < 7.5% increased steadily: 33% (2010), 35% (2011),
40% (2012). Over time the completeness of data increased from
82% to 98% (HbA1c), 78% to 83% (height), 78% to 84% (weight),
50% to 60% (blood pressure), 12% to 22% (microalbuminuria
screening) and 30% to 45% (hyperlipidemia screening).
Conclusions: Ongoing collection of benchmarking data motivates centres to improve data collection and reflects improving
glycemic control in most participating European pediatric diabetes centres. While the degree of completeness is close to 90%
or above for HbA1c, weight and height, the assessment of diabetes-associated co-morbidities leaves much room for improvement. Thus, information technology allows transparent
analysis of real life diabetes treatment data as a basis for local
center improvement, scientific studies and health economic
analyses.
O-15
INTERNATIONAL ASSESSMENT OF DIABETES
MANAGEMENT, GLYCEMIC CONTROL
AND DIABETES-RELATED BURDEN IN YOUTH
WITH TYPE 1 DIABETES (T1D): THE TEENS STUDY
L. Laffel1, V. Peterkova2, C. Domenger3, M.P. Dain3,
V. Pilorget4, C. Candelas4, T. Danne5, M. Phillip6,
C. Mazza7, B. Anderson8, R. Hanas9
1
Pediatric Adolescent and Young Adult Section, Joslin Diabetes
Center, Boston, USA
2
Pediatric Endocrinology, Endocrinology Research Center,
Moscow, Russia
3
Global Diabetes Division, Sanofi, Paris, France
4
Clinical Sciences and Operations, Sanofi, Chilly Mazarin,
France
5
Diabetes Centre for Children and Adolescents, Kinder und
Jugendkrankenhaus ‘‘Auf der Bult’’, Hannover, Germany
6
National Center for Childhood Diabetes, Institute for
Endocrinology and Diabetes at Schneider Children’s Medical
Center of Israel, Petah Tikva, Israel
7
Nutrition Department, Hospital de Pediatrı́a J P Garrahan,
Buenos Aires, Argentina
8
Department of Pediatrics Section of Psychology, Baylor
College of Medicine, Houston, USA
9
Department of Pediatrics NU Hospital Group, Uddevalla and
Sahlgrenska Academy at Gothenburg University, Gothenburg,
Sweden
Background: TEENS, a cross-sectional study in 21 countries, collected data on management, HbA1c, acute complications, and burden from *6200 youth with T1D of ‡ 1 year and
onset < 18 y/o. Results from 1000 participants from 2 countries
completing the study provide direction for future post-hoc
analyses.
Objectives: To examine treatments and HbA1c in T1D youth
from USA/Russia in three predefined age groups and relate
HbA1c to acute complications and diabetes burden.
Methods: 25 US/20 Russian centers uniformly collected data
by interview, record review and survey. A recruitment ratio of
25%/50%/25% was implemented in 3 age groups (8–12/13–18/
19–25 y/o). Participants were sampled sequentially to avoid bias.
A-6
HbA1c was measured uniformly; targets: < 7.5% (58 mmol/mol)
< 18 y/o (ISPAD); < 7% (53 mmol/mol) ‡ 18 y/o (ADA). Burden
was assessed with the PAID (20-item) for patients ( ‡ 13 y/o) and
PAID-PR (18-item) for parents of youth ( £ 18 y/o). Acute
complications were assessed (% with DKA, severe hypoglycemia [seizure/coma]).
Results: Median T1D duration was similar: 7.0 years (0.6–
22.1) in US; 6.3 years (0.8–23.5) in Russia. Both syringes/pens
were used by 36%/80% of US/Russian patients; pumps were
used by 63%/19%, respectively. In both countries, only a small
minority of participants achieved HbA1c targets (24%/16% in
USA/Russia). Parents from both countries perceived greater diabetes burden than patients across all ages. Outcomes (DKA/
hypoglycemia) are shown by age group (table).
Conclusion: Diabetes burden appears to be universal; patients
experience suboptimal HbA1c and acute complications. In both
countries, despite differences in management, there are opportunities to implement management programs to improve HbA1c
and outcomes.
Study sponsored by Sanofi.
(PERI) or postoperatively (POST) initiated protocols for tight
glucose control (TGC).
Material and methods: 2383 patients undergoing elective
cardiac surgery were randomized into either PERI (1134
subjects) or POST (1151 subjects) group according to the
time of initiation of intravenous insulin infusion therapy.
Glycemic variability was calculated using selected formulas
including SD (standard deviation) and MAGE (mean amplitude of glycemic excursions). Adverse events from any
cause were collected during the postsurgical hospital stay.
Results: In the whole cohort, perioperatively initiated TGC
markedly reduced the number of patients with postoperative
complications (23.8 vs. 31.4%, p < 0.001) in spite of only
modest improvement of glucose control (blood glucose 6.6 – 0.7
vs. 6.7 – 0.7 mmol/l, p < 0.001). The positive effect of TGC on
postoperative complications was driven by non-diabetic patients
(20.3 vs. 31.7%, p < 0.001) while no significant effect was seen
in the diabetic subgroup (33.2 vs. 30.5%, n.s.). No clinically
significant difference in glycemic variability could be seen between any of the study groups (SD 3.33 – 0.73 vs. 3.34 – 0.71,
n.s. for PERI vs. POST group). No correlation between the
number of postoperative complications and various glycemic
variability indices was observed in the study.
Conclusion: Perioperative initiation of intensive insulin
therapy during elective cardiac surgery reduces postoperative
morbidity only in non-diabetic subjects. Glycemic variability
does not seem to play an important role in postoperative outcomes of elective cardiac surgery patients.
Supported by RVO-VFN64165, IGA NT13299-4 and
SVV264503.
O-17
LUDIDIAB TRIAL: IMPACT OF A SERIOUS GAME
ON KNOWLEDGE AND SKILLS OF YOUNG PATIENTS
ABOUT THEIR TYPE 1 DIABETES
M. Joubert1, J. Morera1, C. Armand1, L. Tokayeva1,
A. Guillaume1, Y. Reznik1
1
O-16
GLYCEMIC VARIABILITY DOES NOT PREDICT
POSTOPERATIVE OUTCOMES IN ELECTIVE
CARDIAC SURGERY PATIENTS ON TIGHT
GLUCOSE CONTROL
M. Mraz1, P. Kopecky2, M. Lips2, D. Novak3, J. Lindner4,
S. Svacina1, J. Blaha2, M. Haluzik1
1
3rd Department of Medicine, General University Hospital
and 1st School of Medicine Charles University, Prague,
Czech Republic
2
Department of Anaesthesia Resuscitation and Intensive
Medicine, General University Hospital and 1st School
of Medicine Charles University, Prague, Czech Republic
3
Department of Cybernetics School of Electrical Engineering,
Czech Technical University, Prague, Czech Republic
4
Department of Cardiovascular Surgery, General University
Hospital and 1st School of Medicine Charles University,
Prague, Czech Republic
Objective: The aim of our study was to assess the relationship
between glycemic variability and postoperative complications in
elective cardiac surgery patients with either perioperatively
Endocrinology, CHU, Caen, France
We hypothesized that the use of a serious game designed for
education of young T1D subjects could improve their knowledge
and skills, as an alternative to usual education. In this before-after
pilot study, we used the game ‘‘L’affaire Birman’’, designed on a
problem-solving concept, focusing on diet, flexible insulin
therapy and emergency situations. The game was used in an
unstructured program at home: patients were asked to play at
least one complete game then were evaluated before (T0), a few
days after (T1), and 6 months after (T2) this experiment with
PedCarbQuiz (PCQ) and Diabetes Self Monitoring Profile
(DSMP), two validated questionnaires. 47 patients were included
in 5 French hospitals: age 13.9 – 2.1 years; M/F 22/25; diabetes
duration 5.9 – 3.7 years; treatment: MDI 51.1%, CSII 49.9%;
baseline HbA1c 8.4 – 1.3%; baseline PCQ and DSMP scores
31.9 – 6.7 and 59.1 – 9.9, respectively. 20% patient did not play
any complete game and 47% only one game. PCQ improved at
T1 and T2: 33,8 – 5,0 and 36,1 – 3,9 (p < 0.001), respectively.
A greater PCQ improvement was found in patients with higher
baseline HbA1c. DSMP score was not significantly improved.
HbA1c was not different from baseline at T1 and T2: 8,4 – 1,2
and 8,0 – 0,8% (ns). This slight efficiency highlights weaknesses
of such educational tool: methods of use, game design and/or
methods of assessment must be questioned. This result suggests
A-7
to include such game in a complete and structured education
program supervised by health professionals, with initial objectives and regular debriefing.
O-19
O-18
A. Gomez1, G. Umpierrez2, P. Aschner1, F. Herrera1,
O. Muñoz1, C. Rubio1
ARE WE MISSING SOMETHING? CONTINUOUS
GLUCOSE MONITORING COMPARED
WITH POCT AMONG HOSPITALIZED TYPE 2
DIABETES PATIENTS ON BASAL-BOLUS
INSULIN THERAPY
K. Donsa1, K.M. Neubauer2, J.K. Mader2, B. Höll1,
S. Spat1, B. Tschapeller1, P. Beck1, J. Plank3, T.R. Pieber2,
L. Schaupp2
1
Institute for Biomedicine and Health Sciences, Joanneum
Research GmbH HEALTH, Graz, Austria
2
Department of Internal Medicine Medical University of Graz,
Division of Endocrinology and Metabolism, Graz, Austria
3
Department of Internal Medicine, Krankenhaus der
Elisabethinen GmbH, Graz, Austria
Background: Glycaemic management in the hospital is based
on glucose point-of-care testing (POCT) which lacks continuous
information particularly in detecting hypoglycaemic events. The
aim of this study was to analyse and compare the capability to
detect hypoglycaemic events.
Methods: A total of 59 patients with type 2 diabetes (age:
68.9 – 9.5 yr, DM duration 14.3 – 10.3 yr, A1C: 8.5 – 3%,
BMI: 29.9 – 6 kg $ m - 2, length of stay 8 – 4.5 days (mean –
SD)) were treated with basal-bolus insulin therapy. Glucose
POCT was performed at least 4 times per day (premeal, before
bedtime), CGM was performed with the iPro2 system (MiniMed
Medtronic) which was calibrated with the blood glucose measurements retrospectively.
Results: 8,578 hours were recorded with 1,480 paired blood
glucose-sensor readings. After adjusting the offset of sensor data
35 hypoglycaemic events.
Conclusion: Although the sensitivity of the CGM sensor
signal system was low the data indicate a high number of hypoglycaemic events.
Acknowledgement: The study is supported by the European
Commission, Project REACTION (FP7-248590).
INPATIENT GLYCEMIC CONTROL
BY CONTINUOUS GLUCOSE MONITORING (CGM)
VERSUS CAPILLARY POINT-OF-CARE (POC)
TESTING IN TYPE 2 DIABETICS
1
Endocrinology, Hospital Universitario San Ignacio, Bogotá,
Colombia
2
Endocrinology, Emory University, Atlanta, USA
Background: Capillary glucose finger-stick tests are the accepted method of glucose monitoring in hospitals. No previous
studies compared the efficacy of CGM in the management of
hyperglycemia in general medicine type 2 diabetics. This prospective randomized study compared glycemic control (CGM vs
bedside POC testing) in non-ICU patients treated with insulin for
‡ 3 days. Patients and hospital staff were blinded to CGM data.
POC testing measurements were performed before and 2-h after
meals, at bedtime and 3 AM. Primary outcomes were differences
in daily BG, hypoglycemia (180 mg/dl) events between groups.
Methods: 40 insulin-naı̈ve patients (age: 65.8 – 8 yr, DM
duration 14.7 – 9 yr, admission BG: 251 – 9 mg/dl, A1C:
9.7 – 2.4%, – SD) were treated with glargine and glulisine at a
starting total dose of 0.4 U/kg/day if BG was 140–200 mg/dl and
0.5 U/kg/day if BG was 200–400 mg/dl.
Results: We observed no difference in daily BG after the 1st
day of treatment between groups (176,2 – 33,9 vs 176,6 –
33,7 mg/dl, p:0.828). 10 patients with BG180 mg/dl was 36.8%
by CGM and 42.1% by POC, p = 0.828.
Conclusion: The use of CGM recognized more hypoglycemic
events compared to POC testing. It could be beneficial to use realtime CGM in the hospital to detect hypoglycemia more timely.
O-20
PEDOMETER USE TO EVALUATE PHYSICAL
ACTIVITY, AND MOTIVATE TYPE 2 DIABETIC
PATIENTS, FOR BETTER METABOLIC CONTROL
AND WEIGHT REDUCTION
A. Shehu1, F. Toti2, B. Resulaj3, D. Minxuri2
1
Medical Laboratory, Intermedica, Tirana, Albania
Endocrinology & Metabolic Diseases, University Hospital
Center ‘‘Mother Theresa’’, Tirana, Albania
3
Faculty of Medicine, Medical University, Tirana, Albania
2
Background and aims: Physical activity (PA) is at the cornerstone of diabetes prevention and care. It helps to improve
metabolic control, lipid profile, and to reduce weight. The aim of
our study was to demonstrate the positive effect of a single
session of PA to the glycaemic profile, and to use the technology
for increasing daily physical activity, with a positive impact on
metabolic, weight and lipid profile.
Patients and method: 50 patients with type 2 diabetes, were
recruited for an 8-week training session. Every PA session lasted
30 minutes of brisk walking. The number of daily steps was
measured through a pedometer, and the participants were encouraged to complete at least 10000 steps/day. All the patients
had completed anthropometric measures, fat body composition
and lipid profile at the beginning and the end of the study period.
Results: 30 (60%) of the patients completed the 8-week
training session, 17 (56.6%) males. Mean age 52.07 – 11.3 yrs,
A-8
mean diabetes duration 4.37 – 2.9 yrs. Mean HbA1c decreased
from 8.43 – 1.09% to 8.17 – 1.07% (p = 0.07), mean weight
81.74 – 20.8 kg vs 79.47 – 20.11 kg (p < 0.05), mean of daily
steps 4535 – 2590 vs 11315 – 2013.6 (p < 0.01). Body fat
composition decreased from 33.04 – 11.8% to 31.09 – 11.2%
(p < 0.05). The patients had a slight increase in HDL cholesterol
54.7 – 7.65 mg/dl to 59.05 – 7.29 mg/dl.
Conclusions: Physical activity, even in simple everyday actions, should be an integrated part of diabetes treatment and weight
control. Technology, assuring measurable results, could help diabetic patients to implement and increase PA in their daily life.
O-21
EVALUATION OF GLYCEMIC CONTROL USING
AN ALGORITHM FOR BASAL BOLUS INSULIN
THERAPY IN HOSPITALISED PATIENTS
WITH DIABETES MELLITUS TYPE 2
J.K. Mader1, K.M. Neubauer1, L. Schaupp1, F. Aberer1,
T. Augustin2, S. Spat2, B. Hoell2, P. Beck2, J. Plank1,
T.R. Pieber1
1
2
Endocrinology and Metabolism, Medical University of Graz
HEALTH, Joanneum Research, Graz, Austria
Background and aims: Current guidelines recommend
fasting/pre-meal blood glucose (BG) levels of <140 mg/dl in
hospitalized patients. The aim of this study was to evaluate
glycemic control and usability of a workflow-integrated algorithm for basal-bolus insulin therapy (REACTION algorithm) for
glycemic management in patients with diabetes mellitus type 2
(T2D) hospitalized at the general ward.
Methods: In this feasibility study in 30 T2D patients (11 female, age 71 – 10 years, HbA1c 69 – 25 mmol/mol, BMI 30 – 6)
blood glucose management was performed using the REACTION
algorithm running on a tablet PC. BG measurements were performed four times per day (pre-breakfast, pre-lunch, pre-dinner, at
bedtime) and insulin injections were given according to the advice
of the algorithm. A basal-bolus regimen with advice for total daily
dose (TDD) (50% basal insulin, 50% pre-meal bolus insulin with
additional corrective dose if necessary) was generated once daily.
In case of safety concerns nursing staff could overrule the advice.
Results: Mean BG was 155 – 32 mg/dl. 15/913 measurements
(1.6%) were in the hypoglycemic range (< 70 mg/dl). Mean TDD
was 47 – 27 IU (basal: 21 – 12 IU, bolus: 26 – 15 IU). Adherence
to the insulin advices by the algorithm was 223/226 [98.7%] for
TDD, 205/213 [96.2%] for basal insulin and 643/672 [95.7%] for
bolus insulin.
Conclusion: The REACTION algorithm could safely establish glycemic control without increased risk of hypoglycemia.
Adherence to insulin dosing advices generated by the REACTION algorithm was high both for basal and bolus insulin. The
REACTION algorithm has the potential to improve glycemic
management in the hospital setting.
Supported by the European Commission, Project REACTION
(FP7 248590).
O-22
EEG BASED PREDICTION OF HYPOGLYCAEMIA
IN CHILDREN WITH T1D
J. Johannesen1, P. Foli1, S. Fredheim1, G. Laerkholm1,
M.H. Rose2, J. Duun-Henriksen2, C.B. Juhl2, K. Pilgaard1,
B. Olsen1
1
2
Paediatrics, Copenhagen University Hospital, Herlev, Denmark
HypoSafe, Lyngby, Denmark
Background and Aim: The fear of hypoglycaemia is a major
obstacle of obtaining near-normal blood glucose levels (BGL) in
children. Hypoglycaemia avoidance behaviour might adversely
affect glycaemic control in T1D children thereby increasing the
risk for long-term diabetic complications. Here, we test an automated EEG algorithm initially developed in adults in predicting hypoglycaemia in children.
Subjects and Methods: 8 pre-pubertal children (4 males),
aged 9.6 – 2.3 yrs, T1D duration of 3.0 – 1.4 yrs, HbA1c
55 – 3,4 mmol/mol and 7/8 on CSII treatment underwent hyperinsulinimic hypoglycaemic clamp in awake state during daytime.
The hypoglycemia was terminated at nadir either by significant
hypoglycemic symptoms (evaluated by either the patient, parents
or physician) or by a BGL level at 2.2 mmol/l. EEG was recorded
and analysed using an automated EEG algorithm.
Results: The automated algorithm detected the induced hypoglycaemia in all children on average at a BGL of
2,5 – 0.5 mmol/l and 18,4 – 20,3 minutes (range 0–55 minutes)
prior to BGL nadir on average 2.3 – 0.5 mmol/l. No false positive alarms were recorded.
Conclusions: This automated EEG algorithm identified hypoglycaemia in 8/8 pre-pubertal children in awake state before
severe hypoglycaemia developed. The potential of this new automated algorithm should be evaluated in children during sleep
for predicting nocturnal hypoglycaemia.
O-23
HYPOGLYCEMIA REDUCTION IN ASPIRE IN HOME
STUDY
S. Garg1
1
Barbara Davis Center for Diabetes, University of Colorado
Denver, Denver, USA
Introduction: Prevalence and cost of diabetes (both type 1
and type 2) is increasing globally, and according to the International Diabetes Federation (2011) it is predicted to reach 550
million individuals by 2030. (1) Diabetes continues to be associated with a high mortality rate–mainly due to cardiovascular
disease, with approximately 5% of all deaths worldwide being
attributable to diabetes. (2) Intensive diabetes management with
multiple daily injections (MDI) and or continuous subcutaneous insulin infusion (CSII) in type 1 diabetes (T1D) lowers
A1c values effectively which reduces both micro- and macrovascular complications of diabetes. (3) However, intensive
diabetes treatment results in > 3 fold increase in severe hypoglycemia. (3) Despite all the advances in diabetes treatment (new
insulin analogs, glucose meters and continuous glucose monitors
[CGM]), recent data from T1D exchange confirms only small
improvements in glucose control with with A1c values ranging
from 7.7–8.7% in > 50% of patients. In addition severe hypoglycemia continues to be a hurdle in better implementation of
intensive diabetes management.
Using a closed loop system is one way to reduce severe
hypoglycemic events. The low glucose suspend (LGS) feature
on the paradigm Veo sensor-augmented insulin pump system
(Medtronic MiniMed, Inc., Northridge, CA) is a closed loop
system for insulin delivery. (6–9) The use of LGS feature
automatically stops insulin delivery for 2 hours when a preprogrammed glucose threshold is reached with manual intervention option at any time. The Automation to Simulate Pancreatic
Insulin REsponse (ASPIRE) study was done to see if duration and
severity of hypoglycemia could be reduced in subjects with T1D
during an in-clinic exercise induced hypoglycemia. (10, 11)
Subjects and Methods: ASPIRE at home study randomized
247 subjects with T1D (demographics provided below) in to a
Control arm using SAP and a Threshold Suspend (TS) arm using
SAP + TS.
Results: Similar to the studies with ASPIRE in-Clinic (exercise-induced hypoglycemia), ASPIRE at home study (12)
documented a 37% reduction of nocturnal hypoglycemia Figure1. The results were similar in different age groups without any
change in glucose control.
There were total of 1438 2 hour suspensions in ASPIRE study
and the data confirms reduction of hypoglycemia without any
significant hyperglycemia (Figure-2).
Discussion: The LGS feature is designed (recently approved
by the FDA) to imitate the pancreatic beta cells and regulate
A-9
glucose levels by stopping insulin delivery when blood glucose
reaches a pre-defined threshold. The 2 hr suspension time was
designed to decrease rebound hyperglycemia.
Future developments in closed loop systems will include (a)
the use of predictive alarms/ glucose threshold to suspend insulin
delivery (LGS) before hypoglycemia occurs, (b) insulin delivery
when hyperglycemia is detected (>180 mg/dL), and (c) and/or a
hybrid system where subjects will deliver part of their bolus
before meals to imitate normal physiologic function, as currently
available rapid acting insulins are not rapid enough in onset of
action. Newer insulin formulations with more rapid onset of
action are in development. Furthermore, there is development
of dual compartment pumps that may incorporate glucagon to
prevent and treat hypoglycemia or use pramlintide (Symlin) to
limit post-prandial hyperglycemia. Other than developing better
basal insulins e.g. deguldec (approved in Japan and Europe) and
pegylated lispro (phase-3 studies ongoing), more accurate CGMs
are needed to create a true closed loop system.
References:
1. Whiting DR, Guariguata L, Weil C, Shaw J: IDF diabetes
atlas: Global estimates of the prevalence of diabetes for 2011
and 2030. Diabetes Res Clin Pract. 2011 Dec; 94(3):311.
2. Whiting DR, Guariguata L, Weil C, and Shaw J: IDF diabetes atlas: Global estimates of the prevalence of diabetes
for 2011 and 2030. Diabetes Res Clin Pract. 2011 Dec;
94(3):315.
3. The effect of intensive treatment of diabetes of the development and progression of long-term complications in
insulin-dependent diabetes mellitus. Diabetes Control and
Complications Trial Research Group. N Engl J Med
1993;329:977–986.
4. Garg SK, Annual Meeting of Advanced Technology and
Therapeutics for Diabetes, Barcelona, February 2012.
5. Garg SK: T1D Exchange Group (Diabetes, June 2012).
American Diabetes Association Philadelphia, June 2012.
6. Agrawal P, Welsh JB. Kannard B, Askari S, Yang Q,
Kaufman FR: Usage and effectiveness of the low glucose
suspend feature of the Medtronic Paradigm Veo insulin
pump. J Diabetes Sci Technol 2011; 1137–1141.
7. Choudhary P, Shin J, Wang Y, Evans ML, Hammond PJ,
Kerr D, Shaw JA, Pickup JC, Amiel SA: Insulin pump
therapy with automated insulin suspension in response to
hypoglycemia: Reduction in nocturnal hypoglycemia in
those at greater risk. Diabetes Care 2011; 34:2023–2025.
8. Danna T, Kordonouri O, Holder M, Haberland H, Golembowski S, Remus K, Bläsig S, Wadien T, Zierow S, Hartmann R, Thomas A: Prevention of hypoglycemia by using
low glucose suspend function in sensor-augmented pump
therapy. Diabetes Technol Ther 2011; 13:1129–1134.
9. Buckingham B, Wilson DM, Lecher T, Hanas R, Kaiserman K, Cameron F: Duration of nocturnal hypoglycemia
before seizures. Diabetes Care 2008; 31:2110–2112.
10. Brazg RL, Bailey TS, Garg S, Buckingham BA, Slover RH,
Klonoff DC, Nguyen X, Shin J, Welsh JB, Lee SW: The
ASPIRE study: Design and methods of an in-clinic crossover trial on the efficacy of automatic insulin pump suspension in exercise-induced hypoglycemia. J Diabetes Sci
Technol 2011; 5:1466–1471.
11. Garg S, Brazg RL, Bailey TS, Buckingham BA, Slover RH,
Klonoff DC, Shin J, Welsh JB, Kaufman FR: Reduction in
Duration of Hypoglycemia by Automatic Suspension of
Insulin Delivery: The In clinic ASPIRE Study. Diabetes
Technology and Therapeutics 2012; 14:205–209.
A-10
12. Bergenstal R, Klonoff D, garg S et al; Threshold-based
insulin pump-interruption for reduction of hypoglycemia. N
Engl J Med 2013 DOI: 10.0156/NEJMoa1303576
O-24
NOVEL STRATEGIES TO LIMIT HYPOGLYCEMIA
DURING EXERCISE
M.C. Riddell1
tempts have been made to evaluate the impact of this, unfortunately many of these proved to be time consuming for the HCP or
patient’s site, which might prevent the success of this type of
approach in real life.
Use of new technology, both in development or already on the
market, provides an opportunity to develop a new approach to
SMBG. Above all, it will be essential to use a variety of tools
which provide meaningful support to HCP and patients, to truly
improve the treatment success.
Abstract supported by Sanofi.
1
Kinesiology and Health Science, York University, Toronto,
Canada
Balancing blood glucose concentrations during exercise in
patients with type 1 diabetes has always been a major challenge.
Hypoglycemia can be induced within minutes after the start of
exercise and may also occur in both early and late recovery.
Aerobic exercise increases insulin sensitivity and increases blood
glucose disposal into skeletal muscle more than 6-fold compared
to rest. This increase in glucose disposal must be matched with
either increased glucose production by the liver (glycogenolysis,
gluconeogenesis), typically by lowering circulating insulin levels
and by increasing the levels of glucagon, or by the consumption of
‘‘extra’’ carbohydrates (Ex Carbs) during the activity. A number
of novel strategies are being developed to assist with the prevention of exercise-induced hypoglycemia including the use of nutritional agents (e.g. caffeine, maltodextrins), pharmacotherapies
(e.g. low dose glucagon, somatostatin receptor antagonism, SGL2
inhibitors) and modifications to the exercise itself (resistance type
exercise, sprinting). This session will highlight some of these
newer approaches for hypoglycemia prevention that are at various
stages of research from early conceptual work to later proof of
concept studies in rodents to small clinical trials.
O-25
MEANINGFUL SUPPORT OF BASAL INSULIN
TREATED TYPE 2 PATIENTS BEYOND SMBG
RESULTS - WHAT DOES IT TAKE?
F. Flacke1
1
Sanofi, Inc., Frankfurt, Germany
Use of self-monitoring of blood glucose (SMBG) in basal insulin-treated Type 2 diabetes patients is very well accepted in both
the clinical and economic world. In contrast, there is still some
ongoing debate as to whether this is an effective tool for insulin
naı̈ve Type 2 patients; however, there is now increasing evidence
that this population would also benefit clinically and psychologically from the use of SMBG.
Despite the increasing use of SMBG, it is clear that many patients are still not reaching their treatment goals. Even in RCTs, in
which patients have frequent contact with the treating centers and
free access to SMBG supplies, the blood glucose goals set in these
trials are rarely met.
This raises the question as to whether patients actually receive
and fully understand the messages and information that are
provided to them by the treating Healthcare Professional (HCP).
Several patient attributed factors, such as motivation, literacy
and social environment may contribute to prevent treatment
success with regard to metabolic control, despite all necessary
information being at hand.
This suggests that there is a need for an improvement in the
communications between HCP and patient. Whilst several at-
O-26
CHALLENGES IN IMPLEMENTING SAP IN REAL LIFE
F.R. Kaufman1
1
Pediatric Endocrinology, Medtronic Diabetes and Children’s
Hospital LA, Los Angeles, USA
Insulin pumps have been integrated with glucose meters, continuous glucose monitoring sensors (CGM), data analytic systems,
and now closed-loop algorithms that allow for automation of insulin
delivery. The use of an integrated insulin pump and CGM in the
STAR 3 study showed an early and persistent reduction in A1C and
severe hypoglycemia rates of 13 per 100-patient years, some of the
lowest hypoglycemia rates reported. The recent ASPIRE In-Home
trial revealed that automating insulin shut-off at a pre-set threshold
significantly reduced nocturnal hypoglycemia without increasing
A1C. Automatic insulin shut-offs occurred frequently and those
lasting the full 2-hour duration occurred mainly at night. Recently,
predicted low glucose management systems have shown that shutting off insulin when it is predicted that within 30 minutes a low
glucose threshold will be reached have further reduced hypoglycemia. There have been many reports of the use of fully closed-loop
systems at nighttime only, from studies occurring in both the hospital and home settings.
To benefit from sensor augmented pump therapy, patients,
caregivers and diabetes healthcare providers need to work collaboratively, and be adequately trained and motivated. However,
despite many advances and the promise of diabetes technology in
the future, barriers persist to the use of these integrated systems.
These include issues such as body image, cost, meeting criteria for
pump approval, pump/human tissue interface, fear of technology,
diabetes burn-out and being overwhelmed by diabetes management. Success with sensor augmented pump therapy relies on
education and support by a proactive health care team.
O-27
CLINICAL RESULTS FROM TRANSITIONAL
AND HOME TRIALS OF OUTPATIENT
CLOSED-LOOP CONTROL
B.P. Kovatchev1
1
Center for Diabetes Technology, University of Virginia,
Charlottesville, USA
The introduction of the Diabetes Assistant (DiAs) – a portable
outpatient closed-loop control platform based on a smart phone –
opened new possibilities to the transition of the artificial pancreas
to outpatient use. In October 2011, DiAs was tested in pilot trials
done simultaneously in Padova (Italy) and Montpellier (France). A
subsequent multi-site feasibility study was completed in 2012 at
the University of Virginia (UVA), Padova, Montpellier, UC Santa
A-11
Barbara, and the Sansum Diabetes Research institute. A second
multi-site randomized cross-over trial testing the efficacy of DiAs
in outpatient setting was completed in June 2013: compared to
open loop, DiAs reduced significantly the frequency of hypoglycemia (BG < 70 mg/dl) from 2.4 to 1.2 episodes/subject requiring
carbohydrate treatment, p = 0.02. The effect size of this risk reduction was 0.64 (p = 0.003) as assessed by the Low BG Index - a
risk marker for hypoglycemia. In the summer of 2013, DiAs was
deployed at Stanford University camp studies for children with
diabetes, which resulted in very good overnight glucose control
and only one mild hypoglycemic episode during *50 nights of
closed loop use. Outpatient clinical trials of new adaptive advisory/automated control strategies are ongoing at UVA, Padova,
and the Mayo clinic. In this presentation we summarize the results
from these studies and place them in the context of the worldwide
transition of the artificial pancreas to ambulatory use. We conclude that technology has evolved to bring elements of closed-loop
control to patient’s homes, initially in controlled trials, and then
into the clinical practice of diabetes.
O-28
CONTINUOUS GLUCOSE SENSORS AND AP SYSTEMS
The G4AP also performed better than G4 PLATINUM
on several recently proposed metrics for assessing CGM performance in AP applications. The improved accuracy of the
G4AP algorithm is expected to benefit patients routinely using
CGM for management of their diabetes as well as research
groups seeking to develop improved artificial pancreas
prototypes.
O-29
CONTINUOUS GLUCOSE SENSORS AND AP SYSTEMS
H. Eikmeier1
1
Diabetes Care, Roche Diagnostics GmbH, Mannheim,
Germany
Recent discussions on key performance parameters for CGMsensors and their potential usage for Artificial Pancreas (AP)
systems mainly focused on accuracy, often expressed by mean
absolute relative difference (MARD).
This presentation aims to challenge MARD being handled as
exclusive parameter for the assessment of CGM sensors as part
of an AP system. We also see other features of CGM systems as
essential elements of such solutions:
T. Peyser1, A. Garcia1, A.L. Rack-Gomer1, N. Bhavaraju1,
H. Hampapuram1, A. Kamath1, A. Facchinetti2, C. Zecchin2,
G. Sparacino2, C. Cobelli2
Accuracy of CGM signals in critical situations (e.g. hy-
poglycemic levels / fast changing glucose values)
Reliability of CGM signals and built-in features for signal
and operational safety
1
Dexcom, Inc., San Diego, USA
Padova, Italy
Holistic AP system architecture to enhance patients’ con-
2
The viability of artificial pancreas systems depends heavily on
the accuracy and reliability of the continuous glucose monitor
(CGM) providing input data to the closed loop algorithms. The
Dexcom G4 PLATINUM was approved in Europe and the United
States in 2012 and represents a significant improvement in accuracy and reliability compared with the previous generation Dexcom CGM device, the SevenPlus.
The G4 PLATINUM has been widely adopted by patients for
routine clinical use, but also by artificial pancreas groups around
the world.
Dexcom has developed an advanced CGM, called the G4AP,
in collaboration with the University of Padova that utilizes the
same sensor and transmitter as the G4 PLATINUM, but contains
new denoising and calibration algorithms in the receiver. These
algorithms were applied to raw data from an existing G4 PLATINUM clinical study using a simulated prospective procedure.
The results show that the mean absolute relative difference
(MARD) compared with venous plasma glucose was reduced by
1.5%. In addition, there was further improvement in sensor
performance in hypoglycemia.
fidence of having everything they need to effectively
manage their diabetes
Roche’s current sensor system under development will address the 3 aspects mentioned above. Moreover, clinical study
data involving prototypes of this technology already confirm the
effectiveness of the sensor design in patients tested:
Excellent overall MARD (40–400 mg/dl) of 9.4% and
performance during hypoglycemic episodes (<70 mg/dl)
with MARDs of 13.0%, as well as during induced glucose
swings with MARDs of 11%
High precision between 2 simultaneously operating sensors
with overall percent absolute relative deviation (PARD) of
7.8% guarantees a highly reliable signal quality
CGM-data storage on patch and safe transmission of
missed data (if receiver was out of communication range)
safeguards availability of the complete data. Bluetooth low
energy (BLE)-enabled transmission of calibrated CGM
values from the patch at an enhanced frequency of 1/min is
combined with an easy-to-read visualization and userfriendly User Interface (UI) on the controller
O-30
Parameter
MARD
(40 – 400 mg/dL)
%20/20 mg/dL
MAD
(YSI < 70 mg/dL)
MARD
(YSI < 70 mg/dL)
INSULIN PUMPS IN AP SYSTEMS
SevenPlus
G4
PLATINUM
G4AP
15.9%
13.2%
11.7%
76%
16 mg/dL
82%
11 mg/dL
86%
8.8 mg/dL
27%
18%
14.8%
R. Venugopalan1, D.A. Finan1, B.L. Levy2
1
Research & Development, Animas Corporation, Wayne PA,
USA
2
Clinical Affairs, Animas Corporation, Wayne PA, USA
Insulin pumps have evolved into technologically precise medical devices and the value they bring to patients has been widely
demonstrated. CGM integration into insulin pumps has provided
access to trending glucose data and alarms, thereby facilitating
A-12
better glycemic management. Titrating insulin pump dose using
CGM data is a natural next step and can mitigate the severity of
glycemic excursions, particularly hypoglycemic events [1].
Reactive, threshold-based systems represent the first generation of AP systems, but their benefits are limited due to the
simplistic nature of the controller. More sophisticated predictive
controllers that account for CGM trending information can be
used to not just mitigate, but potentially avoid glycemic excursions [2]. The challenges associated with delivering such products to the market lie not only with developing the algorithm
technology, but more broadly with ensuring a rigorous holism
among all components of such a hybrid solution, including
critical human factors aspects.
Lessons learned from real-world use of reactive systems with
simple decision trees will lead to more complex, robust predictive systems to reduce hypoglycemia first, then hyperglycemia.
Continued collaboration across the community (academia, industry, advocacy and government/regulators) is fundamental to
the acceleration of such innovation to patients in need.
[1] TT Ly et al. Effect of sensor-augmented insulin pump
therapy and automated insulin suspension vs standard
insulin pump therapy on hypoglycemia in patients with
type 1 diabetes: a randomized clinical trial. JAMA 2013.
[2] DA Finan et al. Hypoglycemia safeguard capabilities of
the predictive Hypoglycemia-Hyperglycemia Minimizer
(HHM) System. ATTD 2013.
O-31
REPETITIVE HBA1C MEASUREMENTS DURING
PREGNANCY
L. Jovanoviç1
1
Clinical Reserch, Sansum Diabetes Research Institute,
Santa Barbara, USA
During gestational diabetes mellitus (GDM), the current recommendations are to achieve glucose control as near to normal as
possible. We conducted a retrospective chart review of all GDM
patients seen in the Diabetes-Pregnancy Clinic between December 2005 and December 2007 during which the goal of
glucose control was an A1C of 5%. We evaluated the maternal
characteristics and neonatal outcomes of 123 GDM pregnancies.
Maternal A1C (DCA 2000, Bayer) between 35–41 weeks gestation were averaged, and gestational age at delivery, neonatal
weight and neonatal complications were recorded. Data was
available for 120 neonates of which 114 charts had A1C and
birthweight records, with 100 charts also having recorded neonatal mode of delivery, gender and gestational age.
Weight increased 35.8 Gm with each 0.1 increase in A1C.
Macrosomia (birthweight ‡ 4000 Gm) was significantly associated with A1C (O.R. = 5.1, CI = 1.2–21.0). There was no significant difference in frequency of caesarian section relative to
birthweight and mode of delivery. Of 8 macrosomic infants (7?,
1?) 4 were delivered by C-section and four by vaginal delivery.
O-32
DOES THE PLACENTA PLAY A ROLE FOR
THE OUTCOME OF DIABETIC PREGNANCIES
G. Desoye1
1
Department of Obstetrics and Gynecology, Medical University
of Graz, Graz, Austria
The hallmark of the neonate born to T2DM and gestational
diabetic (GDM) pregnancies is its excessive deposition of fat,
which also contributes to the offspring risk for impaired glucose
tolerance and obesity later in life. Fetal fat accumulation is
mainly driven by fetal insulin as a result of fetal hyperglycemia.
Transplacental glucose flux, at least at the end of gestation, is
dictated by the glucose concentration gradient between the maternal and fetal circulation and, thus, is not much under placental
control. The insulin-stimulated enhanced aerobic metabolism in
the fetus increases the oxygen demand. If not adequately covered
at least transient fetal hypoxia can ensue. In such a situation the
placenta responds by upregulating angiogenesis. This leads to
longer placental vessels with increased branching, ultimately
resulting in more capillaries available for oxygen supply to the
fetus.
Poor maternal glycemic control prior to or during the first
weeks of pregnancy may lead to defects in the initial steps of
placental development such as implantation and placental, ie.
trophoblast, invasion. Combined with potentially pre-existing
vascular defects in the maternal circulatory systems, uteroplacental blood flow may be impaired. Whether this contributes
to the increased risk for maternal pregnancy complications associated with T1D (and likely also T2D), such as pre-eclampsia,
is a current speculation.
O-33
FERTILITY IN T1DM AND T2DM PATIENTS
A. Ben Haroush1
1
IVF and Infertility Unit, Rabin Medical Center,
Petach-Tikva, Israel
Patients with diabetes mellitus often have reproductive disturbances. For women these include delayed menarche, menstrual irregularities, subfertility, early onset of menopause, and
increased incidence of spontaneous abortions, and for men impotence, hypospermia, and impaired spermatogenesis.
The exact mechanisms underlying diabetes-related infertility
remain unknown. Studies have implicated a central defect on the
pituitary-gonadal axis, abnormal antral follicle development, as
in polycystic ovary syndrome (PCOS), and microangiopathy or
other tissue-damaging factors.
This presentation reviews the known data on the association
between diabetes and infertility, including the cumulative information on the pivotal role of insulin resistance in the pathogenesis of prediabetic states such as PCOS.
O-34
TREATMENT WITH AN ULTRARAPID INHALED
INSULIN - WHAT DO WE KNOW NOW?
A.H. Boss1
1
Medical Affairs, MannKind Corporation, Paramus NJ, USA
Prandial insulin regimens strive to mimic the physiological
relationship between glucose absorption and insulin release.
Current regimens are challenged by the inadequate synchronization of insulin action to postprandial plasma glucose excursions, leading to post prandial hyperglycemia as well as a
significant risk of late post prandial hypoglycemia and weight
gain. Technosphere Insulin (TI) is an inhaled ultra-rapid acting
human insulin that is quickly absorbed in the alveoli. With a
Tmax of about 14 min and a Emax of 35–40 min, TI more closely
match the postprandial insulin concentrations seen in nondiabetic individuals. Studies have shown that long-term administration of prandial TI in combination with long-acting basal
insulin results in reductions in hemoglobin A1c comparable to
conventional subcutaneously injected prandial insulins, but with
improved control of early postprandial blood glucose, a lower
incidence of hypoglycemia and less weight gain. However, the
different action profile require that the ultra rapid acting insulin is
used differently from current prandial insulins. Dose timing, the
time of measurement and blood glucose target levels used for
dose adjustments all need to be evaluated. In addition, the shorter
duration of action may permit a post prandial dosing, either as the
only dose or as a second dose when a large meal is consumed.
O-35
NOVEL FORMULATIONS TO MODIFY MEALTIME
INSULIN KINETICS
A. Krasner1, R. Pohl1, P. Simms1, P. Pichotta1, R. Hauser1,
E. De Souza1
1
Research and Development, Biodel, Danbury CT, USA
Insulin absorption can be accelerated by formulating recombinant human insulin (RHI) or insulin analogs with ethylenediaminetetracetic acid (EDTA) and citrate. These excipients
have been shown to speed the dissociation of insulin hexamers
into dimers/monomers upon dilution in extracellular fluid. Such
formulations at standard 100 U/ml (U-100) insulin concentrations exhibit distinct pharmacokinetic (PK) profiles dependent on
whether the active ingredient is RHI or lispro. Both RHI and
lispro formulations have been demonstrated in humans to exhibit
accelerated absorption relative to commercial insulin lispro
(Humalog). However declines from peak are slightly longer for
RHI/EDTA/citrate formulations relative to Humalog, whereas
lispro/EDTA/citrate formulations decline from peak faster than
Humalog. The clinical significance of these distinct PK profiles
is unknown, however safety and efficacy of RHI formulation
BIOD-123 has recently been demonstrated in a multi-center
phase 2 trial evaluating patients with type 1 diabetes. BIOD-531
is a concentrated (400 IU/ml, U-400) RHI/EDTA/citrate formulation that has been shown in a diabetic swine model to exhibit
yet a third distinct PK profile characterized by more rapid absorption compared to concentrated regular insulin (Humulin R
U-500) and lispro/protamine prandial/basal mixes but with basal
duration of action comparable to that seen with Humulin R U500. BIOD-531 has entered clinical development and may prove
to be attractive for patients with type 2 diabetes who use either
concentrated insulin or pre-mixed prandial/basal insulins. Understanding the influence of insulin type and concentration on the
PK properties of EDTA/citrate formulations has yielded clinical
development candidates for multiple patient populations.
O-36
RECOMBINANT HUMAN HYALURONIDASE
FACILITATES A CONSISTENTLY ULTRAFAST
INSULIN PROFILE ACROSS INFUSION SET LIFE
IN T1DM PUMP PATIENTS
D.B. Muchmore1
1
Medical, Halozyme Therapeutics, San Diego, USA
A-13
Rapid acting insulins (RAI) represent improvement over
regular insulin, with advantages in post prandial glucose excursions, hypoglycemia, A1C and patient convenience. However,
RAI is still too slow in onset and too long in duration to mimic
endogenous insulin response. We have studied the impact of
recombinant human hyaluronidase (rHuPH20) to increase the
dispersion and accelerate the absorption of RAI in both basal/
bolus treatment and insulin pumps. In pumps we have explored
the use of a formulation of RAI + rHuPH20 in the pump reservoir as well as using a pretreatment of the infusion site with
rHuPH20 at each infusion set change. rHuPH20 results in acceleration of insulin absorption and action, rendering an ‘‘ultrafast’’ insulin profile. Typically, the fraction of total insulin
absorption that occurs in the first hour (fAUC0–60) is doubled
from *15% to *30%, and onset of insulin action (early tGIR50%),
during euglycemic clamp studies is shortened by about 1/3 or
about 10–20 minutes. Duration of insulin action in the clamp,
measured using the same calculation employed in pharmacokinetics to assess Mean Residence Time, is typically reduced by
about 45 minutes. These changes in insulin absorption and action
are accompanied by significant reductions of *30 mg/dL in
postprandial glycemic excursions in response to mixed test
meals. Importantly, rHuPH20 preadministration also eliminates
the systematic acceleration of insulin absorption and action (the
‘‘Tamborlane Phenomenon’’) that occurs as infusion sets age;
this provides consistent, predictable insulin absorption and action over infusion set life and may thus improve diabetes control
by reducing unanticipated variability.
O-37
IMPACT OF STANDARDIZED INJECTION SITE
WARMING ON GLYCEMIC CONTROL
A. Pfützner1
1
Research & Development, IKFE Services - Institute for
Clinical Research and Development, Mainz, Germany
Temperature changes on the skin surface result in changes of
the (sub)cutaneous microcirculation. This well-known phenomenon was used to develop the InsuPad device for improvement of
prandial insulin absorption. Standardized warming cycles applied after insulin injection result in a more rapid increase in
insulin plasma concentrations and faster action. In standardized
meal studies, use of a similar dose of short-acting insulin analogs
resulted in significantly better postprandial control when using
InsuPad. To achieve the same level of control, InsuPad use allows for a mean dose reduction by 20%. Injection of insulin after
the meal still results in a better glycemic control than injecting
the same dose without the device prior to food uptake. Use of
InsuPad under real-world conditions was tested in a controlled
randomized parallel study for three months in 145 patients with
type 1 and type 2 diabetes. Target HbA1c levels (HbA1c:
6.3 – 0.5%) were reached in both treatment groups (with and
without the device). However, InsuPad patients needed 28% less
prandial insulin as compared to the control group (p < 0.001),
12% less total insulin (p < 0.001), and had 46% less hypoglycemic events (p < 0.05). Treatment satisfaction remained unchanged despite the additional treatment procedure and the
overall vast majority continued with the use of the device after
study termination. HbA1c treatment targets were achieved with
InsuPad with substantially less insulin and less hypoglycemic
events.
A-14
O-38
that there has been a documented decline in microvascular disease in line with a reduction in HbA1c but the associated increase
in body mass in our clinic is of concern3.
Other biological markers measured during adolescence show
associations prospectively for microvascular complications (retinovascular geometry, plantar fascia thickness, heart rate variation, small pupil size and health care utilisation). Higher HbA1c
as a measure of poor metabolic control remains in all risk models.
JET ADMINISTRATION OF SHORT ACTING INSULIN
B.E. de Galan1
1
General Medicine, Radboud University Medical Center,
Nijmegen, Netherlands
The pharmacokinetic and pharmacodynamic profile of
rapid-acting insulin analogs, although better than that of regular
insulin, is still far from resembling the profile of endogenous
insulin secretion, in large part due to protracted absorption from
the subcutaneous space. Indeed, the firm extracellular matrix of
the subcutaneous tissue impedes drug transport and hence its
absorption into the circulation. As a consequence, patients with
type 1 or insulin-requiring type 2 diabetes still face the risk of
immediate postprandial hyperglycemia and late postprandial
hypoglycemia, despite using rapid-acting insulin analogs. Jetinjectors, originally introduced for patients with persistent fear of
needles or true needle-phobia, provide a needle-free alternative
for insulin administration. After injection, insulin injected by jet
stream displays a spray-like dispersion pattern in the subcutaneous tissue, which may promote absorption due to a relatively
large surface area. Studies dating back to the 1980s and before
already indicated faster absorption of regular insulin and more
direct glucose lowering effect, when injected by a jet injector
rather than by a syringe. Recently, we showed that insulin analogs are absorbed up to twice as fast when administered by jet
stream compared to injection by conventional insulin pen, both
in healthy subjects and in patients with type 1 or type 2 diabetes.
Jet injection similarly advances the glucose-lowering effect
of insulin analogs, and consequently reduces the hyperglycemic
burden immediately after a meal. Studies on the reproducibility
of the jet injector for insulin administration and its effect on
normalizing hyperglycemia are currently underway.
1. Diabetes Care 26, 1224–1229 (2003).
2. Diabetes Care 30, 77–82 (2007).
3. Diabetes Care 34, 2368–2373 (2011).
O-40
ROUTINE USE OF CGM IN PRESCHOOL CHILDREN
N. Bratina1, U. Tomc1, T. Battelino1
1
Departement of Endocrinology Diabetes and Metabolic
Diseases, University Childrens Hospital, Ljubljana, Slovenia
Continuous glucose monitoring (CGM) provides real-time
information on glucose patterns and trends, thus allowing better
management of diabetes. Many studies have shown that it can
improve glycemic control, especially if used frequently. Next to
it CGM reduces occurrence of severe hypoglycaemic events and
improves the quality of life in adults and children with T1D. But
the evidence for CGM to be as effective in preschool children are
limited and controversial. In current recommendations for young
patients, CGM should be considered when patients:
do frequent blood glucose testing,
have severe hypoglycaemic episodes,
have hypoglycaemic unawareness or nocturnal hypogly-
caemia,
have wide glucose excursions or large blood glucose var-
iability,
O-39
THE CONTRIBUTION OF POOR METABOLIC
CONTROL DURING ADOLESCENCE ON
MICROVASCULAR COMPLICATIONS
K.C. Donaghue1
1
Institute of Endocrinology and Diabetes, The Children’s
Hospital at Westmead, Sydney, Australia
Attaining glycaemic targets often is more difficult during
adolescence compared to adulthood and earlier childhood. In the
DCCT for example using the same treatment protocols the mean
HbA1c achieved was significantly higher in the intensively
treated group (8.1 vs 7.2%). Nevertheless adolescents in the intensive compared to the conventional treatment arm had significantly reduced complications, an effect that persisted for four
years after randomization.
In our noninterventional study investigating the effect of
prepubertal diabetes duration to microvascular complications in
young adulthood, the HbA1c achieved in puberty was an independent contributor to retinopathy and microalbuminuria1. 12 yr
follow-up of adolescents into adulthood showed a 1 unit increase
in HbA1c increased risk by 72% for retinopathy and microalbuminuria2.
Other modifiable risk factors for diabetes microvascular disease in adolescence are higher blood pressure, higher insulin
dose per kilogram and higher body mass index. It is likely that
insulin resistance is therefore another key factor. It is pleasing
have difficulties in identifying hypoglycaemic episodes,
have suboptimal glycemic control,
want to mantain good glycemic control with the aim to
limit the risk of hypoglycaemia.
In the consensus statement on CGM for paediatric population
overall it is concluded that CGM can be used safely and effectively for lowering HbA1c, reaching target HbA1c, reducing the
MAGE without increasing the risk of severe hypoglycaemia; it
can be used effectively for reducing severe hypoglycaemia and
shortening the time in hypoglycaemia. The effectiveness of
CGM is significantly related to the frequency of sensor use.
Education on the use of CGM is crucial for success.
Currently, the use of CGM in preschool children is still not a
routine practice. Further studies are needed to evaluate the effectiveness of CGM in this age group.
O-41
IMPROVEMENT OF METABOLIC CONTROL AFTER
THREE MONTHS OF RT-CGM IN TYPE 1 DIABETICS
WITH CSII. THE GREEK MULTICENTER STUDY
DIAMOND
T. Didangelos1, E. Anastasiou2, C. Vasilopoulos3, C. Zoupas4,
C. Manes5, A. Tsatsoulis6, N. Tentolouris7, M. Benroubi8,
E. Pangalos9, A. Gerasimidi-Vazeou10, A. Pappas11
1
1st Propeudetic Department of Internal Medicine, AHEPA
University Hospital, Thessaloniki, Greece
2
Endocrinology Clinic, Alexandra General Hospital, Athens,
Greece
3
Endocrinology Department, Evaggelismos General Hospital,
Athens, Greece
4
Diabetes Center, Hygeia Hospital, Athens, Greece
5
2nd Department of Internal Medicine, Papageorgiou General
Hospital, Thessaloniki, Greece
6
Endocrinology Department, University Hospital, Ioannina,
Greece
7
Diabetes Department, Laiko General Hospital, Athens, Greece
8
Diabetes Center, Poliklinic General Hospital, Athens, Greece
9
Diabetes Department, Thermi Hospital, Thessaloniki, Greece
10
Diabetes Center, Panagiotis and Aglaia Kyriakou Children’s
General Hospital, Athens, Greece
11
Diabetes Center, Venizelion Hospital, Iraklion, Greece
Aim: To evaluate the efficacy of adding continuous glucose
monitoring (CGM) for three months to insulin pump therapy
(CSII) in patients with Diabetes Mellitus Type 1 (DMT1) in a
multicenter Greek study (THE DIAMOND STUDY).
Patients-methods: Eleven Diabetes Centers in Greece participated to the study. Forty-three patients (24 female) treated with CSII
were enrolled prospectively. All patients were on CSII for three
months before the use of CGM. Then all participants were instructed
to wear the MiniMed Paradigm REAL-Time System, which integrates both CSII and RT-CGM functionalities for the next three
months. At the end of the study we evaluated the following parameters: HbA1c, BMI, hypoglycemic episodes (HYPO), total daily
insulin requirement (TDI), total daily insulin for boluses (TDIBOL),
number of daily boluses (NOBOL), total daily insulin basal (TDIBASAL) and percentage of total time use of sensor (PTTU).
Results: The mean PTTU was 74 – 17.0%. The results of the
other examined variables were as follows in patients before and after
the use of CGM: HbA1c 8.3 – 1.2% vs 7.5 – 1.0% (p < 0.001),
TDI 45.7 – 15.3 vs 50.8 – 23.9 (p = 0.018), TDIBOL 24.1 – 10.4
vs 28.3 – 19.0 (p = 0.033) and NOBOL 4.7 – 1.5 vs 6.3 – 2.4
(p < 0.001). No significant change observed in BMI, HYPO and
TDIBASAL before and after the use of CGM.
Conclusions: In the present study CGM was associated significantly with improvement of glycemic control without BMI
and HYPO change, in patients with type 1 diabetes using CSII.
Better self-management and increase of the doses and units of
insulin may have contributed to these beneficial effects.
O-42
SENSOR AND SOFTWARE USE FOR IMPROVED
GLUCOSE CONTROL IN PEOPLE WITH DIABETES
MANAGED BY MULTIPLE DAILY INJECTIONS
OF INSULIN
R. Ajjan1, K. Abouglila2, S. Bellary3, A. Collier4, B. Franke5,
E. Jude6, G. Rayman7, A. Robinson8, B.M. Singh9
1
Diabetes Research, St James University Hospital, Leeds,
United Kingdom
2
Diabetes Centre, University Hospital North Durham, Durham,
United Kingdom
3
Diabetes Centre, Birmingham Heartlands Hospital,
Birmingham, United Kingdom
4
Ayr Diabetes Centre, University Hospital Ayr, Ayr,
United Kingdom
5
Diabetes Centre, Rotherham General Hospital, Rotherham,
United Kingdom
6
Diabetes Centre, Tameside Hospital, Ashton-under-Lyne,
United Kingdom
A-15
7
Diabetes Centre, Ipswich Hospital, Ipswich, United Kingdom
Diabetes Centre, Royal United Hospital, Bath,
United Kingdom
9
Diabetes Centre, New Cross Hospital, Wolverhampton,
United Kingdom
8
Aim: To assess whether subjects with type 1 diabetes (T1DM)
or T2DM managed by multiple daily injections (MDI) of insulin
could improve glycaemic control by; 1) using and understanding
continuous glucose monitoring (CGM) data, 2) utilising glucose
trend arrows and 3) reviewing ambulatory glucose profiles
(AGP) with their clinician.
Methods: A UK, multicentre (n = 9) 100 day study recruited
105 MDI-treated diabetes subjects aged 18–82 years with HbA1c
of 58–108 mmol/mol. Control group subjects used standard selfmonitoring of blood glucose (FreeStyle Freedom Lite), whereas
the intervention group employed a FreeStyle Navigator and were
asked to turn the alarms off. At days 30 and 45, subjects reviewed
their AGP and summary statistics with their clinician and agreed
therapy adjustments.
Results: In T1DM (n = 25) intervention subjects, a within
subject analysis showed significant reduction in hypoglycaemia
(<3.9 mmol/L) of 0.6 – 1.4 hrs/day (p = 0.0474) and 0.4 –
1.0 hrs/day for time spent < 3.1 mmol/L (p = 0.0644), with no
significant change in HbA1c.
In T2DM (n = 28) intervention subjects, within subject analysis showed a significant increased time within 3.9–10.0 mmol/L
of 1.4 – 3.5 hrs/day (p = 0.0427) without a change in hypoglycaemia and a reduction in HbA1c of 9.5 – 11.8 mmol/mol
(p = 0.0002).
For subjects with T1DM, frequency of blood glucose tests per
day (including calibration) reduced from 4.6 – 1.9 at baseline to
2.2 – 1.2 (p < 0.0001) and in T2DM from 4.0 – 1.4 to 2.1 – 1.2
(p < 0.0001).
Conclusion: T1DM subjects showed reduced time in hypoglycaemia when managed with FreeStyle Navigator CGM (no
alarms). The same intervention in T2DM subjects showed a reduction in HbA1c and significantly increased time in 3.9–10.0 mmol/L.
O-43
DECISION ANALYTIC MODEL: COST IMPLICATIONS
OF RT-CGM USE IN INSULIN REQUIRING PATIENTS
WITH HYPOGLYCEMIC UNAWARENESS
C. Graham1, L. Bowman1, J. Lewis1, B. Murphy2
1
Global Access, Dexcom, San Diego, USA
Consultant, ImageCare, San Diego, USA
2
Introduction: RT-CGM use lowers A1C and reduces hypoglycemia for people with diabetes. However, the economic impact of A1C reduction is not seen for many years; we evaluated
costs of RT-CGM use in patients with severe hypoglycemia
(SH). Patients with long standing diabetes and those with hypoglycemia often lose their ability to detect hypoglycemia developing, ‘hypoglycemia unawareness’ (HUA), which results in
significant decrements in health, quality of life, and economics.
This analysis estimates the economic consequences of RT-CGM
in the insulin requiring adult population with HUA.
Methods: Using a simple decision tree model, costs of severe
hypoglycemia resulting in hospitalizations in T1D and T2D
adults with HUA using RT-CGM is analyzed. The hypothetical
population consists of 10 million people. Assumptions: Diabetes
prevalence of 7%; T1D prevalence of 5%; T2D treated with
A-16
insulin is 27.3%. Percentage of patients with T1D HUA is 20%,
and T2 with HUA is 9.8%; annual number of SH events per pt./
yr. are, 2.6 and 5.9 respectively; percentage of SH events requiring hospitalization is 21%; the reduction in annual SH events
in patients with T1D with HUA using RT-CGM is 45%. All
assumptions are referenced from the published literature.
Results: Using a time horizon of 1 year, for people with HUA
that use RT-CGM, there is an expected net savings of $60,829M
USD when assuming the annual cost of RT-CGM is $5800/yr.
Conclusion: For insulin taking patients with HUA, RT-CGM
can be a cost saving tool. Sensitivity analysis shows flexibility in
pricing of RT-CGM to achieve cost savings.
O-44
COMPARISON OF DIFFERENT CALIBRATION
STRATEGIES FOR CONTINUOUS GLUCOSE
MONITORING SENSORS
M. Vettoretti1, A. Facchinetti1, G. Sparacino1, S. Del Favero1,
C. Cobelli1
1
Padova, Italy
Objective: Calibration of continuous glucose monitoring
(CGM) sensors is the process that transforms the raw current
value, proportional to the interstitial glucose (IG) concentration,
into a glycemic value exploiting few blood glucose (BG) references. Due to the presence of many critical factors, e.g. signal
distortion due to BG-IG kinetics, instability and uncertainty of
measured signals, etc., the accuracy of the CGM profile could be
suboptimal. The aim of this contribution is to understand if and
how much a smart compensation of BG-IG kinetics and the exploitation of a-priori knowledge on the parameters of the calibration law can improve calibration effectiveness.
Methods: We compared three calibration strategies of increasing complexity: i) a 2-point linear regression; ii) the calibration algorithm of Guerra et al. (IEEE-TBME 2012), which
applies nonparametric deconvolution before matching BG and
raw current data; and iii) the algorithm of ii) further developed to
exploit a Bayesian prior available on calibration regression parameters. Algorithms efficacy was tested on 15 CGM traces
collected by the Dexcom G4 Platinum (DG4P) device for 7 days.
BG references on days 1, 4, and 7 were used to assess performance via Mean Absolute Relative Deviation (MARD).
Results: The 2-point algorithm achieves a MARD of 18.6%.
Deconvolution decreases MARD to 16.5%. Exploitation of the
Bayesian prior on calibration parameters further reduces MARD
to 14.7%. Average MARD of original DG4P dataset was 14.3%.
Conclusion: Compensation of BG-IG kinetics distortion via
nonparametric deconvolution and exploitation of a-priori
knowledge on calibration parameters via Bayesian estimation
improve calibration effectiveness.
O-45
FIRST EVALUATION OF AN ORTHOGONALLY
REDUNDANT GLUCOSE SENSOR SYSTEM
IN PEOPLE WITH TYPE 1 DIABETES
S.A. McAuley1, A. Bansal2, J.C. Horsburgh3, T. Dang2,
J.R. Hanna2, R.V. Shah2, D.N. O’Neal1
1
On behalf of the Victorian Type 1 Diabetes Technology
Study Group, (includes L. Bach P. Colman A. Jenkins K.
Kumareswaran R. MacIsaac G. Ward), Melbourne, Australia
2
Sensor R & D, Medtronic Diabetes, Northridge, USA
Department of Medicine St Vincent’s Hospital, University
of Melbourne, Melbourne, Australia
3
Aim: To evaluate the performance of a progressively refined
series of orthogonally redundant sensor (ORS) prototypes employing electrochemical and optical fluorescence-based glucose
sensing in type 1 diabetes (T1D) participants.
Background: The ORS under development integrates two
distinct sensing technologies with independent failure modes
potentially improving continuous glucose monitoring accuracy and reliability.
Method: Eight T1D adults wore an investigational ORS and
non-redundant comparator sensor (NCS) concurrently for 48–
168 hours. Following sensor insertion, and later with a standardised meal, venous samples were collected over 4 hours at 30 and
15 minute intervals respectively for YSI plasma glucose. Between these study visits, subjects wore both sensors in an ambulatory real-world setting for 48–168 hours and undertook
capillary blood glucose testing. Sensor glucose values were
displayed only when trace characterisation algorithms deemed
values to be sufficiently accurate. Sensor glucose readings from
both sensors were compared to plasma and capillary glucose
levels.
Results: The ORS configuration was iteratively evolved resulting in incremental improvements in optical sensors over the
course of the study. After 8 subjects, average sensor display time
was higher for ORS than NCS (97% versus 93%). Mean
absolute relative difference (MARD) and compliance with ISO
15197:2013 accuracy metrics were similar. There was no irritation or infection at any sensor insertion sites after removal.
Conclusion: Increasing sensor display time without compromising accuracy results in improved sensor reliability.
Combining optical and electrochemical sensing technologies is
feasible, and potentially increases glucose sensing reliability
which may facilitate artificial pancreas development.
Acknowledgements: Supported by JDRF, Helmsley Charitable Trust
O-46
PARENTAL SLEEP QUALITY AND CONTINUOUS
GLUCOSE MONITORING SYSTEM USE IN CHILDREN
WITH TYPE 1 DIABETES
Z. Landau1, M. Rachmiel2, M. Boaz3, O. Pinhas-Hamiel4
1
Pediatric Endocrinology Unit, Wolfson Medical Center,
Holon, Israel
2
Pediatric Endocrinology Unit, Assaf Harofeh Medical Center,
Zerifin, Israel
3
Epidemiology and Research Unit, Wolfson Medical Center,
Holon, Israel
4
Pediatric Endocrine and Diabetes Unit, Sheba Medical
Center, Ramat-Gan, Israel
Objective: To compare sleep quality and sleep-wake
patterns in parents of children with type 1 diabetes (T1D)
before routine use of continuous glucose monitoring system
(CGMS) and while using it.
Methods: Thirteen parents completed the Pittsburg Sleep
Quality Index (PSQI), a 7-day sleep diary, and wore an actigraph
(a wristwatch sized motion detector) during the nights for 1 week
before pediatric use of CGMS and 4–8 weeks after initiating
routine use of the CGMS.
Results: The parents mean age was 39 (range: 32–47) years,
with 10 mothers and 3 fathers. The children mean age was 9.3
years (range: 5.5–16.5) years and mean disease duration was 3.4
(range: 0.6 – 11.2) years. PSQI total score demonstrated similar
quality of sleep with and without using the CGM (4.6 and 4.9
respectively, p = 0.45). PSQI score of 6 out of 13 parents was
equal or greater than 5, with and without the CGMS, identified as
having severe sleep problems. The sleep diary indicated more
awakening episodes while using the CGMS vs. without the
CGMS (1.6 and 1 respectively, p = 0.03), and actigraphy documented increase in wake bouts number (22.9 and 19.7, p = 0.03)
and increase in total wake time (48.3 and 42.2 minutes p = 0.03)
while using the CGMS compared to the period prior to CGMS
use.
Conclusions: CGMS use seems to have negative effect on
parental objective sleep continuity measures, while self-perception of sleep quality remains unchanged. Drawing realistic
expectations of the parents regarding the relations between
CGMS use and quality of sleep is desirable.
O-47
PARSIMONIOUS DESCRIPTION OF GLUCOSE
VARIABILITY IN TYPE 2 DIABETES BY SPARSE
PRINCIPAL COMPONENT ANALYSIS
C. Fabris1, A. Facchinetti1, G. Sparacino1, G. Fico2,
A. Guillén3, C. Cobelli1
1
Department of Information Engineering, University
of Padova, Padova, Italy
2
Lifestyle Supporting Technologies Group, Technical
University of Madrid, Madrid, Spain
3
Hospital Solutions Spain, Medtronic Ibérica, Madrid, Spain
Background: Increased glucose variability (GV) is considered a risk factor for the development of diabetes complica-
A-17
tions. To quantify GV, dozens of indices have been developed.
In order to limit redundancy, the use of Sparse Principal
Component Analysis (SPCA) has been recently assessed in
Type 1 Diabetes (T1D), obtaining a parsimonious set of up to 10
indices for describing GV. In this work, we extend the assessment of SPCA to Type 2 Diabetes (T2D) and compare results
with those of T1D.
Methods: N = 27 established GV indices, including SD,
MAGE, ADRR and others, are computed on 13 CGM time-series
collected by the Guardian RT in T2D subjects and on 16 collected by the SEVEN Plus in T1D subjects. SPCA is used first to
determine a reduced data dimension P and, then, to decrease the
number of variables from N = 27 to M via LASSO estimation of
sparse loadings.
Results: For both datasets, SPCA selected P = 2 principal
components (PCs) and M = 5 indices for each PC. The subset of
indices selected for T2D allowed preserving the 87% of the
variance originally explained by all GV metrics, compared to
the 67% preserved for T1D. The selected indices are reported in
the table. Seven out of the 10 selected GV indices are the same
for both datasets.
Conclusion: SPCA can be used to extract a parsimonious set
of indices describing GV from a large dataset. Some of them
seem to be independent on the diabetes type 1 vs 2.
O-48
CGM SENSOR DESIGN PRINCIPLES FOR RELIABLE
AND ACCURATE GLUCOSE MONITORING IN THE
SUBCUTANEOUS TISSUE
M. Schoemaker1, G. Schmelzeisen-Redeker1, J. Jager1
1
Roche Diabetes Care, Roche Diagnostics GmbH, Mannheim,
Germany
The core element of a continuous glucose monitoring
(CGM) system is the glucose sensor, which should enable
reliable CGM readings in the interstitial fluid in subcutaneous
tissue for a period of several days. To achieve accurate CGM
readings, special attention must be paid to the sensor-to-tissue
interface and to physiological processes around the sensor
insertion site.
Various sensor architectures and materials were investigated
in clinical studies in order to better understand some of the
processes that occur after sensor insertion and during the sensor
usage period. Design principles were derived out of these studies
for the development of a prototype CGM sensor with markedly
improved precision and accuracy. Some of these design principles and their impact on sensor performance will be discussed in
the presentation.
Results of a clinical study involving 40 people with type 1
diabetes show markedly improved accuracy and stability of the
novel prototype sensor design. Each subject used 2 to 4 concurrent CGM systems for 7 days. Accuracy (MeanARD – SD)
and sensor-to-sensor precision (PARD – SD) in the overall
glucose concentration range were found to be 9.4% – 2.3% and
7.8% – 2.4%, respectively. When glucose was at or below
70 mg/dl, accuracy (MeanARD – SD) and precision (PARD –
SD) were 13.0% – 5.7% and 11.9% – 5.2%, respectively. In the
overall glucose concentration range 91.1% of all paired data
points fell into the clinical accurate zone A of the Clarke Error
Grid. When glucose was at or below 70 mg/dl, 90.7% of all
paired data fell in zone A.
A-18
O-49
insulin pumps (SAP). After standardization of meals prior to
exercise, each subject underwent 2 moderate-intensity exercise
sessions on different days, one in the morning and one in the
afternoon. Sessions were separated by 7–14 days. Continuous
glucose monitoring (CGM) data were collected during the
24 hours before and 36 hours after each session.
Results: Rate of hypoglycemia was significantly lower
following morning versus afternoon exercise (5.6 vs. 10.7
events/patient, p < 0.001). Most events occurred 15–24 hours
after exercise completion (figure 1). No severe hypoglycemic
events were reported. On days following morning exercise,
there were 20% more CGM readings in the near-euglycemic
range (70–200 mg/dL) as compared to days prior to exercise
(p = 0.003).
Conclusions: Among T1D on SAP therapy, physical activity
in the morning resulted in a lower risk of post-exercise hypoglycemia than afternoon exercise and improved metabolic control on the subsequent day maintaining euglycemia for a longer
period of time.
GLYCEMIC PATTERNS RELATED TO EXERCISE
IN TYPE 1 DIABETES
A. Gomez1, C. Gomez1, O. Muñoz1, P. Aschner1, S. Vallejo1,
C. Rubio1, A. Veloza1
1
Colombia
Background: Although regular physical activity is recommended as part of the treatment of diabetes, it remains to be a
challenge in type 1 diabetics (T1D) as exercise has been related
to hypoglycemia and the actions taken to prevent or reduce it
(lowering insulin dose and carbohydrate consumption) frequently result in hyperglycemia. Moreover, no data exist concerning better exercise and timing for this population. The focus
of this study was to determine the impact of two different exercise schedules on glycemic behavior.
Methodology: This randomized crossover study enrolled
35 T1D (table 1), age > 15 years who used sensor-augmented
O-50
SENSOR-AUGMENTED PUMP THERAPY FOR THE
TREATMENT OF PATIENTS WITH TYPE 2 DIABETES
AND ITS IMPACT ON HYPOGLYCEMIC EVENTS
A. Gomez1, S. Vallejo1, E. Mora1, M. Rondön2, C. Arévalo1
1
Colombia
2
Biostatistics, Javeriana University, Bogotá, Colombia
Background: Insulin pumps have been used in type 1 diabetics (T1D) however, the experience in type 2 diabetics (T2D) is
limited and the few studies that have evaluated this population
have shown contradictory results. We describe our experience
with SAP therapy in T2D with high risk of severe hypoglycemia
that were previously treated with multiple daily injections
(MDI).
Patients And Methods: 28 T2D with hypoglycemia who
were initially treated with MDI and then switched to SAP therapy, with at least three months of treatment, receiving care at a
teaching hospital were analyzed. Data included total daily dose
of insulin (TDD), A1C, severe hypoglycemic events, weight, and
diabetic complications before and after the therapy.
Results: 28 T2D with hypoglycemia were included (see table
1). All patients had an A1C over 8.5% prior to SAP therapy,
A-19
reduction was also seen in the ITAS score (D = 2.0 – 6.5,
p = .20, d = 31).
Conclusion: The study is limited by the uncontrolled design
and small sample size. However, the results and the moderate to
large effects sizes suggest that the use of PAQ has clinically
relevant effects to overcome barriers to insulin treatment, without increasing diabetes related distress.
O-52
53% have had at least one event of severe hypoglycemia. Patients wore the sensor more than 80% of the time, used the
Bolus Wizard for all boluses, 53% of the patients had less
than 5 basal rates. Comparing results before and after the
pump use, there was no difference of body weight but there
was a significant reduction on HbA1C levels (8.6% vs. 7.7%,
p = 0.03), and severe hypoglycemic events (1.21 vs. 0.11
p = 0.0032).
Conclusions: In T2D, SAP therapy is efficacious in glycemic
control. It reduces insulin requirements and makes severe hypoglycemia less likely in those people who have failed MDI
therapy.
O-51
USE OF PAQ, A SIMPLE 3-DAY BASAL/BOLUS
INSULIN DELIVERING DEVICE, REDUCES BARRIERS
TO INSULIN THERAPY IN PATIENTS
N. Hermanns1, L.C. Lilly2, J.K. Mader3, F. Aberer3, J. Pachatz3,
S. Korsatko3, J. Warner2, T.R. Pieber4
1
Diabetes Centre Mergentheim, Research Institute Diabetes
(FIDAM), Bad Mergentheim, Germany
2
CeQur, Corp, Marlborough, USA
3
Medical University of Graz, Internal Medicine/Division of
Endocrinology and Metabolism, Graz, Austria
4
Health Joanneum Research GmbH, Internal Medicine/Division
of Endocrinology and Metabolism, Graz, Austria
Background: PaQ (CeQur SA) is a simple to use patch-on
device which provides set basal rates and bolus insulin on demand. In addition to feasibility of use, safety and efficacy this
study analyzed the impact of the PAQ use on barriers against
insulin treatment, diabetes related distress and negative appraisal
towards insulin therapy in type 2 diabetes patients on a multiple
daily injections insulin regimen.
Methods: This was a mono-center, open label, single arm
study. Three validated questionnaires were completed before and
two weeks after PaQ treatment; Barriers to Insulin Treatment –
(BIT), Problem Areas In Diabetes (PAID) and Insulin Treatment
Appraisal Scale (ITAS).
Results: Nineteen patients (age 59 – 5 y, diabetes duration
15 – 7 y, 21% female, A1C 7.7 – 0.7%) completed the questionnaires. There was a large and significant effect of PaQ on the
mean BIT total score (difference (D) = 0.4 – 0.6; p = .01, effect
size (d) = 0.70). Patients perceived less hardship from insulin
therapy (d = 0.35), less stigmatization by insulin injection
(d = 0.28) and less fear of hypoglycemia (d = 0.29). Diabetes
related distress was reduced (D = 0.7 – 6.7, p = 0.79, d = 10). A
SEVERE HYPOGLYCAEMIA IN PATIENTS
WITH TYPE 1 DIABETES TREATED
WITH INSULIN PUMPS IN A REAL LIFE SETTING
C.S.S. Frandsen1, P.L. Kristensen2, H. Beck-Nielsen3,
K. Nørgaard1, H. Perrild 4, J.S. Christiansen5, T. Jensen6,
H.H. Parving6, B. Thorsteinsson2, L. Tarnow7,
U. Pedersen-Bjergaard 2
1
Department of Endocrinology, Hvidovre University Hospital,
Hvidovre, Denmark
2
Department of Cardiology Nephrology and Endocrinology,
Hillerød Hospital, Hillerød, Denmark
3
Department of Endocrinology, Odense University Hospital,
Odense, Denmark
4
Department of Endocrinology, Bispebjerg Hospital,
Copenhagen, Denmark
5
Department of Endocrinology, Aarhus University Hospital,
Aarhus, Denmark
6
Department of Endocrinology, Copenhagen University
Hospital, Copenhagen, Denmark
7
Department of Endocrinology, Steno Diabetes Center,
Gentofte, Denmark
Background and aims: Insulin pumps deliver insulin in a
more physiologic manner compared with conventional insulin
treatment and may thereby reduce the risk of severe hypoglycaemia (SH). The aim of this study was to evaluate the impact of
insulin pump therapy (CSII) on the frequency of SH compared
with conventional insulin treatment (CIT).
Material and Methods: A questionnaire on hypoglycaemia
and related topics posted from six Danish diabetes clinics to
6112 unselected adult patients with type 1 diabetes was filled
in by 3861 patients (63%). In a subpopulation of 1728 patients (45%) supplementary clinical and laboratory data were
available.
Results: 3813 patients with type 1 diabetes ((CSII vs. CIT):
211 vs. 3602 patients, men 37% vs. 54%, age 45 – 14 vs.
48 – 15 years (mean – SD), duration of diabetes 25 – 13 vs.
23 – 14 years, awareness status (aware/impaired/unaware) 38/
47/15 vs. 46/42/12 %) were eligible. The number of episodes of
SH was 1.3 – 4.3 and 1.2 – 5.0 per patient-year in the CSII and
CIT groups, respectively (p = 0.8). This result was confirmed in
a multiple regression analysis.
In the subpopulation ((CSII vs. CIT): 112 vs. 1616 patients,
awareness status (aware/impaired/unaware) 38/46/16 vs. 44/42/
14%, HbA1c 7.6 – 0.9 vs. 8.0 – 1.0% (p < 0.001)), frequency of
SH was 1.2 – 4.1 and 1.2 – 5.0 episodes per patient-year
(p = 0.2). This finding was confirmed in the adjusted regression
analysis.
Conclusion: Occurrence of SH was similar in patients treated
with CSII and CIT regimens. Results should be viewed in the
context of indications for starting CSII. Attention toward SH
should be maintained after commencing pump therapy.
A-20
O-53
mean HbA1c reduction in CSII-using T1D adults is 0.25%, substantially less than locally. Weight, BP, lipids and ACR did not
change after CSII initiation.
BETTER THAN INTERNATIONAL AVERAGE HBA1C
REDUCTIONS IN AUSTRALIAN INSULIN PUMP
SERVICE FOR ADULTS WITH TYPE-1 DIABETES
A.S. Januszewski1, D.A. Calandro1, K.K. Cuper1, M. Burgess 2,
J. Horsburgh2, M. Loh3, K. Steele3, E. Meares3, F. Weedon4,
B. Cayzer 4, R. MacIsaac5, G. Ward 5, D.N. O’Neal5,
A.J. Jenkins1
1
NHMRC Clinical Trials Centre, The University of Sydney,
Sydney, Australia
2
Department of Medicine, The University of Melbourne,
Fitzroy, Australia
3
Department of Endocrinology and Diabetes, St Vincent’s
Hospital, Melbourne, Australia
4
Department of Endocrinology and Diabetes, Mercy Hospital,
Weribee, Australia
5
Department of Medicine, University of Melbourne, Fitzroy,
Australia
Aim: To follow clinical measures in Type-1 diabetes (T1D)
adults starting insulin pump (CSII) therapy.
Methods: A retrospective review of data of T1D adults
commencing CSII therapy in diabetes clinics. Data collected
included: age, T1D duration, blood pressure (BP), BMI, HbA1c,
lipids, and urinary albumin to creatinine ratio (ACR). Results are
mean – SD.
Results: Data were available from before to up to eight years
after CSII initiation for 88 (34% males) of 103 subjects who
commenced CSII in or after 2003. Age and diabetes duration at
CSII-initiation was 37.5 – 11.5 and 16.0 – 9.3 years respectively. Eleven % of subjects were < 25 years old, 39% were 25–
35 years, 25% were 35–45 and 25% were > 45 years. BMI
was 28.2 – 4.6 kg/m2. BP 123 – 12/75 – 5 mmHg. Follow-up
was 3.9 – 2.4 (range 0.33–8) years. Pre CSII HbA1c (Fig. 1) was
7.8%, with 19% of subjects with HbA1c < 7% at baseline and
38% at year 1 post-CSII. Lipids (mmol/L) were: total cholesterol
4.6 – 0.9, HDL-C 1.6 – 0.4, LDL-C 2.5 – 0.8 and (median(Q1Q3)) triglycerides 1.0(0.6–1.4). Urine ACR (median(Q1-Q3))
was 0.1(0.1–0.5) mg/mmol. Annual mean – SEM HbA1c are
shown in the Figure, with the inset showing HbA1c in the first
2 years.
Conclusions: In T1D adults commencing CSII in our clinics,
mean HbA1c fell from 7.8% to 7.2% at one year, and remained
significantly lower for up to 4 years. In the few patients with longer
follow-up, HbA1c returned towards baseline. Internationally,
O-54
ACCURACY OF A NEW PATCH PUMP, THE JEWEL
PUMP (DEBIOTECH) COMPARED TO THAT
OF TRADITIONAL PUMPS
S. Franc1, L.D. Piveteau2, A. Daoudi3, F. Neftel2,
G. Charpentier3
1
Department of Diabetes, Sud-Francilien Hospital,
Corbeil-Essonnes, France
2
SA, Debiotech, Lauzanne, Switzerland
3
Research Center, Ceritd, Corbeil-Essonnes, France
For patients with insulin-treated diabetes, patch pumps should
soon replace conventional pumps. The Jewel patch pump (JP) is a
smart pump equipped with an electromagnetic motor and no
tubing. We aimed to compare the in vitro JP accuracy to that of
conventional pumps (AccuChek/Combo (AC), Medtronic/
MiniMed (MN), AnimasVibe (AV) and OmniPod (OP)).
The evaluation consisted in a continuous weighing of the infused liquid with a Sartorius MC5 high precision balance. Data
were recorded in the infuscale and processed, in accordance with
the IEC/EN601-2-24 standard.
For a rate of 1U/h, the average flow error tested with three
samples for each pump model was + 1.2% with the JP vs - 1.5
and - 0.7% respectively with the MN and OP pumps, the absolute difference between the three pump models being not significant. At least, for a flow rate of 1U/h and considering short
periods of time (15 and 30 minutes), the accuracy measured with
the method of the trumpet curves, was significantly better with
the JP than with the MN and OP pumps (p < 0.01); similar results
were obtained for the infusion repeatability study.
In conclusion, for a basal rate of 1U/h and for a 24-hour period,
the Jewel pump shows similar accuracy of infusion as conventional pumps in vitro; regarding the infusion repeatability for
short periods, the JP did significantly better. The clinical impact
of these results has to be tested in sensitive systems such as
closed loop systems.
O-55
CONTINUOUS INTRAPERITONEAL INSULIN
INFUSION IN TYPE 1 DIABETES:
A 6 YEAR POST TRIAL FOLLOW-UP
P. van Dijk1, S.J.J. Logtenberg2, K.H. Groenier3,
R.O.B. Gans2, N. Kleefstra1, H.J.G. Bilo1
1
Diabetes Centre, Isala Clinic, Zwolle, Netherlands
Internal Medicine, University Medical Centre Groningen,
Zwolle, Netherlands
3
General Medicine, University Medical Centre Groningen,
Zwolle, Netherlands
2
Continuous intraperitoneal insulin infusion (CIPII) with an
implantable pump is a last resort treatment option for patients
with brittle diabetes. Aim was to describe long-term metabolic
control, quality of life (QoL) and treatment satisfaction among
T1DM patients treated with CIPII, and compare this with their
previous subcutaneous (SC) mode of therapy.
Retrospective, longitudinal analysis of patients with T1DM
treated with CIPII. Data from a previous randomized cross-over
trial using CIPII and SC therapy were compared with 2012 data.
QoL was measured using the SF-36 and WHO-5 questionnaires
and treatment satisfaction using the DTSQ.
Nineteen patients (52.6% male, mean age 45.8 – 9.9 years,
diabetes duration 24.9 – 17.3 years) were included. Duration of
follow-up was 6.4 – 0.4 years. Mean HbA1c in 2012
(65.3 – 23.2 mmol/mol) did not differ from HbA1c at the end of
the CIPII (7.1 mmol/mol (95% CI - 3.3, 17.5) and SC treatment
phase (-0.1 (95%CI - 10.5, 10.3)). The number of severe hypoglycaemic events in 2012 was lower compared to the SC
treatment in 2006 and more time was spent in hyperglycaemia.
QoL remained stable using CIPII and treatment satisfaction was
better than with SC therapy. Seven CIPII related complications
necessitated re-operation with a hospital admission duration of
0.6 (IQR 0.3, 0.8) days.
Among patients with T1DM treated with CIPII, long-term
metabolic control and QoL remains stable over time. Treatment
satisfaction with CIPII is superior to SC insulin and complications are scarce. CIPII is a safe and effective treatment option
for selected patients with T1DM.
O-56
EXTENDED INSULIN BOLUSES CANNOT CONTROL
THE POSTPRANDIAL GLUCOSE RISE AS WELL
AS STANDARD BOLUS FOR PERSONS
USING INSULIN PUMP THERAPY
P. Lopez1, B. King1, C. Smart1, C. Morbey2
1
Paediatric Endocrinology, John Hunter Children’s Hospital,
Newcastle, Australia
2
Endocrinology, John Hunter Hospital, Newcastle, Australia
Background: Extended insulin pump boluses (EBs) have been
recommended for high fat and protein meals and banquets, however early postprandial hyperglycaemia has been shown. We
aimed to determine if an EB could control the postprandial glucose
rise as well as a standard bolus (SB) after a standardised meal.
A-21
Methods: Twenty children and adults participated in a randomised, repeated-measures trial comparing the glycaemic excursions following five different EBs of insulin with a SB as
control. The insulin dose was determined according to the participants’ insulin: carbohydrate ratio. The EB was delivered over
2 hours. EB100 = 100% of the insulin dose per hour (i.e. 200%
normal insulin dose), EB50 = 50% insulin dose per hour,
EB33 = 33% insulin dose per hour, EB25 = 25% insulin dose
per hour and EB16 = 16% insulin dose per hour. Continuous
glucose monitoring assessed glucose levels for 2 hours following
the test meal.
Results: Figure 1 shows the postprandial glycaemic excursions following the test meal. The postprandial glycaemic excursion at 60 min was lower for SB compared to all EBs
(p < 0.05). The area under the curve was lower for SB compared
to all EBs (p < 0.05). The peak postprandial glycaemic excursion was lower for SB compared to all EBs.
Conclusions: The EB results in higher postprandial glycaemic
excursions at 1 hour than a SB, regardless of the total bolus
insulin dose. The EB was unable to adequately control the
postprandial glucose rise.
O-57
OPT2MISE: RANDOMIZED CONTROLLED TRIAL
COMPARING INSULIN PUMP THERAPY
WITH MULTIPLE DAILY INJECTIONS IN TYPE 2
DIABETES — RESEARCH DESIGN AND METHODS
R. Aronson1, O. Cohen2, I. Conget3, S. Runzis4, J. Castaneda4,
S. de Portu4, S. Lee4, Y. Reznik5
1
Executive Director, LMC Diabetes & Endocrinology, Toronto,
Canada
2
Institute of Endocrinology, Ch. Sheba Medical Centre,
Tel Hashomer, Israel
3
Diabetes Unit. Endocrinology and Nutrition Department,
Hospital Clı́nic i Universitari, Barcelona, Spain
4
Medtronic International Trading Sàrl, Medtronic, Tolochenaz,
Switzerland
5
Endocrinology & Diabetes Department, Centre Hospitalier
Régional Universitaire de Caen Côte de Nacre, Caen, France
Background: In type 2 diabetes (T2D), current insulin therapy approaches have not consistently achieved optimal glycemic
control. Previous studies have suggested benefit to continuous
subcutaneous insulin infusion (CSII) in these patients. The
OPT2MISE study is a multicenter, randomized, trial comparing
CSII to multiple daily injection (MDI) of insulin in a large cohort
of T2D subjects with persistent hyperglycemia.
Methods: Subjects were enrolled into a run-in period to optimize their MDI regimen. Subjects with persistent hyperglycemia (HbA1c ‡ 8%) were randomly assigned to CSII or
continuing an MDI regimen. The primary endpoint was the
between-group difference in mean HbA1c change from baseline
to 6 months. Secondary endpoints included change in mean 24hour glucose values; area under the curve, time spent in hypoglycemia and hyperglycemia; measures of glycemic excursions;
change in postprandial hyperglycemia; and treatment satisfaction and safety endpoints including hospitalizations and emergency room visits.
Results: Subject enrollment was completed in May 2013. 590
patients were screened and 495 were enrolled into the run-in
phase. 164 patients (33.1%) benefited from the run-in phase titration and were not randomized. A total of 331 patients, from
A-22
35 investigative sites from Europe, Canada, Israel, USA and
South Africa, were successfully randomized.
Study completion for the Primary endpoint is expected in
January 2014.
Conclusions: OPT2MISE represents the largest comparison
of CSII to MDI in a cohort of T2D patients with persistent
hyperglycemia despite optimized MDI therapy. OPT2MISE
will help define the role of CSII in insulin intensification including safety, hypoglycemia, patient adherence and treatment
satisfaction.
O-58
DEVELOPING PAQ: A SAFE AND EASY TO USE
INSULIN DELIVERY DEVICE
1
2
3
L.C. Lilly , A.Y. Strohlic , J. Warner
1
Clinical Research, CeQur, Marlborough, USA
2
Human Factors Engineering, UL-Wiklund (a UL LLC
Company), Concord, USA
3
Commercial and Clinical Development, CeQur, Marlborough,
USA
Aim: To develop an insulin delivery device for people with
type 2 diabetes mellitus (T2DM) that is safe and easy to use.
Usability testing was utilized throughout PaQ development to
assess prospective users’ ability to assemble, fill, prime, and
apply PaQ, as well as deliver boluses doses and interpret communication signals, without committing use errors that could
lead to user harm.
Methods: Usability tests, simulating PaQ use, involved 93
untrained and trained people with T2DM and/or diabetes educators. Participants performed hands-on tasks using PaQ and its
user documentation. Use errors were documented and participants’ ratings of each task’s ease of completion (1 = difficult,
7 = easy) and use-safety (1 = low, 7 = high) were collected.
Results: Use errors were identified with assembly and bolus
dosing, as well as interpreting user documentation. Improvements to PaQ and user documentation were implemented and
assessed with follow-up usability testing resulting in reduced use
error rates. Ease of task completion averaged 5.9 for PaQ assembly, 6.9 with bolus dosing, with and without distraction, and
6.8 for interpreting communication signals. Use-safety ratings
associated with preparing the device for use and interpreting
communications signals averaged 6.7 and 6.8, respectively.
Ratings for delivering bolus doses with and without distraction
averaged 6.4.
Conclusions: Usability testing provided valuable input in the
iterative development of PaQ and its user documentation.
Iterative testing and redesign mitigated safety-related use errors
prior to clinical testing, and resulted in a product that the intended
users reported was easy and safe to use.
O-59
MODULAR ARCHITECTURE OF CLOSED-LOOP
CONTROL – THE BLUEPRINT FOR SEQUENTIAL
PRODUCT DEVELOPMENT OF THE ARTIFICIAL
PANCREAS
B.P. Kovatchev1
1
Center for Diabetes Technology, University of Virginia,
The next logical step in artificial pancreas (AP) development
is the gradual transition of the AP into product development and
mainstream ambulatory use. A critical element of this transition
would be wide availability of outpatient Modular AP Systems
(MAPS) capable of running closed-loop algorithms and communicating with CGMs and insulin pumps. Running MAPS on
consumer electronics (e.g. smart phone, Google Glass) will drive
a paradigm shift in the technology-based treatment of diabetes by
allowing any sufficiently capable mobile device to become inherently a medical system running closed-loop control.
The key characteristics of MAPS are:
Informed by a Body Sensor Network;
Modular – layered architecture that distributes data pro-
cessing tasks across various application modules; individual modules are easily replaceable;
Scalable – naturally supports new and expanded functionality and multiple data sources;
Local and Global modes of operation – certain processes
and patient interaction are available through the portable
device; other services and analytics are available via
telecommunication.
In this presentation, we introduce a multi-module architecture
of MAPS consisting of system level (e.g. medical OS), sensor/
pump interface, safety modules (e.g. prevention of hypoglycemia), real-time control modules, and Cloud interface.
We conclude that the artificial pancreas is a mobile medical
network which coordinates multiple devices and multiple
control modules. Such a modular structure allows the sequential deployment of treatment modalities in the field, beginning with mitigation of hypoglycemia and progressing with
control-to-range and fully-automated closed loop. Regulatory
environment and clinical preferences favor the concept of
MAPS as a vehicle towards AP product development.
O-60
ARTIFICIAL PANCREAS USING INTRA-PERITONEAL
INSULIN DELIVERY: WHY SHOULD IT BE
DEVELOPED AND HOW TO MOVE TOWARD
MARKET APPROVAL
E.M. Renard1
1
Endocrinology Diabetes & Nutrition Dept., Montpellier
University Hospital, Montpellier, France
The pharmaco-kinetics and –dynamics of subcutaneous (SC)
insulin represent a true challenge for closed-loop delivery. The
prevention of post-meal hyperglycemia and hypoglycemia following physical exercise leads to very sophisticated algorithms
aiming at the modulation of insulin delivery following mandatory announcements of carbohydrate intakes or exercise practice.
Some models include glucagon infusion to counteract excess of
insulin action in late post-meal or post-exercise periods. The
usefulness of a quicker and shorter insulin action is consensually
admitted. Intra-peritoneal (IP) insulin infusion route has shown
quicker insulin action and return to baseline thanks to a more
direct insulin absorption combined with a liver-oriented distribution. Lower peripheral plasma insulin level and restored glucagon response to hypoglycemia and to exercise are other
characteristics. IP delivery systems have remained confidential at
the market level although still very useful for patients with disorders of SC insulin absorption or high blood glucose variability
resulting in recurrent severe hypoglycemia. Integration of IP
delivery in closed-loop trials has shown effectiveness in reducing
post-meal hyperglycemia and reaching very stable overnight
basal control. These results match well with the wish of a quicker
and very reproducible insulin action. The patients who present
high variability in insulin action would be the first candidates for
closed-loop delivery with IP route but indications could extend to
a wider population who expect further reduction of the device
burden associated with current closed-loop systems. Evolution
toward market approval will need both a wider experience with
IP insulin delivery systems and further trials documenting the
benefits for closed-loop.
O-61
MONOGENIC DIABETES: UPDATE IN DIAGNOSIS
AND TREATMENT
L. Philipson1, S.A. Greeley1, R.N. Naylor1, J. Hwang1,
D. Carmody1, G.I. Bell1
1
Medicine / Kovler Diabetes Center, University of Chicago,
Chicago IL, USA
Here I will describe our web-based registry for monogenic diabetes (MDM) (http://monogenicdiabetes.uchicago.edu/
neonatal-registry/). Low-cost web-based tools, including surveys,
A-23
discussion groups and electronic data capturing has facilitated
enrollment and support for patients with MDM. For diabetes
presenting in the first year of life (neonatal diabetes mellitus,
NDM), the registry has helped identify mutations in >140 patients. The most common mutations are in the genes encoding the
two subunits of the ATP-sensitive potassium channel, KCNJ11
(n = 78) and ABCC8 (n = 20). Over 90% have been transitioned
from insulin to oral sulfonylurea therapy. Those with abnormalities in chromosome 6q24 (n = 20) may have early transient
diabetes with recurrence of hyperglycemia in early adulthood.
Through longitudinal follow-up and recruitment for dynamic
studies we have seen benefit from non-insulin based therapies.
These are dramatic example of personalized genetic medicine
leading to improved glucose regulation and quality of life with
decreased costs. Maturity-onset diabetes of the young (MODY)
is a clinically heterogeneous group of monogenic disorders
characterized by autosomal dominant inheritance of youngonset, non-insulin-dependent diabetes. A correct genetic diagnosis can yield appropriate treatment, identifies associated
syndromes, and help at-risk family members and future generations. Recent identification of >200 individuals with
MODY through our registry shows genetic testing in a population with increased prevalence of MODY can be costeffective. Our results make a compelling argument for routine
coverage of genetic testing costs in patients with a high clinical
suspicion of MODY, confirming the importance of a diagnosis of MDM and the utility of web-based technologies for
attracting subjects.
O-62
CURRENT THINKING FOR THE DIAGNOSIS
AND TREATMENT OF CYSTIC-FIBROSISRELATED-DIABETES
I. Hirsch1
1
Med Ctr-Roosevelt, University of Washington, Seattle, USA
Since CF impacts pancreatic endocrine function, cysticfibrosis-related-diabetes (CFRD) is common. After the age of
30 years about 40–50% of individuals have CFRD. While microvascular disease is starting to be seen more often, cardiovascular disease has never been reported.
One of the greatest controversies is how often individuals with
CF should be screened for diabetes. Current guidelines state this
should be done yearly after the age of 10 years, yet the only way
to diagnose this population is with an oral glucose tolerance test
which is burdensome and often not done. Furthermore, hypoglycemia is not uncommon at the end of this test, mostly likely
related to a delayed glucagon response.
The other major controversy is the impact of glycemic control
on pulmonary function. The one intervention study showed a
statistically significant (but clinically insignificant) improvement
of BMI but no change in pulmonary function.
Given these individuals are living much longer due to improved treatments, including lung transplants, it seems that since
we have definitive proof about the impact of tight control on
microvascular complications in both type 1 and type 2 diabetes,
the same is extremely likely to be the case with CFRD.
The other practical issues are the many issues that impact the
diabetes treatments on a regular basis. Frequent infections, steroid therapy, advanced liver disease, and pregnancy can all
complicate the diabetes management, thus a team expert in the
care of this population should ideally manage these patients.
A-24
O-63
ALTERATION IN GLUCOSE DYNAMICS FOLLOWING
WITHDRAWAL OF USUAL THERAPY AND
CLOSED-LOOP INSULIN DELIVERY
IN INSULIN-NAIVE TYPE 2 DIABETES SUBJECTS
H. Thabit1, K. Kumareswaran1, A. Haidar2, L. Leelarathna1,
K. Caldwell1, M. Nodale1, M.E. Wilinska1, A.M. Umpleby3,
M.L. Evans1, R. Hovorka1
1
Wellcome Trust-MRC Institute of Metabolic Science,
University of Cambridge Metabolic Research Laboratories,
Cambridge, United Kingdom
2
Institut de Recherches Cliniques de Montréal,
McGill University, Montreal, Canada
3
Postgraduate Medical School, University of Surrey,
Guilford, United Kingdom
Discontinuation of antihyperglycemic oral agents and initiation of insulin is recommended in certain clinical situations for
inpatients with type 2 diabetes (T2D). We studied alterations in
glucose turnover following withdrawal of non-insulin therapy.
Twelve subjects with insulin-naive T2D were studied during
two 24-hour visits. During control visit, subject’s usual antihyperglycaemic therapy was continued. At another visit, usual
therapy was discontinued and replaced by closed loop insulin
delivery. Subjects consumed 50–80 g carbohydrate at each meal,
matched for both visits. Stable-label [6,6-2H2]glucose was infused intravenously to measure the systemic glucose appearance
and glucose disposal.
Plasma glucose during both visits were comparable (p = 0.57).
Glucose appearance (Ra) significantly increased during the day
[21.4 (19.5, 23.5) vs. 18.6 (17.0, 21.6) lmol/kg/min, p = 0.019]
and decreased overnight [9.7 (8.5, 11.4) vs. 11.6 (10.3, 12.9)
lmol/kg/min, p = 0.004] when usual therapy was discontinued
but no difference over 24-hours was observed (p = 0.79). Similarly, increased glucose disposal (Rd) was observed during the
day [21.2 (19.4, 23.9) vs. 18.8 (18.3, 21.7) lmol/kg/min,
p = 0.002] and decreased overnight [10.4 (9.1, 12.0) vs. 11.8
(10.7, 13.7) lmol/kg/min, p = 0.005] when closed loop replaced
usual therapy. There was increased hepatic insulin resistance [1.4
(0.8, 2.5) vs. 1.3 (0.6, 2.2) mmol/kg/min · pmol/l, p = 0.023] and
decreased peripheral insulin sensitivity [0.05 (0.03, 0.07) vs. 0.06
(0.04, 0.08) lmol/kg/min per pmol/l, p = 0.034] when usual
therapy was discontinued.
Discontinuation of non-insulin therapy affects glucose turnover by altering Ra and insulin sensitivity, highlighting the need
of appropriate insulin dose adjustments to compensate for these
changes.
overnight closed loop. We tested the safety of overnight operation of a closed loop system, using a proportional-integral-derivative (PID) algorithm, with the maximum permissible
calibration error prior to starting.
Methods: 8 subjects with type 1 diabetes were recruited. They
underwent overnight closed loop control in a clinical research
facility on two occasions. A calibration error of 30% was deliberately induced on one of the experiments in random sequence. YSI glucose was measured every 30 minutes through the
night [11pm–6am]. We present preliminary analysis of the first 5
paired experiments
Results: 5 subjects [2 male and 3 female] with type 1 diabetes
treated with insulin pump therapy have been studied till date. The
mean absolute error on calibration was 23.3%. Mean YSI glucose
was 115 mg/dl vs 108 mg/dl between the two arms and there was
no difference in time < 70 mg/dl [5.5 vs 6.2% control vs error;
p = NS]. There was a reduction in time > 180 mg/dl [4.3% vs
0.0%; p = 0.34].
Summary: The PID based overnight closed loop system can
accommodate at least a 30% error in initial calibration without
detriment to the patient. Given the likelihood of patients starting
closed loop on a rapidly changing glucose, this information enhances the safety of the system.
O-65
O-64
SAFETY OF AN OVERNIGHT CLOSED LOOP SYSTEM
WITH INDUCED CALIBRATION ERROR
P. Choudhary1, S. Amiel1, A. Roy2, J. Han2, N. Kurtz2,
B. Keenan2
1
Diabetes, King’s College London, London, United Kingdom
2
Diabetes, Medtronic Ltd, Northridge, USA
Introduction: Closed loop systems rely on sensor glucose
values to determine insulin dosing which in turn are reliant on
calibration by capillary glucose readings. Capillary and interstitial glucose concentrations may differ during rapid glucose
fluctuations such as in the post-meal phase prior to starting
CLINICAL TRIAL OF AN ARTIFICIAL PANCREAS
WITH LARGE UNANNOUNCED MEALS
F. Cameron1, G. Niemeyer 2, D. Wilson3, K. Benasi3,
P. Clinton3, B.W. Bequette1, B. Buckingham3
1
Chemical and Biological Engineering, Rensselaer Polytechnic
Institute, Troy, USA
2
Imagineering, Disney, Los Angeles, USA
3
Pediatric Endicronology, Stanford University, Stanford, USA
Closed-loop control of blood glucose (BG) levels in people
with type 1 diabetes can reduce patient burden and the incidence
of complications. We tested a multiple model probabilistic predictive controller (MMPPC) on six patients. Each admission
lasted for 32 hours with five unannounced meals each containing
1 g/kg of carbohydrate (CHO).
The controller used an Abbott Navigator CGM and Insulet
Omnipod insulin pump implemented through the UCSB artificial
pancreas system. Therapy began at 9 AM with unannounced meals
at 9 AM, 1 PM, 5:30 PM, and 9 AM and 1 PM the next day. The
patients had a mean ( – SD) HbA1C of 7.3 – 0.6%, age of 28 – 5
years, total daily dose of 43 – 13 U, and weight of 74 – 13 kg.
The algorithm predicts the BG value with explicit uncertainty
estimates. Insulin boluses are calculated to maintain a roughly 3%
risk of BG levels below 80 mg/dl. At night, a target of 100 mg/dl
was used, with attenuated control providing smooth corrections.
On a 24-hour basis, the mean reference/CGM values of 161/
142 mg/dl, with 63/78% of time spent between 70 and 180 mg/dl.
One CHO intervention was given for a nocturnal glucose of
66 mg/dl with a rate of change of - 0.25 mg/dl per min. Three
CHO interventions occurred due to system failures. For the 30
unannounced meals the mean pre-meal, post-meal maximum,
and 3-hour post-meal values were 139/132, 223/208, and 168/
156 mg/dl respectively.
The MMPPC was tested in-clinic against repeated, large, unannounced meals and maintained good control overnight and
during meals.
O-66
OVERNIGHT CLOSED-LOOP CONTROL WITH A
PROPORTIONAL-INTEGRAL-DERIVATIVE BASED
ALGORITHM IN CHILDREN AND ADOLESCENTS
WITH TYPE 1 DIABETES AT DIABETES CAMP
T. Ly1, P. Clinton1, D.B. Keenan2, A. Roy2, J. Han2,
B. Grosman2, M. Cantwell2, N. Kurtz2, D.M. Wilson1,
B.A. Buckingham1
1
University Medical Center, Stanford, USA
2
Medtronic Minimed, Medtronic, Northridge, USA
The Medtronic Android-based proportional-integral-derivative
with insulin feedback (PID-IFB) system is designed for overnight
closed-loop (OCL) control in patients with type 1 diabetes. The
automated system consists of a Revel 2.0 insulin pump and Enlite
glucose sensor, PID-IFB algorithm based on an Android phone,
Bluetooth-RF translator and remote monitoring capabilities.
The objective was to evaluate the efficacy and safety of this
OCL controller in participants (10–35 years) with type 1 diabetes
on insulin pump therapy, in a camp setting.
Participants were randomized to either OCL (n = 50) or
sensor-augmented pump (control) (n = 52) on alternate nights in
up to 6 consecutive nights at camp. There were 21 subjects with
mean – SD age 14.7 – 3.9 y, duration of diabetes 7.9 – 5.3 y
and A1C 7.9 – 1.4%. OCL was commenced in 50 of 55 potential
nights (91%). Full OCL lasting a minimum 6 hours was achieved
in 37 (67%) nights. OCL was stopped in 18% of nights due to
sensor error being > 20%, 4% due to a sensor failing to pass a
performance evaluation upon restarting OCL and 2% due to loss
of communication between devices.
The median (IQR) percent time spent between 70–150 mg/dL
was 46% (32,76) for controls vs. 86% (58,98) for full OCL
(n = 37), P < 0.001. There was less time spent in the hypoglycemic range < 70 mg/dL with a median 9% (0,39) in the control
period vs. 0% (0,0) in full OCL, P < 0.001.
Overnight closed-loop control with the Android-based PIDIFB controller resulted in a significant reduction in nocturnal
A-25
hypoglycemia and increased time spent in range compared to
sensor-augmented pump therapy.
O-67
CLINICAL ASSESSMENT OF A RETROFITTING
ALGORITHM FOR A POSTERIORI ENHANCEMENT
OF CGM TRACES
S. Del Favero1, A. Facchinetti1, G. Sparacino1, C. Cobelli1,
on behalf of the AP@home consortium2
1
Information Engineering, University of Padova, Padova, Italy
Italy
2
Objective: When assessing new diabetes therapies in outpatient trials, only a few blood glucose (BG) references can be
collected and the sole use of unprocessed Continuous Glucose
Monitoring (CGM) may lead to under/overestimation of the indicators quantifying treatment efficacy.
Recently, we proposed a ‘retrofitting’ algorithm (Del Favero
et al., ATTD 2013) that produces accurate continuous-time BG
profile by simultaneously exploiting the accuracy of the few BG
references available and the high temporal-resolution of CGM.
Here we assess the method on a large clinical dataset, showing
that it reduces the error in outcome-metrics computation with
respect to the use of unprocessed CGM.
Method: The retrofitting algorithm was tested on data of 47
subjects studied within a trial of the AP@home project (Luijf et
al., Diabetes Care, in press). Each patient underwent three 20 hadmissions. Frequent YSI measurements were available: about
12 references/day were given to the algorithm to enhance CGM
and the remaining (about 80% of the collected ones) were used
for testing the reconstructed profile.
Result: The retrofitted profile were more accurate than unprocessed CGM: MAD was reduced by 48.5% (almost halved)
and MARD was reduced by 47.86%. Error in the evaluation of
time below 70 mg/dl and time in target [70–180]mg/dl reduced
by 45.7% and 64.8%, respectively, when compared to the unprocessed CGM.
Conclusion: The use of the retrofitted profile rather than unprocessed CGM reduces errors in assessing treatment-efficacy.
O-68
UTILIZING PHYSICAL ACTIVITY TRACKERS
IN MOBILE DIABETES SELF-MANAGEMENT
M. Muzny1, E. Årsand 2, G. Hartvigsen3
1
Spin-off Application Centre, First Medical Faculty
of Charles University, Prague, Czech Republic
2
Norwegian Centre for Integrated Care and Telemedicine,
University Hospital of North Norway, Tromsø, Norway
3
Department of Computer Science, University of Tromsø,
Tromsø, Norway
For people with diabetes, continuous feedback about their
physical activity can be of importance for maintaining a healthy
blood glucose level. A variety of activity trackers are available
on the market today. Their step-counting functionality is frequently accompanied by an estimation of energy expenditure.
Unfortunately, these sensors’ automatic data interpretation does
not provide additional information about physical activity and
are hard to integrate in digital diabetes diaries. Their unprocessed
data itself do not shape particular activities, but holds a potential
A-26
2
Steno Diabetes Center, Steno Diabetes Center, Gentofte,
Denmark
3
CGM R&D, Medtronic Diabetes, Northridge CA, USA
4
Medtronic International Trading Sàrl, Diabetes, Tolochenaz,
Switzerland
5
Medtronic R&D, Diabetes, Hoersholm, Denmark
6
Medtronic, Bakken Research Center, Maastricht, Netherlands
FIG. 1. Overview of multiple Fitbit devices in the context
of activity data import into the Diabetes Diary application
through the associated Web-service.
to render such information in connection with mobile-phonebased applications.
The solution we present provides a compact and specific
overview of the user’s daily physical activity. This is achieved
through the use of preprocessed records of steps and calories and
can easily be applied onto existing application architectures. In
our Diabetes Diary application [1] we access this data from a Fitbit
Flex activity tracker [2] and its Web-service [3] that records steps
and calories values captured in 1-minute intervals. The built-in
algorithm identifies basic activity types and corresponding intensity levels for significant segments of the logged data series.
This approach represents a promising way of helping patients
with managing physical activity as part of their diabetes selfmanagement. Its simplicity and straightforwardness shows a
potential for future usage, which could cover a wide selection of
activity tracking devices.
References:
1. Årsand E, Skrøvseth SO, Joakimsen RM, Hartvigsen G.
Design of an Advanced Mobile Diabetes Diary Based on a
Prospective 6-month Study Involving People with Type 1
Diabetes. The 6th International Conference on Advanced
Technologies and Treatments for Diabetes, February 27, –
March 2, 2013, Paris. France.
2. Fitbit Inc., 2013, Available from: http://www.fitbit.com/flex.
CA, USA.
3. Fitbit Inc., 2013, Available from: http://dev.fitbit.com/. CA,
USA.
O-69
PERFORMANCE, USER SATISFACTION AND SAFETY
EVALUATION OF CONNECTED CARE DEVICE IN
PATIENTS WITH DIABETES MELLITUS
H.J. Veeze1, E. Hommel2, D. Simm1, K. Rytter2, M. Gharib3,
A.S. Racault4, L.G. Rasmussen5, J. Castaneda6, H. Wenstad3,
R. Shah3
1
Diabetes Clinic and Research Centre, Rotterdam, Netherlands
Objective: To evaluate the performance, patient satisfaction,
and safety of the Connected Care device. The Connected Care
device transfers CGM and pump data to CareLink online every
5th minute, thereby making it available to patients and/or care
partners on their individual web connected devices such as
smartphones, tablets and PCs.
Methods: This was a multi-center, non-randomized premarket study of the Connected Care device. Forty subjects with
Diabetes Mellitus being treated with a Sensor-Augmented Pump
(SAP) participated for 15 days. Connectivity and usability of
Connected Care was evaluated and device related safety was
assessed. Subject and care partner acceptance of the Connected
Care device and training materials were measured by questionnaires using 7-point likert scale.
Results: Preliminary analysis on 19 T1DM subjects (12–26
years) shows overall average system connectivity of 22 – 2.45 hr/
d. On average, the mobile displays were viewed 11.08 times/d
with the highest frequency in evenings (6 PM-12 AM; 36.2% of
all views). The most frequent text message sent was regarding the
high glucose alarm (692 SMS sent). Questionnaire results indicated overall device feature satisfaction, with care partners being
more aware of the patient’s BG levels post-study (daytime:
77.8%; nighttime: 57.9% agreement).
Conclusion: Incorporating the Connected Care device into
everyday use for patients with Diabetes Mellitus that use SAP,
increases accessibility of CGM and pump data via web connected devices. It is projected to improve satisfaction, safety and
convenience for patients on SAP and their care partners. The
full dataset of 40 subjects will be discussed to support this
conclusion.
O-70
LONG-TERM TELEMONITORING OF PATIENTS
WITH DMT2: PRELIMINARY RESULTS OF THE
GREEK PILOT OF THE RENEWING HEALTH
MULTICENTER RANDOMIZED TRIAL
G.E. Dafoulas1, V. Giata2, H. Giannakakos3, P. Stafylas4,
V. Aletras5, K. Theodorou1, P. Pechlivanoglou6, G. Koukoulis7,
A. Bargiota7
1
Faculty of Medicine, University of Thessaly, Larisa, Greece
Telehealth Center, Intermunicipal Digital Community
of Central Greece, Trikala, Greece
3
University Hospital, 5th Regional Health Authority
of Thessaly and Sterea, Larisa, Greece
4
Medical Coordinator, HIM SA, Brussels, Belgium
5
Department of Business Administration, University
of Macedonia, Thessaloniki, Greece
6
Toronto Health Economics and Technology Assessment
Collaborative, University of Toronto, Toronto, Canada
7
Department of Endocrinology and Metabolic Diseases,
University Hospital, Larisa, Greece
2
Objective: To study the impact of a long-term telemonitoring
program for patients with type 2 diabetes mellitus (DMT2) on
glycemic control and health-related quality of life (QoL) compared to usual care.
Participants: 154 patients with DMT2 capable to use the
telemonitoring device, with an HbA1c > 53 mmol/mol (7.0%
according to NGSP), were randomly assigned in the telemonitoring (I), (N = 74) and the control (C), (N = 80) group
after having signed the informed consent.
Methods: In the (I) group patients’ blood glucose profiles
were collected weekly using a mobile phone health platform, for
a period of one year. Allocated health professionals provided by
phone the appropriate counseling on lifestyle and medication
changes when required. Patients in (C) group received usual care
with face-to-face consultations. QoL was assessed using a generic (SF36v2) questionnaire and a disease-specific questionnaire, the Problem Areas in Diabetes (PAID) scale. (Local Trial
Registration NCT01498367.)
Results: A greater reduction in HBA1C was observed in the
telemonitoring group [(I) - 1.27, (C) - 0.85, p = 0.001]. There
was a statistically significant improvement in the generic QoL,
both in the mental component summary [MSC: (I) + 3.46, (C)
- 3.24, p = 0.000] and in the physical component summary
[PSC: (I) + 1.17, (C) - 1.26, p = 0.00] in the telemonitoring
group. Disease specific QoL was also significantly improved in
the intervention group compared to control (11.25 PAID score
units, 95% CI, p = 0.000).
Conclusion: Our preliminary results indicate that home telemonitoring is more effective in improving glycemic control and
QoL in DMT2 patients compared with the usual care.
O-71
NOVEL MENDOR BALANCE GLUCOSE PROFILING
TOOL SHOWS SIGNIFICANT POST-MEAL BLOOD
GLUCOSE EXCURSIONS IN INSULIN-TREATED
TYPE 2 DIABETIC PATIENTS
A. Virkamaki1, J.J. Westerbacka1, J. Kaukua2
1
2
Diabetes Clinic, Mehilainen, Helsinki, Finland
Diabetes, Sanofi, Helsinki, Finland
Background: Majority of patients with type 2 diabetes on
basal insulin are uncontrolled but real-life glucose excursions in
this population are unknown.
Methods: 70 uncontrolled (HbA1c > 7%) type 2 diabetes
patients on stable dose of basal insulin – oral medications were
recruited in Finland. Any other injectables (meal insulin, premixed insulin or GLP-1 agonists) were not allowed. Mendor
Balance was used as a novel tool for glucose profiling to investigate post-meal blood glucose excursions.
FIG. 1.
A-27
Patients were introduced the Mendor Balance, which analyses blood glucose profile automatically from three daily routines (sleep, breakfast and main meal). Subjects performed
carefully-timed measurements before bedtime and at wake-up
(overnight pairs) and before and 1.5–2.5 h after each meal
(breakfast pairs and main meal pairs). Over 2 mmol/L average
post-meal excursion was considered clinically significant.
Results: 90% of subjects completed profiling successfully.
Interim analysis showed that 79% of subjects showed at least
+ 2 mmol/L average breakfast excursions, whereas excursions on
main meal were not as frequent (56%). Overnight negative excursions more than - 4 mmol/L occurred in 48% of the subjects.
Conclusions: Glucose profiling using Mendor Balance, is a
simple, high-compliance tool to evaluate blood glucose profiles
in real-life setting. Vast majority of uncontrolled patients with
type 2 diabetes on basal insulin have significant post-meal
excursions.
O-72
INTRADERMAL INSULIN INFUSION ACHIEVES
FASTER INSULIN ACTION THAN SUBCUTANEOUS
INFUSION FOR THREE DAY WEAR
E. McVey1, D. Sutter1, C. Rini1, L. Nosek2, C. Kapitza2,
K. Rebrin3, R. Pettis1
1
Advanced Medical Technologies, BD Technologies,
Research Triangle Park, USA
2
Operations, Profil Institut fur Stoffwechselforschung GmbH,
Neuss, Germany
3
Diabetes Care, BD Medical, Billerica, USA
Aims: This study investigated the ability of intradermal (ID)
basal/bolus delivery of a fast-acting insulin analog to maintain
an advantage of faster insulin action (Tmax) compared to
subcutaneous (SC) delivery over the course of a three day
infusion period. Pharmacodynamics (PD) and other measures
of device performance and patient experience were also
assessed.
Design: This was a single center, open-label, 2-period crossover study in 28 type 1 diabetes patients on continuous subcutaneous insulin infusion (CSII). Each subject was administered a
three-day infusion for each route across two in-clinic visits in a
randomized order. Insulin aspart (NovoRapid) was administered via an Animas Vibe insulin infusion pump connected to
a Medtronic Quick-Set (SC) or investigational intradermal
microneedle infusion set (1.5 mm, 34 gauge). Individual bolus
doses were determined based on the subjects’ insulin sensitivity.
At each visit bolus insulin infusions were given prior to a standardized breakfast and lunch test meal on each of the three
Illustration of a typical excursion analysis in the study (variation and average excursion)
A-28
treatment days. Before and after each bolus, blood was drawn to
measure insulin aspart and blood glucose in serum.
Results: ID bolus infusion had a significantly shorter Tmax
than SC infusion (D 20 minutes), and this difference was maintained over three days. Intra-subject variability of Tmax was
significantly smaller for ID delivery, but inter-subject variability
was not. For 0–2 hours post-prandially, the insulin and glucose
DAUC values were significantly larger and smaller, respectively,
with ID delivery.
Conclusion: The faster insulin action that ID delivery provides over SC can be maintained over a three-day basal/bolus infusion period.
O-73
EFFECTIVENESS OF TITRATION ALGORITHMS
WITH INSULIN GLARGINE IN PATIENTS WITH
TYPE-2 DIABETES MELLITUS
A. Pfützner1, B. Stratmann2, K. Funke3, H. Pohlmeier4,
L. Rose4, J. Sieber5, F. Flacke5, T. Forst6, D. Tschöpe2
0.4 U/kg Gla-100 once daily in randomised order. Trough values
of M0, M1 and M2 were determined for 7 days; a 36-h euglycaemic clamp was conducted on Day 8. M0, M2 and M1 were
quantified by LC-MS/MS (LLOQ 0.2 ng/mL).
Results: M1 was the principal active moiety circulating in
blood after administration of both Gla-100 and Gla-300. Trough
values of M1 were quantifiable after 2–3 injections regardless of
treatment. Steady state concentrations of M1 were achieved after
2 days for Gla-100, and 3–4 days for Gla-300. Trough concentrations of M0 and M2 were low and only detected in a few
samples in a few participants.
In steady state, M1 defined concentration time profiles which
were dose dependent and even flatter after Gla-300 administration than Gla-100 administration. Steady state M1 PK profiles
were consistent with those from unspecific radioimmunoassay
measurements.
Conclusion: Insulin glargine metabolism is the same after
administration of Gla-100 and Gla-300, and M1 is the main
circulating active component.
Study sponsored by Sanofi (NCT01349855).
1
IKFE-Services, Mainz, Germany
IKFE-Potsdam, Potsdam, Germany
3
HDZ, Bad Oeynhausen, Germany
4
Diabetes Research Center, Münster, Germany
5
Sanofi, Frankfurt, Germany
6
Profil Mainz, Mainz, Germany
2
In this study, we collect data regarding the effectiveness of
different dose titration algorithms (TA) for optimization or initiation of basal insulin supported oral therapy (BOT) in type 2
patients.
Methods: A total of 50 patients were enrolled in this trial (33
men, age: 63 – 8 yrs., 7.9 – 0.8%). The investigator decided on
an individual basis for one of four standard titration algorithms
(TA): standard (S: fasting glucose target 90–130 mg/dL, n = 39),
standard-fast titration (S-FT: 90–130 mg/dL, larger dose increments at FBG).
Investigator-initiated trial supported in part by Sanofi.
O-74
METABOLISM OF INSULIN GLARGINE
IN HUMANS IS THE SAME AFTER
ADMINISTRATION OF GLA-100 AND GLA-300
R. Schmidt1, K. Bergmann1, R. Dahmen1, R.H.A. Becker2
1
Research and Development, Sanofi-Aventis Deutschland
GmbH, Frankfurt am Main, Germany
2
Diabetes Division, Sanofi-Aventis Deutschland GmbH,
Frankfurt am Main, Germany
Aims: Investigational new insulin glargine U300 (Gla-300;
300 U/mL) has improved PK and PD profiles compared with Gla100 (100 U/mL). Insulin glargine (M0) is a 21A-Gly-modified
mimic of a human insulin intermediate with low solubility at
tissue pH, which is processed in vivo into soluble M1 (predominantly responsible for metabolic effects). This sub-study
compared metabolism of Gla-300 with Gla-100 in people with
T1DM.
Methods: Blood samples were collected during a doubleblind, 2-treatment, 2-period, 2-sequence cross-over study. Participants received 0.4 (n = 18) or 0.6 U/kg Gla-300 (n = 12), and
O-75
INVESTIGATIONAL NEW INSULIN U300: GLUCOSE
CONTROL AND HYPOGLYCAEMIA IN TYPE 2
DIABETES PEOPLE ON BASAL INSULIN
AND OADS (EDITION II)
R.M. Bergenstal1, M.C. Riddle2, M. Ziemen3, M. Wardecki4,
I. Muehlen-Bartmer5, E. Boelle5, H. Yki-Järvinen6
1
International Diabetes Center, Park Nicollet Institute,
Minneapolis, USA
2
Endocrinology Diabetes & Clinical Nutrition, Oregon Health
& Science University, Portland, USA
3
Research and Development, Sanofi-Aventis Deutschland
GmbH, Frankfurt am Main, Germany
4
Research and Development, Sanofi, Warsaw, Poland
5
Research and Development, Sanofi, Paris, France
6
Division of Diabetes, Helsinki University Central Hospital,
Helsinki, Finland
Aims: Investigational new insulin glargine U300 (Gla-300)
has even flatter and more prolonged PK and PD profiles than
insulin glargine 100 U/mL (Gla-100). EDITION II compared the
efficacy and safety of Gla-300 vs Gla-100 in people with T2DM
using basal insulin and OADs.
Methods: In this multicentre, open-label, 6-month study,
participants were randomised to Gla-300 or Gla-100 once daily
in the evening. Primary endpoint was change in HbA1c (baseline to month 6). First main secondary efficacy endpoint was
participants (%) with ‡ 1 severe or confirmed ( £ 3.9 mmol/L)
nocturnal hypoglycaemia (month 3–6).
Results: Gla-300 was non-inferior to Gla-100 for change in
HbA1c at month 6 (LS mean change - 0.57 [0.09] % and - 0.56
[0.09] %; difference - 0.01 [95% CI: - 0.14–0.12] %). Significantly fewer participants had ‡ 1 severe or confirmed nocturnal hypoglycaemia (month 3–6) with Gla-300 vs Gla-100
(87 [21.6%] vs 113 [27.9%]; RR 0.77 [95% CI: 0.61–0.99];
p = 0.038). A similar, consistent reduction in severe or confirmed nocturnal hypoglycaemia was observed during the first 8
weeks (13.2% vs 24.6%; RR 0.53 [95% CI: 0.38–0.75]) and
over the 6-month treatment period (28.3 vs 39.9%; RR 0.71
[0.58–0.87]).
Over the 6-month period, fewer participants experienced
‡ 1 nocturnal hypoglycaemic event with Gla-300 vs Gla-100
(30.5% vs 41.6%; RR 0.73 [95% CI: 0.60–0.89]), and any
hypoglycaemia at any time of day (71.5% vs 79.3%; RR
0.90 [95% CI: 0.84–0.97]).
Conclusion: Gla-300 provides similar effective glycaemic
control, with less confirmed or severe nocturnal hypoglycaemia,
compared with Gla-100.
Study sponsored by Sanofi (NCT01499095).
O-76
BRAIN RESPONSES TO FOOD INGESTION AFTER
ROUX-EN-Y GASTRIC BYPASS (RYGB): A [18F]FLUORODEOXYGLUCOSE POSITRON EMISSION
TOMOGRAPHY (FDG-PET) NEUROIMAGING STUDY
K.F. Hunt1, J.T. Dunn2, A.M. Pernet1, L.J. Reed3,
P.K. Marsden2, S.A. Amiel1
1
Diabetes Research Group, King’s College London, London,
United Kingdom
2
Imaging Sciences, King’s College London, London,
United Kingdom
3
Neuropsychopharmacology Unit, Imperial College, London,
United Kingdom
Background: Mechanisms of weight loss post-RYGB are
unclear. Modulation of appetite may contribute.
Aim: To investigate whether brain responses to food ingestion
are different post-RYGB compared to non-operated obese and
normal-weight subjects.
Materials and Methods: Twelve normal-weight (NW, age
32.3 – 9.3 years, BMI 22.3 – 1.4 kg/m2), nine obese (Ob,
age 32.7 – 10.1 years, BMI 33.8 – 2.6 kg/m2) and nine postRYGB (age 45.1 – 10.7 years, BMI 33.9 – 3.7 kg/m2) subjects
underwent FDG-PET neuroimaging twice: once FED, once
FASTED. Brain FDG uptake, a marker of neuronal activation,
was compared using Statistical Parametric Mapping. Satiety
was assessed using visual analogue scales and post-scan
ad-libitum meal.
Results: The FED state was associated with increased fullness
(p < 0.001) and reduced ad-libitum food consumption (p = 0.006).
Post-RYGB had higher fullness scores (p = 0.009) and lower adlibitum consumption (p = 0.021).
The FED state was associated with increased (voxelwise
p < 0.001, cluster-level-corrected p < 0.05) FDG uptake (neuronal activation) in interoceptive and reward regions (insula,
globus pallidus, ventral striatum, amygdala, hippocampus, ventral cingulate) and decreased uptake (deactivation) in inhibitory
control regions (dorsolateral frontal cortex (DLFC)) and default
mode network (DMN) (posterior cingulate, precuneus, angular
gyrus).
There were differences between groups in brain responses
to food ingestion (rmANOVA p < 0.01, cluster-size >50
voxels) in: medial orbital cortex (reward salience) with
activation post-RYGB versus deactivation in NW; inhibitorycontrol regions (DLFC) with deactivation in NW and postRYGB attenuated in Ob; and DMN, with exaggerated
deactivation post-RYGB.
Conclusions: Increased fullness and decreased food consumption post-RYGB are associated with differences in brain
responses to food ingestion. These differences may represent
negative rather than positive experiences of eating and improved
inhibitory control and may contribute to weight loss.
A-29
O-77
NEW INSIGHTS INTO OXIDATIVE MODIFICATION
OF PROTEINS IN DIABETES. GLYCATED ALBUMIN
AS A RELEVANT BIOMARKER
E. Bourdon1, F. Boyer1, J. Baraka Vidot1, A. Guerin Dubourg1,
D. Girard1, A. Catan1, C. Planesse1, P. Rondeau1
1
GEICO Laboratory, University of la Reunion,
St Denis cedex 9, Reunion
Oxidative stress and protein modifications are frequently
observed in numerous disease states. Albumin, the major
circulating protein in blood, can undergo increased glycoxidation in diabetes. Protein glycoxidation can lead to the
formation of advanced glycoxidation end products, which
induce various deleterious effects on cells.
Works in our group, revealed structural damages induced by
the glycoxidation of blood-purified Human Serum albumin
(HSA) and of albumin purified from diabetic patients.
Oxidative modifications was found to be enhanced in in vitro
or in vivo glycated albumin, after determination of their free thiol
group content, relative electrophoretic migration, carbonyl content. Impaired antioxidant and drug-binding capacities (warfarin
and ketoprofen) of glycated albumins were evidenced.
Also we identified deleterious pathophysiological effects of glycated albumin on human adipose and monocyte
cell lines as well. We observed an overgeneration of intracellular reactive oxygen species, impairments in proteasomal
activities and an accumulation of carbonylated proteins in
glycated-albumins treated cells. We established links between HSA modifications with the oxidative impact on the
protein structures and on cells pathophysiology.
Involvement of glycated albumin in diabetes pathology was
evidenced in vivo in a model of isolated perfuse rat heart and in
Db/Db transgenic mice.
All our recent data provide new information supporting albumin as an important biomarker to be considered for monitoring
diabetic pathophysiology.
O-78
TECHNICAL FEASABILITY AND SAFETY
OF ILEAL INTERPOSITION FOR TYPE-2
DIABETES–MULTI-CENTER DATA
S. Ugale1, A. Celik2
1
Advanced Laparoscopy & Metabolic Surgery, Kirloskar
Hospital, Hyderabad, India
2
Metabolic Surgery, Alman Hastanesi, Istanbul, Turkey
Introduction: In morbidly obese patients with type 2 diabetes
(T2DM), bariatric surgery offers effective treatment with low
mortality ( < 0.5%). Ileal Interposition with sleeve gastrectomy
(IISG) is a novel procedure, shown to be safe and effective in the
treatment of T2DM in morbidly obese as well as low weight
patients. We present our morbidity and mortality data and
technical feasibility with IISG surgery in poorly controlled type
II diabetic patients.
Methods: A total of 411 patients treated at 2 centers – Kirloskar Hospital, Hyderabad, India & Alman Hastanesi, Istanbul,
Turkey, between Feb 2008 to May 2013. Mean Age = 45.5; Sex
Ratio = 270 males and 141 Females; Mean BMI = 30.5. 65.7%
of the patients had BMI < 35 and 34.3% had BMI > 35 kg/m2.
Most patients had long standing diabetes (mean 10.3 years);
A-30
with a mean preoperative HbA1c of 9.41%. Follow-up from
5-65 months.
Results: Remission of T2DM (HbA1c < 6.5% without medication) in 81.2%; hypertension in 96.1% and dyslipidemia in
92.2%. Mean reduction in BMI was 6.27 kg/m2, 7.91 kg/m2,
10.41 kg/m2, 13 kg/m2 where preoperative BMI was < 30, 30–
35, 35–40 and > 40, respectively.
Total complication rate: 7,5%.
Mortality rate from procedure: 0.25%; Other Cause Mortality
– 1.7%
Conclusion: With this 2 center and 2 surgical teams study,
IISG is seen to be technically feasible with safety and sequelae
that are comparable with other Bariatric and Metabolic procedures, with a high remission rate for diabetes and other comorbidities, even in lower BMI patients.
O-79
INCREASED INSULIN CLEARANCE AND
NORMALIZATION OF C-PEPTIDE SECRETION
IN DIABETIC PATIENTS AFTER ROUX EN Y GASTRIC
BYPASS
J. Pender1, W. Pories1, W.H. Chapman1, R. Bowden1,
E. Tapscott2, M. Reed3, G.L. Dohm2
1
Surgery, East Carolina University, Greenville, USA
Physiology, East Carolina University, Greenville, USA
3
Kinesology, West Chester University, West Chester, USA
2
Introduction: We previously reported that Roux En Y gastric
bypass normalized fasting insulin and insulin response to a
mixed meal in diabetic patients. In this study we investigated
whether this was a result of changes in insulin secretion and/or
insulin clearance.
Methods: In nine obese-diabetic patients a standardized liquid meal was given after an overnight fast. Blood samples were
drawn at several intervals relative to the start of the meal. Cpeptide and insulin, were measured. AUC for insulin secretion
(in pmol/min/m2) divided by the AUC of plasma insulin (in
pmol/L) was used to determine insulin clearance. Incremental
area under the curve (AUC) was calculated using the pre-meal
values as baseline. The subjects were tested again at 1 week and 3
months post surgery.
Results: Compared to 1 week and 3 months post surgery, presurgery fasting c-peptide was higher (P < 0.05) in the diabetic
group. C-peptide area under the curve after surgery was
unchanged in the patients with type 2 diabetes. In the type 2
diabetic patients, insulin clearance doubled from pre-surgery to
3 months post-surgery (0.46 – 0.07 L/min/m2 pre-surgery vs.
0.93 – 0.31 L/min/m2 3 months post-surgery).
Conclusions: Fasting insulin and insulin response to a meal
are normalized in diabetic patients through changes in both insulin secretion and insulin clearance.
O-80
TOWARDS GDM SCREENING AND CARE IN LOW
RESOURCE SETTINGS WITH A NEW GENERATION
OF ALTERNATIVE BIOMARKER ASSAYS
B.H. Weigl1
1
Technology Solutions, P.A.T.H, Seattle, USA
Gestational diabetes is a global epidemic where many urban
areas in Southeast Asia exceed the highest prevalence rates in the
developed world. In addition to the serious risk GDM poses during
birth, GDM leads to increased risk to both mother and child of
developing T2DM later in life and its related complications. While
the Oral Glucose Tolerance Tests (OGTT) is an acceptable and
accurate screening method for GDM in developed countries, few
women in developing countries are screened for GDM primarily
due to the complexity and fasting requirement of the OGTT requiring additional visits and added cost. To increase awareness of
the disease, and cost-effective prevention and treatment, a lowcost, easy to use, and convenient screening approach is needed.
Several biomarkers have been identified that may allow the
development of low cost, fasting-free, easy to use rapid GDM
screening assays, including glycated albumin, CD59, glycated fibronectin, and other glycated and glycosylated proteins such as
Glycosylated Alpha-1 acid glycoprotein (A1AG) and glycosylated
alpha-1 antitrypsin (A1AT).
In this presentation, we will give an overview over current
assay development efforts for these markers, and present progress towards a new, simple, low-cost semiquantitative rapid diagnostic strip test for glycated albumin, which determines the
ratio of glycated albumin to total albumin as a marker for gestational diabetes without the use of a reader instrument. We will
also discuss how the new test could be integrated into health
systems with an emphasis on antenatal care in rural and periurban
low resource settings.
A-31
this is far from the truth. Ongoing research is refining the exercise
prescription for patients of all ages, with the main types of diabetes (gestational, type 1 and type 2) and discovering new ways
in which exercise has benefits. Alterations in metabolism caused
by diabetes and new types of exercise modalities are also actively
being researched. A search, of several hundred articles on exercise published between July 1st 2012 to June 30th 2013, uncovered the following 10 articles we felt had the most relevance
to patients with diabetes or pre diabetes.
O-83
EXPLOITING INFORMATION TECHNOLOGY,
GUIDED BY EVIDENCE-BASED MODELS
OF HEALTH BEHAVIOR CHANGE, TO STRENGTHEN
SELF-MONITORING OF BLOOD GLUCOSE
AND SELF-MANAGEMENT ACTION
W. Fisher1
1
O-81
METABOLIC SURGERY IS NO LONGER JUST
BARIATRIC SURGERY
W. Pories1
1
Brody School of Medicine, East Carolina University,
Greenville North Carolina, USA
Six decades mark the maturation of the specialty of metabolic
surgery. Originally intended as a treatment for severe obesity, it
has proven to be the most effective therapy not only for the
obesity but also for type 2 diabetes, hypertension, hyperlipidemias and even non-alcoholic steatotic hepatitis (NASH), polycystic ovary syndrome (PCOS).
The observation that these disparate diseases, often referred to
as the ‘‘metabolic syndrome’’, are usually associated with elevated insulin levels and that the hyperinsulinemia is corrected by
the gastric bypass operation has stimulated the development of a
new understanding of these illnesses and a new skepticism about
the current insulinocentric therapies of type 2 diabetes.
This presentation will review 1) the development of metabolic
surgery, 2) the outcomes of the four accepted operations, i.e.
gastric banding, gastric sleeve, gastric bypass and biliopancreatic
bypass with a duodenal switch and 3) early explanations of the
effects of surgery on the pathologic metabolic pathways of the
TCA and Cori cycles.
O-82
M. Riddell1, S. Pollack2, H. Shojaei1, J. Kalish2, H. Zisser2
1
Kinesiology and Health Science, York University, Toronto,
Canada
2
Sansum Diabetes Research Institute, University of Santa
Barbara, Toronto, Canada
Exercise has been prescribed for diabetes treatment since at
least 600 B.C. The early East Indian text, the Shushruta, described a reduction in the sweetness of urine from diabetic patients after exercise. One might think that very little could be left
to discover in the field of exercise and diabetes, yet surprisingly
Department of Psychology and Department of Obstetrics and
Gynaecology, Western University, London, Canada
The current approach involves texploitation of information
technology guided by evidence-based models of health behavior change, to strengthen self-monitoring of blood glucose
and self-managment action, in efforts to achieve and maintain
glycemic control. We review the Information–Motivaiton–
Behavioral Skills (IMB) model of health behavior change
(Fisher & Fisher, Psychological Bulletin, 1992), and applications of this model aimed at understanding and promoting selfmonitoring of blood glucose and maintainence of glycemic
control. According to the IMB model, information that is
relevant to self-monitoring of blood glucose and appropriate
self-management action, and which is easy to translate into
action, is an essential prerequisite of optimal diabetes selfmanagement. Motivation to act on what one knowns with
respect to adherene to self-monitoring of blood glucose and
self-management action is a second, critical determinant of
whether well-informed indivudals with diabetes will be inclined to act on what they know with respect to self-monitoring
and self-management. Behavioral skills for acting effectively
are a third, essential determinant of whether or not even wellinformed and well-motivated indivduals will be capable of
acting effectively with respect to self-monitoring and selfmanagment. Discussion will consider studies which have
linked diabetes information, motivaiton, and behavioral skills
to self-monitoring adherence and glycemic control among
indivdiuals with type 1 and type 2 diabetes, and review research that has employed technology to target the information,
motivaiton, and behavioral skills demands of diabetes selfmanagement and resulted in improved adherence to selfmonitoring. The leveraging of information technology, guided
by evidence-based models of health behavior, is advocated in
efforts to advance diabetes self-managment.
O-84
OBESITY IS NOW A DISEASE IN ADDITION TO
IMPACTING DIABETES: CAN INTERNET-BASED
BEHAVIOR CHANGE INTERVENTIONS HELP?
N. Kaufman1
1
UCLA Schools of Public Health and Medicine, DPS Health,
Los Angeles, USA
A-32
Obesity is a known driver of a variety of poor health outcomes
and high healthcare cost. It is the main driver for increasing the
rate of progression from pre-diabetes/metabolic syndrome to
full-blown type 2 diabetes.
Until a person with obesity develops complications of associated diseases with an increase in hospitalization and emergency
department visits, their increased healthcare cost is usually associated with increased outpatient, pharmacy and durable medical equipment claims. This makes strategies for cost savings
different than traditional disease management approaches which
focus on avoiding hospitalization. These individuals also don’t
respond to traditional wellness approaches which are often not
intensive enough to improve outcomes and lower costs.
Given the marked increase in the prevalence of overweight
and obesity, healthcare providers must implement effective approaches to support patients’ weight loss. To do this it is essential
individuals are given the knowledge and skills to adopt and
sustain healthy habits that lead to sustained weight loss. The
challenge for healthcare providers is to be able to provide successful, affordable, and scalable approaches. There is increasing
evidence that technology-enabled self-management support interventions can be approaches that work and which can show a
positive return on investment (ROI).
This presentation provides information about unique aspects
of the overweight/obese population that need to be taken into
account when implementing a program and the qualities of interventions that make a difference. It also provides a demonstration of a research-proven online approach to weight loss in
adults and provides information about associated outcomes and
ROI.
O-85
MOBILE HEALTH: PATIENT ENGAGEMENT
IN DIABETES CARE
C. Quinn1
1
Epidemiology and Public Health Division of Gerontology,
University of Maryland School of Medicine, Baltimore, USA
Increased access to mobile devices and applications offer
great promise for assisting adults with diabetes to self-manage
health behaviors. A main concern is whether levels of patient
engagement are adequate to promote and sustain behaviors to
improve diabetes outcomes.
Engagement is a popular term in mobile and wireless health.
Methods for defining and measuring patient engagement are
challenging to link patient characteristics, usage, retention,
self-care behaviors, and health outcome change over time.
Evaluating engagement spans multiple research methods and
scientific disciplines including behavior, communication, social, and clinical sciences. Two themes emerge in current
research explorations (1) identifying active psychosocial and
communication components of mobile interventions and (2)
examining the impact of increasing tailoring on health behavior
change. Understanding these points is important to developers
and researchers.
The primary purpose of this paper is to first, discuss recent
study methods and results for evaluating patient engagement in
diabetes type 2 interventions. Second, based on results in a
randomized clinical trial (RCT), we report on overall engagement communications between study patients and providers,
components of the mobile health and website portal usage,
which patient characteristics were associated with usage and
correlations between different measures of patient engagement
and diabetes outcomes over a one year treatment period.
Rapidly changing interfaces, software, and capabilities of
mobile/wireless health require dynamic approaches to evaluating
patient engagement.
O-86
USE OF INSULIN PUMPS IN T2D IN INDIA:
MERITS AND DEMERITS LEARNT OVER A DECADE
J. Kesavadev1
1
Diabetes, Jothydev’s Diabetes Research Centre,
Thiruvananthapuram, India
Use of Insulin pumps in T2D in India: Merits and Demerits
learnt over a decade.
Though insulin pumps are primarily meant for T1D, in India
80% of users are patients with T2D. Insulin can be delivered with
a syringe, pen or pump. Hence, pumps are an alternative delivery
device for any patient either with T1D or T2D requiring insulin.
Studies have shown clinically and statistically significant improvement in numbness and pain of peripheral neuropathy and
improvement in erectile dysfunction in > 85% affected individuals switched over to Insulin Pump Therapy (IPT) from MDI. For
those T2D with significant glucose excursions, nocturnal hypoglycemia, frequent traveling, recurrent hypoglycemia, IPT offer
significant improvement in their quality of life. Though insulin
pumps are an absolute indication in majority of patients with
T1D, only a minority of patients can afford pump and consumables since in India there exists no reimbursement or government
run policies for CSII based therapies. When pumps were introduced in India in early 2000, majority of the users were rich T2D
insulin requiring subjects. Failure to follow up, adhere to instructions etc led to necessity for country specific document and
resulted in publication of suggested guidelines for IPT in India.
The guidelines clearly state that affordability should never be the
criteria to deploy insulin pump. Willingness to attend pump
training, motivation to use technology and gadgets and a track
record of regular self monitoring were incorporated into the
guidelines. Considering multiple benefits of IPT in T2D, eligible
and affordable candidates should never be denied of this
technology.
O-87
A report from labs: the NIDDK PROJECT
‘‘LONGITUDINAL ASSESSMENT
OF BARIATRIC SURGERY’’
W. Pories1
1
Brody School of Medicine, East Carolina University,
Greenville North Carolina, USA
The Longitudinal Assessment of Bariatric Surgery (LABS) is
a National Institutes of Health (NIH)-funded consortium of six
clinical centers (Columbia/Cornell, East Carolina University,
and the Universities of North Dakota, Oregon, Pittsburgh and
Washington) at ten clinical sites and a data coordinating center
(the University of Pittsburg) working in cooperation with NIH
scientific staff to plan, develop, and conduct coordinated clinical,
epidemiological, and behavioral research in bariatric surgery.
The initial study[i], funded in 2003 with 6,118 patients,
documented the safety of bariatric surgery with a 30 day
mortality of 0.3%, identical to the risk of routine cholecystectomy. Of these, 2,458 were continued into the current long-term
study[ii].
At baseline, participants were 18 – 78 years old, 79% were
women, median BMI was 45.9 (IQR, 41.7–51.5), and median
weight was 129 kg (IQR, 115–147). For their first bariatric surgical procedure, 1738 participants underwent RYGB, 610
LAGB, and 110 other procedures. At baseline, 774 (33%) had
diabetes, 1252 (63%) dyslipidemia, and 1601 (68%) hypertension. Three years after surgery, median actual weight loss for
RYGB participants was 41 kg (IQR, 31–52), corresponding to a
percentage of baseline weight lost of 31.5% (IQR, 24.6%38.4%). For LAGB participants, actual weight loss was 20 kg
(IQR, 10–29), corresponding to 15.9% (IQR, 7.9%-23.0%). The
majority of weight loss was evident 1 year after surgery for both
procedures. Five distinct weight change trajectory groups were
identified for each procedure. Among participants who had diabetes at baseline, 216 RYGB participants (67.5%) and 28 LAGB
participants (28.6%) experienced partial remission at 3 years.
The incidence of diabetes was 0.9% after RYGB and 3.2% after
LAGB. Dyslipidemia resolved in 237 RYGB participants
(61.9%) and 39 LAGB participants (27.1%); remission of hypertension occurred in 269 RYGB participants (38.2%) and 43
LAGB participants (17.4%).
Conclusions and Relevance.
Among participants with severe obesity, there was substantial
weight loss 3 years after bariatric surgery, with the majority
experiencing maximum weight change during the first year.
However, there was variability in the amount and trajectories of
weight loss and in diabetes, blood pressure, and lipid outcomes.
[i]. Smith MD, Patterson E, Wahed AS, Belle SH, Berk PD,
Courcoulas AP, Dakin GF, Flum DR, Machado L, Mitchell
JE, Pender J, Pomp A, Pories W, Ramanathan R, Schrope
B, Staten M, Ude A, Wolfe BM. Thirty-day mortality after
bariatric surgery: independently adjudicated causes of death
in the longitudinal assessment of bariatric surgery. Obes
Surg. 2011 Nov;21(11):1687–92. doi: 10.1007/s11695-0110497-8. PubMed PMID: 21866378.
[ii]. Courcoulas AP, Christian NJ, Belle SH, Berk PD, Flum
DR, Garcia L, Horlick M, Kalarchian MA, King WC,
A-33
Mitchell JE, Patterson EJ, Pender JR, Pomp A, Pories WJ,
Thirlby RC, Yanovski SZ, Wolfe BM; for the Longitudinal
Assessment of Bariatric Surgery (LABS) Consortium.
Weight Change and Health Outcomes at 3 Years After
Bariatric Surgery Among Individuals With Severe Obesity.
JAMA. 2013 Nov 4. doi: 10.1001/jama.2013.280928.
[Epub ahead of print] PubMed PMID: 24189773.
O-88
TYPE 2 DIABETES IN THE PEDIATRIC AGE GROUP:
INSULIN RESISTANCE, INSULIN DEFICIENCY,
BOTH, MODY?
M.A. Sperling1
1
Pediatric Endocrinology and Diabetes, Childrens Hospital
University of Pittsburgh, PittsburghPa 15224, USA
TYPE 2 DM IN THE PEDIATRIC AGE GROUP:INSULIN
RESISTANCE? INSULIN DEFICIENCY? BOTH? MODY?
The incidence and prevalence of T2DM is increasing in the
pediatric population, in parallel with the pandemic of obesity and
the Metabolic Syndrome, particularly in specific ethnic groups.
In the USA, the incidence of T2DM in those diagnosed with
diabetes between the ages of 10–20 years varies from approximately 2/100,000/yr in Caucasians, to 15/100,000/yr in African
in Americans, and 30/100,000/yr in Native American Indians.
Although ‘‘Insulin Resistance’’ is commonly ascribed to be the
link between obesity and the development of T2DM, accumulating data implicate genetic defects in the ability to compensate
for resistance to insulin by increasing it’s secretion as the ultimate cause of T2DM. In addition to known genetic defects in
insulin secretion associated with MODY (Monogenic Diabetes
of Youth) or Neonatal Diabetes (NDM), newly identified factors
include the hormones Betatropin, which mediates the sensing of
resistance to augment secretion of insuIin, including beta cell
hypertrophy, Irisin, which mediates beneficial effects of exercise
by augmenting catabolism of fat, and the role of the zinc transporter ZnT8 in hepatic insulin clearance. Together, these discoveries point to new mechanisms responsible for T2DM, it’s
diagnosis and it’s treatment.
ATTD 2014 Poster Presentations
P-89
P-90
OUR EXPERIENCE WITH REAL TIME CGMS
IN NEWBORNS OF MOTHERS SUFFERING
FROM TYPE 1 DIABETES
REAL-TIME CONTINUOUS GLUCOSE MONITORING
IN PREGNANT WOMEN WITH TYPE 1 DIABETES:
PATIENT EXPERIENCES AND OPINIONS
K. Stechova1, M. Cerny2, R. Brabec2, T. Ulmannova1,
D. Bartaskova3, I. Spalova4, P. Zoban2
H.W. de Valk1, M.S. Stolze2, B. Silvius2, L.B.E.A. Hoeks2,
G.H.A. Visser3
1
Dpt. of Paediatrics, Charles University 2nd Faculty of
Medicine and University Hospital Motol, Prague, Czech
Republic
2
NICU Dpt. of Obstetrics and Gynaecology, Charles University
2nd Faculty of Medicine and University Hospital Motol,
3
Dpt. of Internal Medicine, Charles University 2nd Faculty
of Medicine and University Hospital Motol, Prague, Czech
Republic
4
Dpt. of Obstetrics and Gynaecology, Charles University 2nd
Faculty of Medicine and University Hospital Motol, Prague,
Czech Republic
In babies of diabetic mothers perinatal complications including hypoglycaemia are still seen more frequently than in newborns of healthy mothers.
We analysed by real time continuous glucose monitoring (RTCGMS) newborns of mothers suffering from type 1 diabetes
(T1D group; n = 20) in comparison with controls (6 newborns
born in term to healthy women).
Median of gestation age in T1D group was 264 days (range
221–271 days), 9/20 of these newborn required intensive care
during their first days of life. The first Enlite sensor was
placed immediately after the birth (connected to Guardian real
time device, Medtronic, Minneapolis, MN, USA). The median
of monitoring in T1D group was 6 days (range 3–8 days) and
4 days in controls (range 4–6 days).
RT-CGMS revealed higher frequency of later hypoglycaemia (£ 2.5 mmol/l) after 3rd monitoring day in T1D group
(p = 0.01). In control newborns hypoglycaemia episodes were
present too but during the first 4 days of life only and were
less frequent and shorter.
In T1D group the occurrence and severity of hypoglycaemia
were influenced by: the presence of macrosomia (p = 0.024),
length of the newborn (p = 0.003), maternal HbA1c in 3rd trimester (p = 0.001), maternal weight gain (p = 0.022), maternal
total insulin dose (p = 0.021) and by maternal age (p = 0.042).
Hypoglycaemia events were always confirmed and in general sensor readings correlated well with laboratory findings
(r = 0.817, p = 0.004).
RT-CGMS was useful in revealing late postnatal hypoglycaemia which together with an adequate treatment can improve
adaptation of these newborns.
Supported by the Project of MHCR for conceptual dev. of
research org.00064203.
1
Internal Medicine, UMC Utrecht, Utrecht, Netherlands
3
Obstetrics, UMC Utrecht, Utrecht, Netherlands
2
Background: Real-time-continuous glucose monitoring (RTCGM) improves glycaemic control in non-pregnant patients.
Less is known about RT-CGM in pregnant diabetic women.
Analysis of personal experiences provides information to optimally implement RT-CGM during pregnancy.
Patients and Methods: Women delivering in 2012 using RTCGM were interviewed using a structured questionnaire on user
preferences, technical problems, effects on daily life and care
received.
Results: Twenty women with type 1 diabetes delivered in
2012; 12 (60%) chose RT-CGM, all on CSII, 10 (83%) started
during the first trimester. Most (11 women, 92%) pregnancies were
planned. Education: university in 4, higher vocational in 5, middle
vocational in 3. Two-thirds used RT-CGM continuously; others
allowed themselves a few days off. Two-thirds needed 1–4 weeks
to learn to use RT-CGM; blood glucose was measured on average
3–5 times a day. Social and working activities did generally not
suffer from RT-CGM. Technical problems were minimal; delay
between changes in plasma and interstitial glucose values were
frequent mentioned practical problem, especially in the lower
range. Most women continued RT-CGM during lactation and all
would use RT-CGM a next pregnancy. All women expressed that
care was best given by a small team well-attuned to their condition.
Conclusion: RT-CGM in pregnancy in well-educated women
with type 1 diabetes is associated with high maternal compliance,
minimal effect on daily life and greatly appreciated with about
half of the pregnant women wanting to use it. Delay in timely
detecting hypoglycaemia is a major issue and optimal use of RTCGM requires care by a small, local team.
P-91
STANDARDIZED PROCEDURE FOR THE
ASSESSMENT OF NEW-TO-MARKET CONTINUOUS
GLUCOSE MONITORING (CGM) SYSTEMS (SPACE2)
J. Kropff1, W. Doll2, J.K. Mader2, T. Pieber2, A. Farret3,
J. Place3, E. Renard3, F. Boscari4, D. Bruttomesso4,
S. Galasso4, J.H. DeVries1
1
Internal Medicine, Academic Medical Center, Amsterdam,
Netherlands
A-34
ATTD 2014 POSTER PRESENTATIONS
A-35
2
Department of Internal Medicine, Medical University Graz,
Graz, Austria
3
Montpellier University Hospital, Montpellier University
Hospital, Montpellier, France
4
Department of Clinical and Experimental Medicine, University
of Padova, Padova, Italy
2
2nd Dep Int Med, Charles University 3rd Faculty of Medicine,
3
Diabetology, Private Department of Diabetology Internal
Medicine and Metabolism, Kosice, Slovakia
4
Institute of Physics, Czech Academy of Science, Prague, Czech
Republic
Aims: To assess accuracy and reliability of the two most
widely used CGM systems.
Methods: We studied the Dexcom G4 Platinum and Medtronic
Enlite, in 24 patients with type 1 diabetes. Sensors were tested
during a six days home study and a nested 6 hours Clinical Research Centre (CRC) visit. During the CRC visit frequent venous
blood glucose samples were taken while patients received a meal
with an increased insulin bolus to induce an aggravated postprandial glucose nadir. At home, patients performed at least 6
reference fingersticks per day. Wilcoxon signed-rank test was
performed on all data points ‡ 15 min apart.
Results: System uptime was 99.2% for Dexcom and 97.9% for
Medtronic. Overall Mean Absolute Relative Difference (MARD)
(SD) measured at the CRC was 13.6 (11.0)% for Dexcom and 16.6
(13.5)% for Medtronic (P < 0.001 n = 532). Overall MARD assessed at home was 12.2 (12.0)% for Dexcom and 19.9 (20.5)% for
Medtronic (P < 0.001 n = 843). During the CRC visit, MARD in
the hypoglycaemic range (£ 70 mgdL), was 17.6 (12.5)% and 24.6
(18.8)% for Dexcom and Medtronic respectively (P < 0.0001
n = 117). Both sensors showed lower accuracy during hypoglycaemia as compared to euglycaemia (70–180 mgdL) (Dexcom
17.6% vs. 13.0% and Medtronic 24.6 vs. 14.2%).
Conclusions: During circumstances of intended use, including both a CRC and home-phase the Medtronic sensor was noticeably less accurate than the Dexcom sensor. Both sensors
showed lower accuracy in the hypoglycaemic range.
This study was funded by Dexcom, San Diego, USA
Background and aims: Hypoglycemia is an uncomfortable
episode which besides another problems may also swing
glycemic curve and cause an improper diabetes control. We
analysed CGM records to see how successful are our patients
in selftreatment of hypoglycemia.
Material and methods: We analyzed CGM records of patients
with type I diabetes mellitus treated with CSII and MDI. Each
patient used CGMS for 3–6 days and was asked to record all
improtant events such as insulin injection, meal, exercise, hypoglycemic episodes. We reviewed glycemic profiles to identify
glycemic excursions after hypoglycemic episodes. We evaluated
the number of recurent hypoglycemias within next two hours after
every episode. We considered self-treatment as successful if glycemic curve after hypoglycemia kept between 5 and 12 mmol/l.
Results: We evaluated 3763 hoursof CGM records in 32 patients with type I diabetes mellitus (21 men, 11 woman). We
found 98 hypoglycemic episodes (0,6 per day), 18 of all the
episodes were followed by reccurent hypoglycemie within 2
hours (18,4%). We found glycemic curve during next 2 hours
after hypoglycemia in target limits (5–12 mmol/l) in 44 cases
(44,9%). In the rest of the cases (36) glycemic values exceeded
12 mmol/l (36,7%). Precise amount of sacharides used in selftreatment were able to control only 18 patients.
Conclusion: We found that in more than half of hypoglycemic
episodes another hypogycemia follows or hyperglycemia occures. Self-treatment of hypoglycemia should be matter of repeted education. Automatic analysing of posthypoglycemic
curve could possibly become another part of CGMS software.
P-93
HEMATOCRIT INTERFERENCE IN MODERN BLOOD
GLUCOSE METERS FOR PATIENT SELF-TESTING
F. Demircik1, S. Ramljak1, J. Spatz1, J. Pfützner1, J. Sieber2,
F. Flacke2, A. Pfützner1
1
IKFE - Institute for Clinical Research and Development,
Mainz, Germany
2
Sanofi, Frankfurt, Germany
P-92
CONTINUOUS GLUCOSE MONITORING CAN
UNCOVER MISTAKES IN SELF-TRETMENT OF
HYPOGLYCEMIA IN PATIENTS WITH TYPE 1
DIABETES MELLITUS
J. Broz1, J. Urbanova2, D. Janickova Zdarska1, V. Donicova3,
M. Brabec4
1
Dep Int Med, Charles University 2nd Faculty of Medicine,
Background: Dynamic electrochemistry (DE), has been
shown to correct for hematocrit (HCT) interference. This laboratory investigation assessed the HCT stability of a new DEbased device (MyStar Extra, Sanofi) in comparison to seven
competitive devices (AccuChek Aviva Nano & AccuChek
Performa, Roche Diagnostics; Contour XT and Contour Link,
Bayer; FreeStyle Freedom Lite, Abbott; MyLife Pura, Ypsomed; OneTouch Verio Pro, LifeScan).
Method: Venous heparinized blood was immediately aliquoted and manipulated to contain 3 different blood glucose
concentrations (50–80 mg/dL, 150–180 mg/dL, and 350–
400 mg/dL) and 5 different HCT levels (20–25%, 30–35%, 40–
45%, 50–55%, and 60–65%). After careful oxygenation to normal blood oxygen pressure, each of the 15 different samples was
measured 8x with two devices and two strip lots of each meter
( = 32 measurements/meter/sample). YSI Stat 2300 served as
laboratory reference method. Stability to HCT influence was
A-36
assumed, when less than 10% difference occurred between the
highest and lowest mean glucose deviations in relation to HCT
(HIF: Hematocrit Interference Factor).
Results: Four of the devices showed stable performance:
Contour XT (HIF: 6.09%), MyStar Extra (7.07%), OneTouch
Verio Pro (7.30%), and Contour Link (9.32%). The four other
meters were influenced by HCT (AccuChek Performa: 20.92%,
AccuChek Aviva Nano: 22.40%, FreeStyle Freedom Lite:
24.49%; MyLife Pura: 28.74%).
Conclusions: In this study, 50% of the tested meters, including MyStar Extra, were shown to reliably correct for potential hematocrit influence on the meter results.
Investigator-initiated trial supported in part by Sanofi.
P-94
PERFORMANCE OF THE EA1C ALGORITHM IN
T1DM: SMBG BASED A1C TRACKING
M.D. Breton1, J. Sieber2, F. Flacke2, B. Kovatchev1
1
2
University of Virginia, Charlottesville, Virginia, USA
Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany
Introduction: Hemoglobin A1c (HbA1c) has become an
established clinical marker for average glycemic control.
While methods to link HbA1c to average glycemia have been
developed, their application to estimate HbA1c from episodic
SMBG readings has proven more challenging. A novel algorithm, using SMBG data to track HbA1c daily, was presented
at EASD 2013[1,2], showing significantly improved accuracy
over previous methods in Type 2 diabetic subjects. The presented work validates this method is T1DM.
Method: Previously reported data from 120 type 1 diabetic
subjects [3] was used to assess accuracy of the estimation
procedure. The data contained 188,219 SMBG measurements
that were randomly distributed in time, on average 4–5
readings per subject per day. Fasting, pre- and post-meal tags
were assigned based on daytime.
The eA1c algorithm was applied retrospectively and reference
HbA1c was used to assess accuracy; reporting mean absolute
deviation, mean relative absolute deviation, and correlation. An
established glycemic average method [4] provided a point of
comparison with previous research.
Results: eA1c was computable for 457 of the 478 reference
HbA1c (15 without enough fasting BG, 3 without current profiles, and 3 references before eA1c initialization. Results are
presented in Table 1.
Conclusion: Performances of the eA1c algorithm in T1DM
were comparable to previously reported performance in T2DM,
and confirmed improved accuracy when compared to established
average methods.
Acknowledgments: Study supported by Sanofi.
1.
2.
3.
4.
Kovatchev et al. EASD 2013;
Breton et al. EASD 2013;
Kovatchev et al. Diabetes Care 2011;34:302–307;
Nathan et al. Diabetes Care 2008;31:1473–1478.
P-95
ROLE OF NON-INVASIVE SCREENING METHODS IN
ESTIMATING PREVALENCE OF DYSGLYCAEMIA IN
PATIENTS ADMITTED TO HOSPITAL WITH ACUTE
CORONARY SYNDROME
M. Karamat1, W. Hanif 2, S. Manley3, A. Tahrani1, M. Stevens1
1
Diabetes, Heartlands Hospital, Birmingham, United Kingdom
Diabetes, Queen Elizabeth Hospital, Birmingham,
United Kingdom
3
Biochemistry, Queen Elizabeth Hospital, Birmingham,
United Kingdom
2
Aims: To determine the prevalence of undiagnosed diabetes
and impaired glycaemic state (IGS) and compare WHO 1998 and
IEC criteria in patients admitted to hospital with acute coronary
syndrome. In addition we also looked at using novel screening
algorithms to determine glycaemic status.
Methods: A prospective 3 year study carried out in two large
inner city hospitals in United Kingdom.
Results: 118 Patients were included in the analysis. The prevalence of diabetes mellitus was 20% and 16% respectively according to the W.H.O and IEC criteria at baseline. The prevalence
remained similar at 3 months. However two thirds of participants
with IGS and a third of those with DM changed their glycaemic
status at 3 months. This could be due to stress hyperglycaemia as
urinary cortisol creatinine ratio was elevated in patients who had
T2DM at baseline compared to other groups. Our screening algorithm had sensitivity of over 85% at baseline in comparison with
W.H.O criteria. We also designed diabetes predictor score based
on age, fasting plasma glucose and HbA1c and it had excellent
sensitivity of over 80% and negative predictive value of over 90%.
By contrast the sensitivity of IEC criteria was only 57%.
Conclusion: The W.H.O and IEC diagnostic criteria identify
different populations with diabetes at baseline as well as 3
months. This is clinically relevant as we are basing screening in
high risk population on these criteria. The IEC criteria do not
identify patients with IGS which is known to be associated with
increased cardiovascular morbidity and mortality.
P-96
TRANSITION OF CSII SYSTEMS IN A VERY SHORT
TIMEFRAME AS A CONSEQUENCE OF A PUBLIC
TENDER PROCESS. FEASIBILITY AND SAFETY
ISSUES
N. Casado1, O. Matas1, P. Rios2, M. Martı́n1, S. Iglesias1,
M. Giménez2, I. Conget2
1
Diabetes, Medtronic Ibérica S.A., Barcelona, Spain
Diabetes Unit, Endocrinology and Nutrition,
2
Background: CSII is widely reimbursed by National Health
Systems. The procurement of pumps/supplies through a tender
process is common practice of public services. We describe the
feasibility and safety of the transition from a CSII system to another
in a very short timeframe as a consequence of a public tender.
Methods: The CSII replacement process in a large population
for a very short time frame (< 1 month) was designed. The most
remarkable aspects were an intensive structured training program and 24-h technical/clinical support availability. Training
was performed in groups of 4 patients. Educational contents were
organized in modules and adapted to the necessities of each
A-37
group. The program was composed of 3 sessions: (i) system startup training and a patient satisfaction questionnaire; (ii) 72-h later, a telephone call from the technical-education staff; and (iii) a
session of training after 3 months.
Results: 219 subjects were included (62% women,
45.1 – 11.2 yr-old, duration of diabetes 25.2 – 9.7 yrs, on CSII
7.3 – 3.4 yrs). 30 calls were performed to reinforce training. 7
technical incidences occurred and rapidly sorted out. 24 out of 31
clinical events were considered mild, 6 moderate needing medical
assistance (5 hyperglycemia/1 ketosis) and 1 severe requiring
hospitalization (ketoacidosis). All were related to infusion sets
issues and were satisfactorily solved. Overall satisfaction of the
patients with the training process scored 9.4 out of 10.0.
Conclusions: The transition of CSII systems in large populations in the context of a public tender could be performed safely
and in a very short time using a specific training program.
P-97
HOW DO PRE-GESTATIONAL BMI AND WEIGHT
GAIN INFLUENCE PREGNANCY OUTCOME IN
WOMEN WITH GESTATIONAL DIABETES?
F. Macri’1, S. De Carolis1, C. Martino1, S. Garofalo1,
A.C. Vitucci1, E. Di Pasquo1, S. Moresi1, E. Di Stasio2,
D. Pitocco3, A. Lanzone1
1
Obstetric and Gynecology, Catholic University of the Sacred
Heart, Rome, Italy
2
Biochemistry, Catholic University of the Sacred Heart, Rome, Italy
3
Internal Medicine, Catholic University of the Sacred Heart,
Rome, Italy
Introduction: The maternal obesity could be an additional
risk factor for complications, regardless of diabetes. The aim of
this study was to evaluate the pregnancy outcome among women
affected by GDM, according to pre-pregnant BMI and GWG.
Materials and Methods: Four hundred-twelve patients with
393 singleton pregnancies (17 twin pregnancies and 2 triple
A-38
distinguishing abdominal obesity rather than severe obesity,
while some patients may have MS and some may not. Otherwise,
data concerning non-morbid obesity patients with MS has rarely
been reported. It is important to investigate if the same principles
of GBP that improve diabetes with MS could be applied to the
diabetes without MS in non-obesity patients.
Objective: We sought to determine effects of laparoscopic
gastric bypass on weight loss and diabetic remission in patients
with MS compared with appropriately matched cohort without MS.
Methods: Retrospective analysis of 42 T2DM patients with
BMI 28–35 kg/m2, stratified by MS into two groups (group 1,
MS group, group 2, non-MS group). Anthropometric, biochemical, and clinical evaluations were performed preoperatively and
then at 1,3,6 and 12 months postoperatively.
Results: During the one year follow-up, all groups showed a
significant reduction in BMI, waist circumference, LDL-C and
HOMA-IR. However, remission of T2DM is different, higher in
MS group (18/20, 90%) and lower in non-MS group (14/22,
64%), which total remission is 86% (32/42).
Conclusions: Laparoscopic gastric bypass has an independent
mechanism with weight loss on non-obesity T2DM, which is associated with resolution of insulin resistance. Furthermore, BMI is
not the only main inclusion criteria for gastric bypass on diabetes
while metabolic disorders maybe the next important one.
pregnancies) complicated by GDM were considered. According
to HAPO study, the diagnosis of GDM was made. After the
diagnosis, all women started a diet therapeutic regimen and the
capillary blood glucose self-monitoring; in patients in which
the glicemic control did not result optimal, we convert the diet
therapeutic regimen to a pharmacological management. All
women were monthly assisted by both the physicians and glycaemic values and maternal weight were controlled.
Results: Seventy-six (18.4%) women were affected by hypertensive and 108 (26.2%) were affected by thyroid disorders
and this complications were correlated with the increasing of
BMI classes. The incidence of macrosomia was 5.3%. Even the
foetal complications were correlated with the pre-pregnant maternal BMI. Women who delivered a macrosomia had a significantly greater pregnancy weight gain and a major fasting glucose
levels at OGTT. Thirteen newborns (3.0%) presented malformations at delivery closely correlated to a maternal BMI ‡ 30.
Conclusions: A patients training to lifestyle modifications is
recommended. Obese and diabetic pregnant women need of a
multidisciplinary team management that, according to our study,
can give very good results even if closely outpatient.
P-98
EQUIVALENT WEIGHT LOSS BUT DIFFERENT
DIABETES BENEFITS WITH METABOLIC
SYNDROME IN NON-MORBID OBESITY T2DM
PATIENTS AFTER GASTRIC BYPASS
H. Gao1
1
Dept of General Surgery, The General Hospital of Chinese
People’s Armed Police Forces, Beijing, China
Background: Metabolic syndrome (MS), a constellation of
metabolic abnormalities, has an intertwined link with morbid
obesity and type 2 diabetes (T2DM). Gastric bypass (GBP) is
considered an effective option for the management of these patients. However, most of the diabetes patients in China have
P-99
INSULIN: TOO MUCH OF A GOOD THING
J. Pender1, W.J. Pories1, W. Chapman1, M.A. Reed2,
M. Koury1, R. Bowden1, L.G. Dohm3
1
Surgery, East Carolina University, Greenville, USA
Kinesiology, West Chester University, West Chester, USA
3
Physiology, East Carolina University, Greenville, USA
2
Introduction: In 1984 we first documented that the Roux-enY gastric bypass achieved full and durable remission of type 2
diabetes (T2DM) in a matter of days (Ann Surg) and in 1992, we
reported that the basal insulin levels in patients with advanced
type 2 diabetes mellitus was 900% higher than those found in
euglycemic individuals (Am. J. Clin. Nutr). We have documented that these elevated basal levels of insulin are corrected in
a matter of days, long before there are significant improvements
in insulin resistance (J. Endocrin & Metabol 2011).
Methods: Nine obese non-diabetic and nine obese diabetic
women were studied before surgery, one week and 3 months
after RYGB. Nine lean females not undergoing surgery were
used as controls. Fasting blood samples were drawn before a
mixed meal test. Sequential blood draws were then performed
over a 3 hour period, measuring changes in insulin and glucose.
An intravenous glucose tolerance test was also performed after
an overnight fast. Changes in insulin and glucose concentrations were measured.
Results: Recalculated data from the previously reported
studies document (figure below) the remarkable finding that the
RYGB uncouples the insulin/glucose, i.e. after the operation, the
normal direct relationship between insulin vs. glucose is abolished. Thus, even though glucose levels rise in these patients, the
expected rise in insulin is abolished.
Conclusion: These results contradict the current understanding of the hyperinsulinemia of T2DM. We should re-direct
our search for anti-diabetic medications into these pathways
rather than the pursuing medications which increase insulin
levels in patients.
P-100
METABOLIC SYNDROME – NEUROTROPHIC
THEORY EFFECTS OF METFORMIN AND NONSTEROIDAL ANTIINFLAMMATORY DRUG
TREATMENT
M. Hristova1
1
Division of Endocrinilogy, Medical Centre Varna, Varna,
Bulgaria
Metabolic syndrome (MS) presents with central obesity, impaired glucose metabolism, dyslipidaemia and hypertension. Our
aim was to examine the effect of metformin treatment alone and in
combination with non-steroidal antiinflammatory drugs (NSAID)
on plasma levels of nerve growth factor (NGF) and brain-derived
neurotrophic factor (BDNF) in patients with early stage MS (MSes) and generalized MS (MS-ge).
Materials/methods: The study covered 35 female patients
with MS-es (at mean age of 43.39 – 1.54 years) and 40 ones with
MS-ge (at mean age of 45.69 – 2.18 years) compared to 10 agematched controls each. Patients with MS-es were administered
metformin in a dose of 850 mg twice daily. The patients with
MS-ge were divided in two groups of 20 patients each. They
received metformin either alone, or in combination with aspirin
in a dose of 500 mg daily and Diclac in a dose of 150 mg daily.
Plasma NGF and BDNF levels were measured by ELISA. Statistical data processing was done by ANOVA method.
Results: Plasma NGF and BDNF levels were significantly
higher in MS-es patients and lower in MS-ge ones than in controls. NGF levels were decreased after treatment with metformin
in both groups. NGF levels were significantly higher in MS-ge
patients on combined therapy than in those on metformin only.
Conclusions: The combination of metformin and NSAID
exerts a better effect than metformin alone on NGF and BDNF
production, metabolism-related anthropometric and laboratory
features as well. It represents a pathogenetic therapeutic mechanism in MS because of its strong antiinflammatory effect and
improves MS-ge manifestations.
P-101
GROUP EDUCATION IN TYPE 1 DIABETES
PATIENTS ON INSULIN PUMP THERAPY
L. Ibragimova1, Y. Filippov1, A. Mayorov1
A-39
1
Institute of Diabetes, National Research Centre for
Endocrinology, Moscow, Russia
Aim: To assess the effectiveness of group education on glycemic control and Quality of Life (QoL) among users of continuous subcutaneous insulin infusions (CSII).
Methods: Cross-sectional study included 43 subjects (18
male, mean age 28 years [24; 36]) with type 1 diabetes (duration
of diabetes 14 years [8; 19]). All patients were transferred from
multiple daily injection regimen to insulin pump therapy using
special structured program for group education for CSII which
included basic information about general diabetes self-management and technical aspects of pump therapy for 9 days. QoL
was assessed using questionnaire ADDQoL, WB12, SF-36. We
estimated metabolic and QoL parameters in 16 weeks after
education.
Results: After 16 weeks HbA1c significantly decreased from
8,9% [7,9; 9,5] to 7,4% [6,6;7,9] ( p = 0,0001) without increasing
the frequency of hypoglycemia; absolute decrease of HbA1c was
1,2% [0,5; 1,8]. There were significantly improvements in all
aspects of QoL accordingly ADDQoL, SF36 and WB12 compared to baseline data.
Conclusion: Our study showed that using CSII after special
structured program for group education improved glycemic
control and QoL. So it recommended to educate patients about
basic principles of general diabetes self-management in group
transferring to CSII.
P-102
PATIENTS PROFILE EVALUATION WITH TYPE 1
DIABETES IN INSULIN PUMP IN BRAZIL
A.C. Ramalho1, C. Tess1, S. Travassos2, M. Hissa2, D. Franco2,
E. Calliari2, H. Pedrosa2, B. Tschiedel2, W. Minicucci2,
G. Study Group of Continuous Insulin Infusion System2
1
Endocrinology, Federal University of Bahia, Salvador Bahia,
Brazil
2
Diabetes, Brazilian Diabetes Association, São Paulo, Brazil
To date, there is no data about features of patients using insulin
pump in Brazil. Our goal was to describe these patients and
evaluate how they are using their pump. This is a cross sectional
study, using patients with type 1 diabetes in insulin pump in
different states in Brazil. A questionnaire was applied; simple
frequency was used and Mann-Whitney test.
Results: 415 patients, 59% female and 41% male. The indications to use pump were: quality of life (74%), unsatisfying
glycemic control (55,2%), to decrease injections (41,4%) and
severe hypoglycemia (30,1%). Approximately 47,9% patients said
the main advantage is the improvement of glycemic control and
19,7% flexibility. As main disadvantage: cost (40,5%) and skin
spots (27,8%). Insulin pump therapy decreased fear of hypoglycemia in 60,3% and 49% improved the perception of hypoglycemia. An increase number of patients has some difficulty to use
important resources of the pump (86,4%): 60,8% never use temporary basal and 53,5% never use different bolus. Severe hypoglycemia was less frequent after pump. They showed a decrease in
A1c after 6 months using pump (8,69 – 1,82 vs.7,62 – 1,18%).
Conclusion: There was an improvement in A1C and a decrease in severe hypoglycemia after insulin pump. Patients didn’t
know how to use some important resources of the pump. These
show as the needs to improve education after beginning insulin
pump therapy.
A-40
P-103
IDENTIFICATION OF VARIABILITY IN
POSTPRANDIAL BEHAVIOR OF PATIENTS WITH
TYPE 1 DIABETES FROM INSULIN PUMP DATA
A. Laguna1, P. Rossetti2, F.J. Ampudia-Blasco3, J. Vehı́ 4,
J. Bondia1
1
Institut Universitari d’Automàtica i Informàtica Industrial,
Universitat Politècnica de València, Valencia, Spain
2
Departamento de Medicina Interna, Hospital Francesc de
Borja, Gandia, Spain
3
Diabetes Reference Unit Endocrinology Department, Clinic
University Hospital of Valencia, Valencia, Spain
4
Institut d’Informàtica i Aplicacions, Universitat de Girona,
Girona, Spain
Individual model identification in diabetic patients is considered a challenge mainly due to uncertainty in glucose measurements and glycemic variability, especially in the postprandial
period. Previous work showed that identifying patients’ interval
models characterizing intra-patient variability from blood glucose and insulin concentration data is feasible. Good model
predictions were achieved for a 5-hour prediction horizon in a
cross-validation study, especially when the identification data
was fully representative of the patient’s variability.
In this work, the existing patient model is extended to include
a SC route of insulin absorption. Data from twelve type 1 diabetic
patients who underwent four mixed meal studies registering
blood glucose reference data. Three postprandial periods were
used for identification and one for validation following a oneday-leave-out cross-validation study. From the subcutaneous
insulin infusion model two parameters were identified: subcutaneous insulin absorption and plasma insulin elimination rates.
Despite the use of less information as compared to the previous
study fed with plasma insulin data, prediction capability of the
resulting model was satisfactory. MARD for the validation days
was 4.3% in median, with respect to the predicted glucose envelope containing all possible patient responses (median glucose
band width of 72.7 mg/dL) and 56.8% of the data predicted within
the glucose envelope. Data prediction was much better for the best
case permutation fully representing variability, with a 94.5% of
samples predicted with a width of 99.1 mg/dL in median. No
further overestimation was registered in the fitting of the best cases
when compared with the cross-validation fitting performance.
Phases are defined as early follicular, mid-late follicular, periovulatory (ovulation – 1 day), and early-mid-late-luteal phase.
Glycemic risks and variability are reported (LBGI, HBGI, ADRR).
Overall change significance was assessed by repeated measure
ANOVA, specific phases were then emphasized using contrasts.
Results: 12 subjects were studied (Age 34.8 – 6.2 yrs, BMI
26.6 – 2.9 kg/m2, A1c 6.9 – 0.6%) with ovulation confirmed in 33 of
36 cycles. Risk for Hyperglycemia changed significantly during the
cycle (p = 0.023), with HBGI increasing until early luteal phase and
returning to initial levels thereafter (see figure). LBGI was steady in
follicular phase, decreasing thereafter (ns). ADRR increased significantly after ovulation (p = 0.02) to slowly return to initial levels
during the luteal phase. Total daily insulin, as well as total daily
carbohydrates or calories did not show any significant fluctuations.
Conclusions: Women with T1D have glycemic variability
changes that are specific to the individual and are linked to phase of
cycle. Higher glucoses were observed during the periovulatory
period and early luteal phases compared to the early follicular phase,
greater glucose variability was present in the early luteal phase.
P-105
IMPACT OF A REDUCED ERROR RANGE OF SMBG
IN INSULIN-TREATED PATIENTS IN GERMANY
P-104
O. Schnell1, M. Erbach2
RISKS OF HYPOGLYCEMIA AND HYPERGLYCEMIA
ARE LINKED TO MENSTRUAL CYCLE PHASES
IN WOMEN WITH T1D
1
S.A. Brown1, M. McElwee-Malloy1, C.A. Wakeman1,
B.P. Kovatchev1, M.D. Breton1
1
Center for Diabetes Technology, UVA, Charlottesville, USA
Background/aims: A challenge in management of Type 1
Diabetes (T1D) and development of an artificial pancreas is
defining and predicting factors that affect daily glycemic variability. Our aim is to define glycemic variability over several
menstrual cycles, an important inadequately studied area.
Methods: Women with T1D using CSII were studied for 3
consecutive menstrual cycles. Glycemia was assessed using CGM
(Dexcom Platinum) and cycle phases determined using ovulation
prediction kits and repeated serum hormone measures. Cycle
Clinical studies, Forschergruppe Diabetes e.V. at the
Helmholtz Center, Munich Neuherberg, Germany
2
Medical Education, Sciarc Institute, Baierbrunn, Germany
Background: Modelling approaches demonstrate that improvement of accuracy of blood glucose (BG) meters may lead to
cost savings. An improvement of accuracy of BG meters on the
basis of a reduction in error range from 20 to 5% has been reported to be associated with substantial cost savings in Germany.
The aim of this study is to analyse potential cost savings related
to a reduction in error range from 20% to 15% and 10% of
glucose meters in Germany.
Methods: The health economic analysis included the
number of type 1 diabetic and the number of insulin-treated
patients in Germany, the costs for glucose monitoring, a
model on the effects of the improvement of accuracy on the
impact of severe hypoglycemic episodes, HbA1c, and
A-41
subsequently myocardial infarctions and the costs of diabetesrelated complications in Germany. In the model, a reduction
of 1% and 3.5% reduction in severe hypoglycemic episodes,
and a 0.14% and 0.28% reduction in HbA1c were included.
Results: In type 1 diabetes the savings could be equal to a reduction in health care expenditures of more than e1.0 million (20%
vs. 15% error range) and e3.4 million (20% vs. 10% error range).
Respectively, potential savings of more than e6.0 million and e20.1
million were calculated for the group of insulin-treated patients.
Conclusions: The model demonstrates that a reduction of error
range of blood glucose meters from 20% to 15 and 10% may
translate into substantial savings for the German health care system.
P-106
CLINICAL UTILITY OF CGM IN PRE-DIABETES
AND ITS IMPACT ON MODIFYING LIFESTYLES
J. Kesavadev1, A. Shankar1, G. Sanal1, J. Lally1, G. Krishnan1,
S. Jothydev1
1
Diabetes, Jothydev’s Diabetes Research Centre,
Thiruvanathapuram, India
Glycemic excursions in pre-diabetes are seldom evaluated in
clinical practice.
We assessed clinical utility of CGM in pre-diabetes and its
impact on modifying lifestyles to prevent diabetes.
6 patients were enrolled in 3 month study via convenience
sampling based on ability and willingness to follow instructions.
Mean age 48.5 yrs, mean BMI 26.73 kg/m2. Measured blood
glucose were < 126 mg/dl during fasting and < 150 mg/dl post
breakfast. CGM was performed using iPro2 recorder at 0 and 3
months (5–7 days). Advice on lifestyle modifications were repeated once in 2 weeks by a multi-disciplinary team of doctors,
dietitians, pharmacist, nurse educators, device technician, psychologist etc. who made detailed analyses of CGM recordings.
Trends observed in CGM at month 0 included hyperglycemic
spikes 30–90 mins after breakfast and dinner and glycemic
variability missed in usual SMBG. At 3 months, CGM revealed
smooth curves with average weight reduction of 2.35 kgs (Table).
CGM may prove an excellent tool to unravel glycemic excursions most often missed in SMBG in pre-diabetes patients.
CGM could evolve as motivational tool in pre-diabetes patients
to prevent progression to overt diabetes.
CGM
Parameters
(n = 6)
FBS
HbA1c
No: of High
Excursion
No: of Low
Excursion
Highest
Sensor
Value
Lowest
Sensor
Value
Duration
within
70-40 mg/dl
Mean
Standard
Mean
Standard
(mg/dl) deviation (mg/dl)
deviation
(0 month) (0 month) (3 months) (3 months)
110.8
5.9%
7.2
20.77
0.38
5.23
91
5.4%
2.2
6.42
0.28
2.14
2.8
3.82
1.5
1.52
178.2
28.99
151.5
6.44
66
12.33
73.8
3.06
9.27
96.3
2.73
89.7
P-107
SOCIAL MEDIA AND DIABETES: A TOOL TO
IMPROVE GLUCOSE CONTROL IN TYPE 1 DIABETIC
ADOLESCENTS ON INSULIN PUMP: CROSS-OVER
STUDY
G. Petrovski1, T. Milenkovic1, S. Subeska1, B. Jovanovska1,
I. Ahmeti1, M. Zivkovic1
1
Center for insulin pump, University Clinic of Endocrinology,
Skopje, Macedonia
Background and aims: To evaluate results from Facebook as tool to improve glucose control in adolescents with
type 1 diabetes.
Materials and methods: A total of 114 adolescents with type
1 diabetes on insulin pump, ages 13–23, were randomized in two
groups: Regular visits (Group 1)- 55 type 1 diabetes patients
were treated using standard medical protocol with regular visits
at clinic (evaluation glycemic control and education) were given
to the patient and Internet visits (Group 2)- 59 type 1 diabetes
patients were treated using Facebook, Skype and Carelink personal program (Medtronic Diabetes), where the data was
downloaded by the patient at home and interventions (same as
group 1) were given via Facebook. After a period of 6 months
with washout period of 8 weeks, a crossover study was performed for next 6 months, where patients from regular group
switched to internet group and patients from internet group
switched to regular group. A1C was obtained before and every
three months during the study in one year period.
Results: Regular visits were 0.4. – 0.8 per patient/month in
group 1 and Internet visits were 0.5 – 0.9 per patient/month retrospectively. There was significantly improvement in both
groups (group 1 and 2 retrospectively, 7.8 – 0.7% and 7.9 – 1.0%
on beginning with 6.4 – 0.8% and 6.3 – 1.2%, p < 0.05) in the first
six months. After the crossover (the next 6 months), A1c in both
groups (regular 6.5 – 0.7% and internet 6.4 – 0.6%) stays on
satisfactory level without significant difference.
Conclusion: We can conclude that social media such as
Facebook and Skype with special glucose software can be used
as treatment option for type 1 diabetics on insulin pump.
P-108
EFFECT OF GLYCEMIC VARIABILITY ON QUALITY
OF LIFE IN TYPE 1 DIABETES
P. Beato-Vibora1, M.A. Tormo-Garcia2, R. Rodrı́guez-López3,
F.J. Arroyo-Dı´ez4, F. Morales-Pérez1, C. Tejera-Pérez1
1
Department of Endocrinology and Nutrition, Badajoz
University Hospital, Badajoz, Spain
2
Department of Physiology, Extremadura University, Badajoz,
Spain
3
Genetics Unit, Badajoz University Hospital, Badajoz, Spain
4
Department of Paediatrics, Badajoz University Hospital,
Badajoz, Spain
Background and aims: Poor glycemic control impacts
quality of life (QL). The aim of the study is to evaluate
the influence of glycemic variability (GV) on QL in type 1
diabetes.
Material and Methods: We performed a CGM (Ipro2,
Medtronic Minimed) for 4.3 – 1.8 days in 32 type 1 diabetes
patients, 19 women, aged 34 – 10 years old, duration of diabetes
A-42
15 – 7 years, HbA1c 8.2 – 1.1%. GV parameters were calculated
by EasyGVª program. A validated QL questionnaire was used.
Results: Health scores correlated negatively with CONGA (r = - 0.446), J-index (r = - 0.352) and HBGI (r =
- 0.376), (p < 0.05). Patients with lower health scores had
higher CONGA (8.7 – 1.7 vs 7.4 – 1.4), J-index (55.6 – 16.2
vs 42.3 – 14.7) and HBGI values (12.4 – 5.1 vs 8.4 – 3.7)
(p < 0.05) than patients with higher health scores. CONGA
was significantly higher in patients with lower psychological scores (8.8 – 1.9 vs 7.3 – 1.3; p = 0.020).
In women and patients older than 32 years old, GV parameters
correlated with different QL indexes (Table 1), while in men and
patients younger than 32 years old, no correlation was found.
15.1 – 3.2 y, diabetes duration was 5.6 – 3.5 y and A1C of
8.1 – 1.1%. OCL was started in all 54 potential nights. Full OCL
lasting a minimum 6 hours was achieved in 41 nights (76%). OCL
was stopped on 13 nights, mainly due to sensor error > 20% or loss
of sensor reading (12%) and pump or infusion set failure (9%).
The median percent time spent between 70–150 mg/dL was
55% (25, 80) on control nights (n = 52) vs. 73% (50, 91) with
OCL (n = 41), p = 0.012. Time spent in the hypoglycemia
( < 70 mg/dL) was reduced with median of 0% (0,11) during
control vs. 0% (0,0) in full OCL period, p < 0.001.
Overnight automated insulin delivery in children and adolescents with type 1 diabetes resulted in a significant reduction of
nocturnal hypoglycemia and increased time spent in range
compared to sensor-augmented pump therapy.
Table 1. Correlation Coefficient Between
GV Parameters and QL Indexes
P-110
Age ‡ 32
Women
Overall QL
Health
Health
Socio-economic
- 0.504
- 0.486
- 0.483
- 0.469
NS
NS
- 0.629
- 0.538
- 0.549
- 0.575
NS
NS
- 0.636
- 0.634
- 0.611
- 0.524
NS
NS
NS
NS
NS
NS
- 0.505
- 0.640
CONGA
J
HBGI
M
DS
MAGE
All p < 0.05
Conclusions: QL indexes reflecting overall QL, health, psychological and socio-economic aspects are affected by GV,
mainly in women and older patients.
P-109
OVERNIGHT GLUCOSE CONTROL WITH MODULAR
CONTROL TO RANGE ALGORITHM IN CHILDREN
AND ADOLESCENTS WITH TYPE 1 DIABETES
AT DIABETES CAMP
T. Ly1, D. De Salvo1, P. Clinton1, M.D. Breton2,
D. Chernavvsky2, B. Mize2, P. Keith-Hynes2, B.P. Kovatchev2,
D.M. Wilson2, B.A. Buckingham2
1
University Medical Center, Stanford, USA
2
Center for Diabetes Technology Department of Psychiatry and
Neurobehavioral Sciences and Department of Medicine
Division of Endocrinology, University of Virginia,
The objective of this study was to determine the efficacy of an
automated insulin delivery system in overnight closed-loop
(OCL) control in participants with type 1 diabetes aged 10–35
years in a camp setting.
The system was informed by a G4 Platinum continuous glucose
sensor (DexCom, Inc.) and controlled a modified t:slim insulin
pump (Tandem Diabetes Care, Inc.). Insulin doses were computed
to avoid hypoglycemia and prolonged hyperglycemia, whilst
slowly achieving glycemic control overnight. The system was implemented on the DiAs mobile platform (University of Virginia).
Twenty participants were randomized to either OCL (n = 54) or
sensor-augmented pump (control) (n = 52) on alternate nights in
up to 6 consecutive nights at camp. The mean – SD age was
‘‘STRESS TESTING’’ A FUZZY LOGIC ARTIFICIAL
PANCREAS CONTROLLER
C. Greenbaum1, I. Hirsch2, R. Kircher3, D. Matheson3,
R. Mauseth4
1
Diabetes Research Program, Benaroya Research Institute,
Seattle, USA
2
Metabolism Endocrinology and Nutrition, University of
Washington, Seattle, USA
3
Engineering, Dose Safety Inc., Seattle, USA
4
Medicine, Dose Safety Inc., Seattle, USA
Background: We have developed an Artificial Pancreas (AP)
dosing controller, the FLC, using Fuzzy Logic methodology.
Methods: To assess the robustness of the ver 2.0 FLC in the
clinical environment we ‘stress tested’ it under two different
protocols, one involving exercise and another involving consumption of 120 gm CHO pizza meal involving a sixteen subjects. We used repeat studies on the same subjects increasing or
decreasing the dosing intensity by varying the personalization
factor (PF) for a total of 27 studies. After completing nine ‘pizza’
and four exercise studies, we used a dosing analysis tool to
evaluate the v.2.0 FLC dosing matrix rules. Changes in the FLC
dosing rules matrix in v.2.1 FLC that were validated through
regression testing with clinical datasets. 7 studies were then
conducted on 6 subjects in the exercise protocol and 7 studies on
3 subjects in the pizza protocol using v.2.1 FLC.
Results: V. 2.1 FLC showed dramatic improvements over
version 2.0. For the 19-hour exercise studies, mean glucose
dropped 27% to 146 mg/dL ( + /-13), % time in 70–180 mg/dL
range increased 50% to 80% ( + /-9.4), %time > 180 mg/dL decreased 59% to 19% ( + /-1.9). Midnight to 8 am %time in 70–
180 mg/dL increased 58% to 96% ( + /-4.1). For the six hours
following the pizza meal the mean %time > 250 mg/dL decreased from 62% to 32%. %time < 70 mg/dL for both FLC
versions was less than 1% for the pizza and exercise studies.
Conclusion: Stress testing an AP Controller can lead to improved glucose control.
P-111
NO EFFECT OF AGE OF INSULIN CATHETER
ON OVERNIGHT CLOSED-LOOP GLUCOSE
CONTROL IN HOME SETTINGS
M. Nodale1, D. Elleri1, J. Allen1, R. El-Khairi1, H. Murphy1,
M.E. Wilinska1, C. Acerini2, D. Dunger2, R. Hovorka1
1
Wellcome Trust-MRC Institute of Metabolic Science,
University of Cambridge Metabolic Research Laboratories,
2
Department of Peadiatrics, University of Cambridge,
Objective: Insulin catheter wear-time can influence insulin
absorption and may affect glucose control. We investigated the
relationship between the age of the insulin catheter and overnight
glucose control in adolescents with type 1 diabetes during home
use of automated closed-loop insulin delivery.
Method: 16 adolescents [M 4; age 15.5 – 2.1 yrs; A1C
7.9 – 0.8%; BMI 23.3 – 2.2 kg/m2, duration of diabetes 6.1(3.8) yrs;
total daily dose 0.9(0.2) U/kg/day; mean – SD] participated in a
study evaluating overnight closed-loop in home settings. During
a three-week period, overnight insulin delivery was modulated
by a model predictive control algorithm. Mean overnight glucose
was computed from continuous glucose sensor data between
23:00 and 07:00. Instances of infusion catheter replacements
were obtained from pump logs.
Result: Closed-loop was operational for at least 4 hours and
catheter age information available on 184 nights. Mean overnight
glucose was 7.0 (6.3,7.9) mmol/L, median (IQR). A repeated
measures regression model with an autoregressive first-order
covariance structure adjusted for catheter replacements found no
effect of catheter age on overnight mean glucose (p = 0.78).
Conclusion: Overnight glucose control by a model predictive
control algorithm is not affected by the wear-time of the insulin
catheter in adolescents with type 1 diabetes.
A-43
3
Diabetes, Medtronic Minimed, Northridge, USA
Endocrinology and Diabetes, Institute of Endocrinology and
Diabetes, Sydney, Australia
5
Endocrinology and Diabetes, Women and Children’s Hospital,
Adelaide, Australia
6
Endocrinology and Diabetes, Royal Children’s Hospital,
Melbourne, Australia
7
Endocrinology and Diabetes, John Hunter Children’s
Hospital, Newcastle, Australia
8
Endocrinology and Diabetes, Princess Margaret Hospital, Perth,
Australia
4
The aim of the study was to determine the effectiveness of
Predictive Low Glucose Management (PLGM) system in preventing hypoglycaemia in individuals with type 1 diabetes
(T1DM). The primary outcome was the glucose nadir in participants following moderate-intensity exercise and increased subcutaneous insulin bolus with and without PLGM.
PLGM system consists of a Medtronic Veo pump, Enlite
sensor, MiniLink REAL-Time transmitter, Bluetooth-RF translator and PLGM algorithm operating from a Blackberry smartphone.
PLGM suspends basal insulin delivery when the preset hypoglycaemic threshold is predicted to be reached in 30 minutes.
Participants with T1DM performed 30–60 minutes of moderate-intensity exercise or were administered a subcutaneous
bolus of insulin following a glucose stabilisation period on basal
CSII on 2 separate days; randomised to a control day with PLGM
off and an intervention day with PLGM on. On both days, participants were observed until plasma glucose dropped to 50 mg/
dL or were symptomatic.
21 participants were studied with exercise. PLGM suspended
basal insulin in 17 and did not suspend in 4 as hypoglycaemia did
not occur. Plasma glucose nadir with PLGM on was higher than
with PLGM off in 7 of the 17 participants. 8 participants were
studied with insulin bolus. PLGM suspended in 7 and prevented
hypoglycaemia in 6 participants.
PLGM system appears to be more effective when hypoglycaemia is induced by insulin bolus than exercise. This difference,
if confirmed may be due to different rate and trajectory of plasma
glucose decline with exercise as compared with insulin bolus.
P-113
VIRTUAL TRIAL PREDICTS CLINICAL TRIAL
OUTCOMES – ACCELERATING DEVELOPMENT AND
REDUCING RISK THROUGH MODEL-BASED DESIGN
C.C. Palerm1, L. Lintereur1, S. Monirabbasi1, L. Desborough1
1
Diabetes, Medtronic Inc., Northridge, USA
P-112
PREVENTION OF HYPOGLYCAEMIA WITH
PREDICTIVE LOW GLUCOSE MANAGEMENT
SYSTEM: COMPARISON OF HYPOGLYCLAEMIA
INDUCTION WITH EXERCISE AND SUBCUTANEOUS
BOLUS
M. Abraham1, R. Davey2, N. Paramalingam2, B. Keenan3,
G. Ambler4, J. Fairchild5, F. Cameron6, B. King7, T. Jones8,
E. Davis8
1
Endocrinology and Diabetes, Princess Margaret Hsopital,
Perth, Australia
2
Diabetes, Telethon Institute for Child Health Research, Perth,
Australia
Bringing new technologies to market can be expensive and the
process fraught with technical risk. Clinical trials are expensive
and take time to complete; therefore, the desire is to maximize
confidence that the final design meets expectations.
We used model-based design in the development of a predictive
low glucose management (PLGM) algorithm. The goal was to
improve on the performance of the current low glucose suspend
(LGS) algorithm. To this end, we created a model to run virtual
clinical trials. In this virtual trial there were multiple ‘study arms’
with different algorithms and parameter settings. Among these
was a baseline case of a pump without automatic suspend, as well
as the LGS algorithm already in the market.
Recently, the ASPIRE In-Home clinical trial evaluated the
efficacy and safety of the LGS algorithm. This provided an
A-44
opportunity to validate the modeling platform used for the virtual
clinical trials.
The primary effectiveness outcome metric was the area under
the curve (AUC) for hypoglycemic events (< 65 mg/dL). The
virtual trial showed a statistically significant (p < 0.001) reduction in hypoglycemic AUC, with a reduction in the median AUC
of 35.4%. In the ASPIRE In-Home study the LGS group showed
a reduction in the median AUC of 39.5%, also statistically significant (p < 0.001). The safety outcome was also consistent between the two trials.
The consistency of the outcomes predicted by the virtual trials
with those observed in the ASPIRE In-Home study increase our
confidence that the performance improvements of PLGM will be
realized in a clinical setting.
Key words: Hawthorn, HbA1C, blood glucose, lipids level, type 2
diabetes.
P-114
Background: Initial benefits of OHA are caused by increasing
insulin secretion from deteriorating pancreatic beta cells to the
point of total failure. Initial insulin therapy can rapidly address
the glucose toxicity and improve beta cell function in newly
diagnosed type 2 diabetics.
Objectives: This study aims to evaluate the effectiveness of
initial insulin therapy versus oral hypoglycemic agents in terms
of glucose control, pancreatic beta-cell function and adverse
effects.
Search Strategy: PubMed, EMBASE, Cochrane Library,
Science Direct, Clinical Trials.gov were searched using the
medical subject headings (MeSH): diabetes mellitus type 2, insulin, oral hypoglycemic agent.
Selection Criteria: RCTs with adults newly diagnosed with
type 2 DM as subjects and given insulin ( – metformin) vs. OHA
(multiple or monotherapy) with outcomes of glycemic control,
measures of insulin resistance and beta-cell function, weight and
hypoglycemia were included.
Data Collection and Analysis: RCTs with quality grade of
B were included and results summarized as graphs and forest
plots using the random effects due to foreseen sources of
heterogeneity.
Results: Presence of substantial heterogeneity prevents us
from making a conclusion. All four studies showed lower post
treatment BMI among participants in the insulin treatment arm.
An opposite finding was expected as insulin is known to cause
weight gain. Main adverse effects where hypoglycemic episodes
and diarrhea.
EFFECTS OF HAWTHORN (CRATAEGUS) ON HBA1C
AND LIPIDS LEVELS IN DIABETIC PATIENTS (TYPE 2)
A. Aljamal1
1
Medical Technology, Zarqa University, Zarqa, Jordan
The present study was designed to investigate the effects of
supplementation of Hawthorn on HbA1C and lipids levels among
type 2 diabetics. The samples consisted of 55 subjects with type 2
diabetes and the doses of Hawthorn were equally administered
orally in the form of capsules each capsules contain (500 mg), with
breakfast, lunch and dinner. The doses were given for 12 weeks.
Blood samples were taken on the starting day of the experiment and
at the end of 12 weeks. The fasting blood glucose and lipids levels
of types 2 were determined, from the results obtained the mean
value of fasting blood glucose levels for Hawthorn doses on the
starting day, was found to be 223.6 mg/dl and the mean values of
HbA1C was 8.5% and for lipids were triglyceride (235.5 mg/dl),
total cholesterol (310 mg/dl), low-density lipoprotein (LDL)
(155.2 mg/dl) and high density lipoprotein (HDL) (52.4 mg/dl).
When the diabetic individuals used the doses of Hawthorn for 12
weeks, their mean fasting blood glucose level dropped to
186.34 mg/dl, HbA1C 7.2, triglycerides (160 mg/dl), total cholesterol (187.6 mg/dl), LDL (115.5 mg/dl) and increase HDL (69.2.
mg/dl) The reduction in the blood glucose and lipids levels were
significant at P < 0.05 P < 0.001 and respectively.
P-115
INSULIN VERSUS ORAL HYPOGLYCEMIC AGENT
AS INITIAL THERAPY FOR NEWLY DIAGNOSED
DIABETES MELLITUS TYPE 2: A SYSTEMATIC
REVIEW AND META-ANALYSIS
M. Dujunco1, J.H. Gorriceta1, O.A. Dampil1, R. Mirasol1
1
Department of Medicine, St. Luke’s Medical Center,
Quezon City, Philippines
Conclusion: Among newly diagnosed type 2 DM patients,
there is inconclusive evidence that use of insulin compared to
OHA as initial management resulted in improvement glycemic
control, decrease in insulin resistance, and improvement in beta
cell function.
P-116
ASSOCIATION OF INSULIN ANTAGONIST
ADIPOKINES GENE POLYMORPHISM WITH
METABOLIC RISK FACTORS IN POSTMENOPAUSAL
WOMEN
S. Kumar1, V. Gupta1, S. Mishra1, N. Srivastava1, S. Mishra1,
H. Kulshretha1
1
Physiology, King George’s Medical University, Lucknow, India
Introduction: Insulin antagonist adipokines such as TNF-a,
IL-6 and Resistin impart an essential role in lipid metabolism
insulin sensitivity and energy expenditure. Disturbance of these
peptides level could lead to metabolic diseases.
Aim & Objective: The present study was design to investigate insulin antagonist adipokines (TNF-a, IL-6 and Resistin)
gene polymorphism and their correlation with metabolic risk
factors, insulin resistance in postmenopausal women.
Method: This is a case control study. Total 230 postmenopausal with & without metabolic syndrome were recruited for the
study. Fasting blood samples were collected. Anthropometrical
parameters and metabolic risk factors were measured. Circulating adipokines, insulin was estimated by ELISA and adipokines
gene polymorphism was done by PCR-RFLP.
Result: Homozygous mutant genotype (GG v/s GA + AA)
(p = < 0.042: OR = 1.84: 95% CI = 1.02–3.31) and mutant allele
(A) (p = 0.032: OR = 1.78: 95% CI = 1.04–3.05) of TNF- a and
(CC v/s CG + GG) (p = < 0.005: OR = 2.22: 95% CI = 1.29–3.80)
and mutant allele (G) (p = 0.004: OR = 1.79: 95% CI = 1.21–2.64)
of Resistin gene polymorphism were observed higher in postmenopausal women with metabolic syndrome as compare postmenopausal women without metabolic syndrome. Plasma
glucose, serum TG and serum cholesterol, insulin and circulating
TNF- a, IL-6 and resistin were found significantly high in postmenopausal women with metabolic syndrome.
Conclusion: Our results suggest that the adipokines gene
(TNF- a 308 G/A & Resistin 420 C/G) polymorphism is likely to
play an important role in the development of metabolic syndrome
and metabolic abnormalities.
P-117
THE EFFECT OF NUTRITIONAL EDUCATIONAL
PROGRAM ON GLYCEMIC CONTROL OF ELDERLY
PATIENTS WITH TYPE 2 DIABETES
A. Hassanzadeh1, G.R. Shrifirad2, A. Najimi2, L. Azadbakht3
1
Epidemiology & Biostatistics, Isfahan University of Medical
Sciences, Isfahafan, Iran
2
Health Promotion and Health Education, Isfahan University
of Medical Sciences, Isfahafan, Iran
3
Food Security Research Center, Isfahan University of Medical
Sciences, Isfahafan, Iran
Background: The objective of this study was to determine the
effects of nutritional educational program on glycemic control of
elderly patients with type 2 diabetes.
A-45
Methods: In this parallel randomized controlled educational
trial, 100 diabetic elderly patients ( ‡ 60 years) were chosen (50
in control and 50 in test group). Nutrition education based on
beliefs, attitudes, subjective norms and enabling factors
(BASNEF model) was conducted. Dietary intake and glycemic
indices as well as the components of the BASNEF model were
assessed. The four 70-minute educational sessions were conducted in one month. Three months after training intervention,
questionnaire was completed again and blood tests were performed.
Results: Increased intake in the mean daily servings of fruits
(0.91 – 0.82 vs. 0.17 – 0.79; p < 0.001), vegetables (0.87 – 0.86
vs. 0.03 – 1; p < 0.001) and dairy (0.35 – 0.52 vs. and
0.12 – 0.76; p < 0.001) were reported in the intervention group
compared to the control group (p < 0.001). The amount of fruits,
vegetables and dairy increased in the intervention group at the
end of the study (p < 0.001). However, it was not significantly
changed in the control group. HbA1c and fasting blood sugar
(FBS) levels decreased significantly in the interventional group
compared to the control group (p < 0.001). Comparing the
amount of FBS and HbA1c at the end of the study with the
baseline measurements showed significant reduction in interventional group (p < 0.001).
Conclusions: BASNEF–based nutritional educational intervention improved dietary intakes as well as glycemic control, 3
months after intervention.
P-118
EFFECTS OF CAPTOPRIL AND ENALAPRIL ON
ADVANCED GLYCATION END PRODUCTSINHIBITED NITRIC OXIDE SIGNALING IN HUMAN
RENAL TUBULAR CELLS
J. Huang1, C. Chen1, Y. Huang1
1
Biological Science and Technology, Chung Hwa University of
Medical Technology, Tainan, Taiwan
To explore whether angiotensin-converting enzyme inhibitors captopril and enalapril were linked to altered advanced
glycation end products (AGE)-mediated renal tubulopathy in
diabetic nephropathy, the molecular mechanisms of captopril
and enalapril responsible for inhibition of AGE-reduced nitric
oxide (NO) bioactivity in human renal proximal tubular cells
were examined. We found that raising the ambient AGE
concentration causes a dose-dependent decrease in NO generation when compared with control or non-glycated BSA.
Captopril and enalapril significantly reverse AGE-inhibited
NO generation and induces high levels of cGMP synthesis and
cGMP-dependent protein kinase (PKG) activation in these
cells. Interestingly, treatments with captopril and enalapril,
the NO donor S-nitroso-N-acetylpenicillamine, and the nuclear factor-kappa B (NF-jB) inhibitor pyrrolidine dithiocarbamate markedly attenuated AGE-inhibited inducible
nitric oxide synthase (iNOS) protein synthesis and NO generation. Moreover, AGE-induced synthesis of fibronectin and
collagen IV and cellular hypertrophy were reversed by captopril and enalapril. The ability of captopril and enalapril to
suppress AGE-induced NF-jB activation was also verified by
the observation that it significantly reduced IjBa kinase (IKK)
activity. These findings indicate for the first time that captopril
and enalapril attenuates AGE-inhibited the iNOS/NO/PKG
pathway at least partly by decreasing IKK/NF-jB signaling in
human renal tubular cells.
A-46
P-119
ASSOCIATION OF ESBL GENE (CTX-M, TEM, SHV)
POSITIVITY IN ISOLATES OF DIABETIC FOOT
INFECTION FROM NORTH INDIA:
A 3-YEAR HOSPITAL BASED STUDY
Z. Mohammad1, A. Jamal1, M. Abida2
1
Rajiv Gandhi Centre for Diabetes & Endocrinology, Aligarh
Muslim University, Aligarh, India
2
Department of Microbiology, Aligarh Muslim University,
Aligarh, India
Aim: Aim of this study was to evaluate the incidence and
factors responsible for plasmid mediated ESBL infection among
patients with diabetic foot ulcer (DFU).
Methods: A prospective study on 162 DFU inpatients treated
in a multidisciplinary based diabetes and endocrinology centre of
J. N Medical College of Aligarh Muslim University, Aligarh,
India during the period of 2008–2012. Detailed history and patient’s profile, grade of DFU, co-morbidities and complications,
laboratory data and final outcome were collected. Standard
methods were used for culture identification, sensitivity testing
and ESBL detection. PCR for bla genes was performed and the
risk factors for bla gene positivity were determined by univariate
analysis with 95% of CI.
Result: A total of 127(78.3%) Enterobacteriaceae members
were isolated. The blaCTX–M gene was positive in 81.8% isolates
followed by blaTEM (50%) and blaSHV (46.9%). The significant
predictive factors which were more likely to be associated with
bla(CTX-M, TEM, SHV) gene have an association was LDL-C
( > 100 mg/dl) [OR 13.4, RR 8.65], triglycerides ( > 200 mg/dl)
[OR 6.5, RR 4.11], duration of infection > 1 month [OR 1.25, RR
1.21], nature of ulcer (necrotic) [OR 5.33, RR 4.54], T2DM [OR
2.15, RR 1.92], history of previous antibiotic use [OR 6.75, RR
5.60], Smoking history [OR 1.098, RR 1.08], HDL-C( < 40 mg/
dl) [OR 3.29, RR 2.80], and total cholesterol ( > 150 mg/dl) [OR
3.52, RR 2.9] for bla gene positivity.
Conclusions: ESBL constitutes a major threat to currently
available b-lactam therapy leading to complications in DFUs.
Aminoglycosides, cephalosporin & beta lactam inhibitor drugs
would probably be more appropriate empirical agent often establishing the patient’s history of previous antibiotic use and the
detection ESBL shall be done on routine basis.
P-120
SHORT-TERM RESVERATROL SUPPLEMENTATION
IMPROVES METABOLIC PROFILE IN TYPE 2
DIABETES
A. Movahed1, I. Nabipour1, X.L. Louis2, S. Joseph2, L. Yu3,
T. Netticadan3
1
Clinical Biochemistry, Bushehr University of Medical
Sciences, Bushehr, Iran
2
Physiology, University of Manitoba, Winnipeg, Canada
Canadian Centre for Agri-Food Research in Health and
Medicine, Agriculture and Agri-Food Canada, Winnipeg,
Canada
3
Few earlier studies have tested resveratrol as an anti-diabetic
supplement in humans. However, the results to date on the efficacy of resveratrol to significantly reduce blood glucose have
been inconclusive. Accordingly, the main objective of this study
was to examine the effectiveness of resveratrol in lowering blood
glucose in presence of standard anti-diabetic treatment in patients with type 2 diabetes, in a randomized placebo-controlled
double-blinded parallel clinical trial. A total of 66 subjects were
enrolled to this study, and randomly assigned to intervention
group (n = 32) which was supplemented with resveratrol at a dose
1 g/day for 45 days, and control group (n = 34) which received
placebo tablets. All patients were asked to continue their antidiabetic medications while in the study. Body weight, blood
pressure, fasting blood glucose, haemoglobin A1c, insulin, triglycerides, total cholesterol, low density lipoprotein, high density lipoprotein, and markers of liver and kidney damage were
measured at baseline, and after the treatment period. Insulin resistance and beta cell function was calculated using homeostasis
model of assessments, HOMA-IR and HOMA-b respectively.
Our results show that resveratrol treatment significantly decreased systolic blood pressure, fasting blood glucose, haemoglobin A1c, insulin and insulin resistance, while HDL was
significantly increased, when compared to their baseline levels.
Liver and kidney function markers were unchanged in the intervention group while alkaline phosphatase was significantly
increased in the placebo group. Overall, this study showed that
resveratrol supplementation exerted strong anti-diabetic effects
in patients with type 2 diabetes.
A-47
Purpose: Diabetes is a metabolic disorder and is characterized by high blood glucose level (Hyperglycemia). Antidiabetic
property of bioactive peptide is related to inhibition of Alphaglucosidase and Dipeptidyl Peptidase-IV (DPP-IV) enzymes,
which cause Type 2 diabetes. Therefore, inhibition of Alphaglucosidase and DPP-IV is an effective strategy for controlling/
managing of Type 2 diabetes. Bioactive peptide fragments are
formed during degradation of the milk proteins by digestive
enzymes in the gastrointestinal tract or by proteolytic lactic acid
bacteria (LAB) during fermentation of milk. Hence, the present
study has been designed to exploit the proteolytic activity of
Lactobacillus spp. for the production of anti-diabetic milk
peptides having Alpha-glucosidase and DPP-IV inhibitory
activity
Methods used: In present study, 22 Lactobacillus strains were
procured from National Collection of Dairy Cultures, NDRI,
Karnal. Milk was fermented with Lactobacillus strains and
Evaluated for Proteolysis by estimating peptide content by OPA
method and Alpha-glucosidase and DPP-IV inhibitory activity
by spectrophotometeric method. The process was optimized for
the production of these bioactive peptides in milk during fermentation.
Summary of results: Based on results, all 22 isolates were
observed to possess different proteolytic activity and Alphaglucosidase and DPP-IV inhibitory activity.
Conclusion: The results from this study showed that peptides
with Alpha-glucosidase and DPP-IV inhibitory activity can be
generated by using Lactobacillus spp. from milk proteins.
Therefore, these anti-diabetic peptides can be produced in fermented dairy product by selected proteolytic strains of Lactic
Acid Bacteria or peptides rich formulation can be incorporated
into functional foods or administered via nutraceuticals.
P-122
P-121
PRODUCTION OF ANTI-DIABETIC MILK BIOACTIVE
PEPTIDES BY USING LACTOBACILLUS SPP
METFORMIN REDUCES GLYCEMIC FLUCTUATIONS
IN TYPE 2 DIABETIC PATIENTS WITH CHRONIC
HEART FAILURE
P. Patil1, S. Anand1, S. Tomar1, S. Mandal1
I.G. Pochinka1, L.G. Strongin1, A.A. Volkov1
1
1
Dairy Microbiology, National Dairy Research Institute,
Karnal, India
Department of Endocrinology and Internal Medicine, Nizhniy
Novgorod State Medical Academy, Nizhny Novgorod, Russia
A-48
Background: The increased risk of lactic acidosis may be
considered an argument against metformin in type 2 diabetes
(T2DM) in the presence of chronic heart failure (CHF). Meanwhile, the register data indicate widespread use of metformin in
CHF patients. The purpose of the study is evaluation the efficacy
and safety of metformin in these patients.
Material and Methods: 30 T2DM patients with CHF and
HbA1c >7.5% were randomized into a main group (16 subjects,
metformin in the dose up to 2000 mg was administrated) and
control group (14 subjects). The efficacy was assessed by
HbA1c, glycemia and MAGE. The influence on CHF was assessed by BNP, echo and results of 6-minute walk test (6MWT).
Safety was assessed by pH, BE, lactic acid, ALT and eGFR.
Follow-up was 6 months.
Results: Significant changes of HbA1c, lactic acid, pH, BE,
ALT, eGFR, BNP, echo parameters and 6MWT were not detected during the study in both groups. Significant effect of
metformin on the glycemic fluctuations was identified. The
median of MAGE during 6 months (MAGE was evaluated
weekly) in the metformin group was 2.4 [1.7, 3.4] mmol/l vs 4.0
[3.0, 5.4] mmol/l in the control (p = 0.02, Mann-Whitney). The
figure shows examples of glycemic curves of 2 patients with
equal doses of insulin (red - control, blue - metformin).
Conclusion: Application of metformin in T2DM patients with
CHF reduces glycemic fluctuation without increasing the risk of
lactic acidosis and an unfavorable course of heart failure.
P-123
INCREASED INFLAMMATORY ACTIVITY AND
CHRONIC MICROVASCULAR COMPLICATIONS
IN TYPE 1 DIABETES
D. Popovic1, M. Mitrovic1, D. Tomic-Naglic1, B. Vukovic2,
E. Stokic1, B. Kovacev-Zavisic1
1
Clinic for Endocrinology Diabetes and Metabolic Disorders,
Clinical Center of Vojvodina Medical Faculty University of
Novi Sad, NOVI SAD, Serbia
2
Emergency Center, Clinical Center of Vojvodina Medical
Faculty University of Novi Sad, NOVI SAD, Serbia
Background and aim: Chronic hyperglycemia causes exceeded
Advanced Glycation End-products (AGEs) synthesis. This leads to
increased macrophage activation, oxidative stress and production of
inflammatory cytokines. Chronic inflammation causes endothelial
dysfunction. The aim of our study is analysis of C-reactive protein
(CRP), interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a)
levels in relation to existence of chronic microvascular complications in type 1 diabetes patients.
Methods: Retrospective study included 76 type 1 diabetes
patients. Blood was sampled for glucose metabolism and lipid
parameters, CRP, IL-6 and TNF-a. Classical fundoscopy, neurological examination and 24 hour albuminuria measurement
were performed and 46 patients were diagnosed with at least one
of the chronic microvascular complications. For statistical
analysis we used v2, Mann Whitney and Kruskal Wallis test.
Results: Patients with chronic microvascular complications
were older and had longer duration of disease (p = 0.015;
p < 0.0001). They had higher total (p = 0.021), LDL cholesterol
(p = 0.048) and triglycerides (p = 0.002). CRP and TNF-a were
higher in patients with chronic microvascular complications
(p = 0.004; p = 0.048). Diabetic retinopathy patients had higher
CRP (p = 0.039), IL-6 (p = 0.039) and TNF-a (p = 0.045) than
patients without retinopathy. Patients with diabetic polyneuro-
pathy had higher CRP (p = 0.009) than patients without this
complications. Diabetic nephropathy patients didn’t have higher
values of inflammatory markers than patients with normoalbuminuria.
Conclusion: Chronic microvascular complications are associated with increased inflammatory activity reflected through
higher values of inflammatory markers. This requires investigation of specific anti-inflammatory drugs and their possible
favorable effects on prevention of development of chronic
microvascular complications, especially in patients with long
duration of disease.
P-124
EFFECTIVENESS OF SESAME AND RICE BRAN OILS
BLEND IN TYPE 2 DIABETIC PATIENTS-AN OPEN
LABEL, RANDOMIZED STUDY
D. Sankar1, S. Ravinder2, C. Biprabuddha3
1
Department of Cardiovascular Diseases, Fukuoka University
Chikushi Hospital, Fukuoka, Japan
2
Department of Non-communicable Diseases, Indian Council
of Medical Research, New Delhi, India
3
Research and Development, Adani Wilmar Limited,
Ahmedabad, India
Recently there is substantial interest in the potential health
benefits of sesame and rice bran oils, especially in relation to
cardiovascular health. The objective of the current study was to
examine the extent to which the daily incorporation of the blend of
unrefined sesame (20%) and physically refined oryzanol rich rice
bran oils (80%) as cooking oil in type 2 diabetic patients. This
open label study comprised of three hundred, men (n = 162) and
women (n = 138) with type 2 diabetes mellitus and they were
randomly assigned to three groups, receiving VivoTM, a blend of
sesame and rice bran oils (n = 100), 5 mg/d (single dose) of glibenclamide (n = 100), or their combination (n = 100). Blend of
sesame and rice bran oils was supplied to the respective groups and
instructed to use it as sole cooking oil for 60 days. Blood glucose was measured at 0, 15, 30, 45 and 60th days. HbA1C and
lipid profile were measured at 0 and 60th days. Blood glucose
and HbA1C were significantly lowered in oil alone treated and/
or glibenclamide groups. Total, low-density lipoprotein cholesterols and triglycerides were significantly reduced by oils
blend or combination with glibenclamide while HDL-C was
significantly improved respectively. Replacement of cooking
oils with the blend of sesame and rice bran oils articulates rapid
and clinically vital improvements in blood glucose, HbA1C and
lipids, providing the evidence that this oils blend could be effective edible oil with potentially important anti-diabetic and
cardio protective efficacies.
P-125
ALPHA-LIPOIC ACID AND ANTI-OXIDANT DIET
HELPS TO IMPROVE ENDOTHELIAL DYSFUNCTION
IN CHILDREN AND ADOLESCENTS WITH TYPE 1
DIABETES
A. Scaramuzza1, S. Ungheri1, F. Redaelli1, L. De Angelis1,
E. Giani1, A. Gazzarri1, M. Macedoni1, V. Comaschi1,
M. Ferrari1, G.V. Zuccotti1
1
Pediatrics, University of Milan, Milano, Italy
After evaluating the prevalence of early endothelial dysfunction, as measured by mean of reactive hyperemia in adolescents with type 1 diabetes (T1D), at baseline and after 1-year
follow-up, we started a 6-month, double-blind, randomized trial
to test the efficacy of an anti-oxidant diet ( – a-lipoic acid) in
improving endothelial dysfunction. Sixty-one children and adolescents, ages 16 – 3.5 yrs., with T1D since 8.9 – 4.3 yrs., using
either MDI or CSII, were randomized into 3 arms: a) anti-oxidant
diet 10.000 ORAC + a-lipoic acid; b) anti-oxidant diet 10.000
ORAC + placebo; c) controls. BMI, blood pressure, fasting lipid
profile, HbA1c, insulin requirement, dietary habits and body
composition were determined in each child. After 3 months BMI,
blood pressure, lipid profiles, HbA1c, and body composition did
not change, while insulin requirement significantly decreased
only in patients in arm with anti-oxidant diet and a-lipoic acid
(0.74 – 0.18 U/kg/day vs. 0.83 – 0.26 U/kg/day, p < 0.05), as well
as bolus insulin (22.0 – 9.4 U/day vs. 26.3 – 10.8 U/day,
p < 0.05), but not basal insulin (25.9 – 9.4 U/day vs. 25.5 – 8.6 U/
day, P NS). After 6 month we evaluated till now only 24 patients
(study ended on September 30th). These very first data are very
encouraging (Figure) with a significant improvement of endothelial function in group treated with a-lipoic acid. Insulin requirement and bolus insulin keep to be decreased. Adolescent
with T1D displayed evidence of endothelial improvement after
a-lipoic acid and anti-oxidant diet, but not in controls. Moreover,
to our knowledge these data demonstrate for the first time and
effect in sparing insulin in T1D in pediatrics.
P-126
SILYMARIN INDUCES EXPRESSION OF PANCREATIC
GLP-1 AND b-CELLS NEOGENESIS IN A
PANCREATECTOMY MODEL
C. Soto1, L. Raya2, J. Pérez3, I. González3, S. Pérez3
A-49
mellitus. It has been reported that GLP-1 induces b pancreatic cells
proliferation and differentiation and inhibits its apoptosis. Previously, we reported that Silymarin recovers normal morphology
and endocrine function of damaged pancreatic tissue after alloxaninduced diabetes mellitus in rats. The aim of this study was to
analyze the effect of Silymarin on pancreatic GLP-1 expression
and its consequence in b cells neogenesis. 60 male Wistar rats were
partially pancreatectomized and divided into twelve groups. Six
groups were treated with Silymarin (200 mg/Kg p.o) for 3, 7, 14,
21, 42 and 63 days. Additionally, an unpancreatectomized control
group was performed. GLP-1 and insulin gene expression were
assessed by RT-PCR assay in total pancreatic RNA. b-cell neogenesis was determined by immunoperoxidase assay (double
tinction). Silymarin treated group showed an increase in GLP-1
and insulin genic expression. Also in this group, there was an
increment of b-cell neogenesis in comparison to pancreatectomized untreated group. Silymarin treatment produced a rise in
serum insulin and serum glucose normalization. These results
suggest that Silymarin may improve the reduction of b pancreatic
cells observed in diabetes mellitus type 1 or 2.
P-127
DEVELOPMENT AND EVALUATION OF BI-LAYERED
GASTRO-RETENTIVE TABLET CONTAINING
METFORMIN HCL SR AND PIOGLITAZONE HCL IR
T. Upadhyay1, H.A. Vyas1, J.R. Vyas1
1
Pharmaceutics, Sigma Institute of Pharmacy, Vadodara, India
To get advantage of novel drug delivery in treatment of diabetes mellitus is centered aim of this work. Bi-layered gastroretentive tablet containing Metformin HCl and Pioglitazone HCl
for treatment of type-II diabetes mellitus has been formulated. To
make the system more effective, combination of immediate
layer, Pioglitazone HCl 15 mg and sustained release layer of
Metformin HCl 500 mg were prepared. The core tablet of Metformin HCl was prepared by using different swellable polymers
like HPMC E15, HPMC K100 and carbopol by wet granulation
method and evaluated for swelling index, total floating time and
floating lag time. In vitro release studies were carried out with
0.1N HCl using USP dissolution apparatus 2 (paddle). Tablet
thus formulated using HPMC K100M and E15 provided sustained release of Metformin HCl over a period of 10 hours. The
immediate release layer of Pioglitazone HCl was prepared by
using crosspovidone, a super disintegrant by direct compression
method and evaluated for disintegration time and dissolution
also. Then bilayered tablet was prepared with the selected core
tablet batch of Metformin HCl followed by compression coating
with the selected immediate release layer of Pioglitazone HCl.
The present study concluded that bilayered tablet can be a good
way to treat diabetic patients with combination therapy.
1
Sistemas Biológicos, Universidad Autónoma Metropolitana Xochimilco, Mexico City, Mexico
2
Facultad de Medicina, Universidad Nacional Autónoma de
México, Mexico City, Mexico
3
Sistemas Biológicos, Universidad Autónoma Metropolitana,
Mexico City, Mexico
An important physio-pathological feature of diabetes mellitus is
a significant reduction of b-pancreatic cells. Glucagon-like peptide-1 is an incretin produced in gut L-cells of intestine that accounts for approximately 70% of total insulin secreted upon oral
administration of glucose, whereas it is reduced in type 2 diabetes
P-128
PREDIABETES AND TYPE 2 DIABETES SIMULATOR:
IN SILICO TESTING OF NEW DRUGS
R. Visentin1, S. Del Favero1, A. Facchinetti1, F. Micheletto1,
Y.Y. Chan2, C. Dalla Man1, C. Cobelli1
1
Padova, Italy
2
The Epsilon Group, an Alere Company, Charlottesville
(VA), USA
A-50
FIG. 1.
Screenshots of in silico experiment configuration (left) and simulation results (right panel).
The increasing incidence of diabetes stimulates research on
new drugs. However, their development is complex, costly
and time consuming. Computer simulation can allow relevant
time- and cost-saving, alleviating the need of animal trials and
providing useful information for optimal experiment design
and drug dosing. In this contribution, we present a prediabetes
and type 2 diabetes simulator for in silico testing of new
molecules.
The simulator is based on a large-scale model of glucoseinsulin system (Dalla Man et al., TBME 2007), which can be
extended to incorporate pharmacokinetics-pharmacodynamics
(PK-PD) of a new test drug. The simulator has been equipped
with a user-friendly graphical interface, which allows an easy
design of new in silico experiments. Specifically, it is possible to
select the in silico population (Type 2 Diabetic, Prediabetic,
Nondiabetic), configure protocol attributes (duration of the experiment, sampling schedule, glucose doses, etc.) and define
treatment details (drug dose and PK-PD). Moreover, the user can
choose the outcome metric variables to be computed and the
results to be displayed.
The simulator has been successfully validated using metformin as a case study: metformin PK-PD model has been incorporated in the simulator, and the simulation results are in
agreement with those observed in in vivo clinical experiments.
In conclusion, the proposed prediabetes and type 2 diabetes
simulator is a valuable tool for the design and in silico testing of
new antidiabetic drugs.
P-129
NO DIFFUSE HEPATIC STEATOSIS IN TYPE 1
DIABETIC PATIENTS RECEIVING
INTRAPERITONEAL INSULINOTHERAPY
1
1
1
2
S. Baillot-Rudoni , J.M. Petit , P. Buffier , A. Farret ,
B. Bouillet1, G. Vaillant1, B. Vergès1
1
Diabetology and Endocrinology, Hospital, Dijon, France
2
Diabetology and Endocrinology, Hospital, Montpellier, France
Background: Recent studies published conflicting data about
whether steatosis could be associated with diabetes mellitus type
1 or not. One of the criteria is a moderate elevation of alanine
transaminase (ALAT). Furthermore, rare cases reported focal
hepatic steatosis in type 1 diabetes treated with implantable
pumps.
Aim: We investigated whether treatment with an implantable
pump was more likely than treatment with a subcutaneous pump to
induce biological profile for diffuse steatosis in type 1 diabetes.
Patients and methods: Seventeen patients receiving intraperitoneal insulin (group 1) were matched with 17 subjects receiving subcutaneous insulin (group 2) for sex, age, duration of
diabetes and pump. We compared transaminases before internal
or external pump at one year and at the end of the study.
Results: Initially, the 2 groups were comparable in term of
age, BMI, transaminases, duration of diabetes and pump
(11 – 5.3 versus 9.1 – 7.2 years); there was a trend toward better
metabolic control in group 1 than in group 2 (p = 0.058). In
2013, mean ALAT were similar in the 2 groups (26.1 – 11.8
versus 28.3 – 18.1 UI/L); HbA1c was lower in patients treated
with implantable pumps than in those with external pumps
(p = 0.02), in spite of similar BMI and increased weight in each
group (NS).
Conclusions: ALAT in patients long-term treated with an
implantable pump was no higher than that in patients treated with
an external pump, which argues against an increased risk of
diffuse hepatic steatosis in such patients.
P-130
DOES THE PUMP SPECIFIC DOSE ADJUSTMENT FOR
NORMAL EATING (PUMP DAFNE) PROGRAMME
PROVIDE ADDED GLYCAEMIC OUTCOMES IN
ESTABLISHED PUMP USERS?
A. Beckwith1
1
Nutrition and Dietetics/Diabetes, King’s College Hospital,
Aim: To establish if there are added glycaemic benefits for
CSII established adults attending the pump specific structured
education programme: Pump DAFNE.
Methods: Improvement in glycaemic outcomes following
MDI DAFNE is well documented in adults with T1DM; of which
attendance is usually compulsory before CSII eligibility is considered in the UK. However, there is a cohort of DAFNE naive,
CSII managed patients attending King’s College Hospital.
Twenty-nine of these patients attended Pump DAFNE between
2009 and 2011. Retrospective case note analysis extracted glycaemic outcomes and self-management behaviours (SMB) data
at baseline, 2, 6 and 12 months.
Results: Completed records of 28 patients (age 35.1 – 10.8; 19
female) with type 1 diabetes (duration 16.7 – 9.0 years) were
retrieved. Mean A1c was 8.1% ( – 1.2) at baseline; 7.5 – 0.7%
(p = 0.004) at 2 months; 7.6% ( – 0.8) at 6 months and 7.9%
( – 1.2) (p = 0.392) at 12 months follow-up. Severe hypoglycaemia rates fell from 0.8 to 0.2 episodes/patient/year from baseline
to 12 months (p < 0.05). DKA episodes fell from 0.15 to 0.00
episodes/patient/year from baseline to 12 months (p < 0.0001).
Effective diabetes/pump SMB were absent at baseline, but were
widely adopted post-intervention.
Conclusions: Pump DAFNE provides significant improvements in glycaemic outcomes and SMB in pump established
adults. Clinicians and policy makers need to consider resourcing
in order to deliver quality structured follow-up to maintain these
effects long-term.
P-131
FUNCTIONAL INTENSIFIED INSULIN THERAPY
AND BOLUS CALCULATOR USE IN PAEDIATRICS
PRACTICE: 2012 SITUATION IN THE ‘‘AIDE AUX
JEUNES DIABETIQUES’’ CAMPS
A. Bodet1, C. Choleau2, R. Coutant3, V. Ribault1, E. Sonnet4
1
Pédiatrie, CHU Caen, Caen, France
Chargée des missions scientifiques, AJD, Paris, France
3
Endocrinologie Pédiatrique, CHU Angers, Angers, France
4
Endocrinologie, CHU Brest, Brest, France
2
Introduction: Functional Intensified insulin Therapy (FIT)
practice is very complex, due to many calculations. The use
of a bolus calculator (BC) could help children to manage
FIT. Our study evaluated FIT practice and real life experience in children attending an ‘‘Aide Aux Jeunes Diabétiques’’ French 2012 summer camp.
Methods: We compared data between 167 children who
practiced FIT (FIT + ) and 636 who did not (FIT-), and between
children who used a BC in FIT practice (BC + ; n = 27) and those
who did not (BC-; n = 73). Statistical analyses were performed
using T-test, and Chi2 test.
Results: FIT + were predominantly girls (sex ratio 0.84 vs
1.21 p = 0.04), and more aged (13.7 years [11.9–15.4] vs 12.83
[10.9–14.6]) than FIT-. Diabetes or FIT duration, sex ratio,
age, BMI z-score, HbA1c and QoL were similar between
BC + and BC- except a lower insulin daily dose (0,84 U/kg
vs 0,94, p = 0,04). The use of the BC wasn’t associated with
a better assiduity, neither accuracy in the carbohydrates
counting.
Conclusion: In our study, the use of a BC in children practicing FIT did not change HbA1c, QoL or other parameters except insulin daily dose. So it could improve adequacy between
insulin dose and what the children really need.
P-132
MONITORING DIFFERENT PARAMETERS DURING 3
WEEKS WALKING IN A TYPE 1 DIABETIC PATIENT
WITH INSULIN PUMP AND CMGS
F. Casiraghi1, S. Benedini2, A. Ciucci3, L. Luzi2
A-51
1
Department of Biomedical Sciences for Health, University
of Milan, Milan, Italy
2
Metabolism Research Center, I.R.C.C.S. Policlinico San
Donato, Milan, Italy
3
Diabetes, A.O. Ospedale Sant’ Anna, Como, Italy
The purpose of this project is monitoring different parameters
in a T1DM patient using an insulin pump with a Continuous
Glucose Monitoring System (CGMS) performing a 3 weeks
walking exercise (700 km). In a 40 years old T1DM patient we
evaluated body composition by bioelectrical impedance analysis,
continuously monitored the glycemic profile for 3 weeks via
CGMS, and evaluated the energy expenditure 3 days each week
during the walking. We registered a decrease in total body weight
(PRE = 83.5 to POST = 81.1 kg) and fat mass (PRE = 12.2 to
POST = 8.9 kg), and an increase in fat free mass plus water
(PRE = 71.3 to POST = 72.9 kg). The CGMS data showed a 9%
decrease in the average glucose concentration comparing the first
week (W1 = 133 mg/dl) to the third week (W3 = 121 mg/dl). The
average daily insulin decrease by 12% was (W1 = 38, to
W3 = 33.5 IU), resulted from the sum of average daily basal insulin (W1 = 16.2 to W3 = 12.6 IU) and average daily insulin bolus
(W1 = 21.8 to W3 = 20.9 IU). The % in which glucose level
stayed on target [between 80 – 160 mg/dl] increase by 7%
(W1 = 57 to W3 = 64%) and decrease by 8% during hyperglycemia (W1 = 26 to W3 18%). Data showed that an aerobic exercise performed for 3 weeks can improve the glucose profile and
the other metabolic parameters in a T1DM patient. A simple
walking exercise without engaging in any risky high intensity physical activity can have overall beneficial effects on health in a
T1DM patients.
P-133
GLYCEMIC CONTROL AND PREGNANCY
OUTCOME IN WOMEN WITH TYPE 1 DIABETES
ON CONTINUOUS SUBCUTANEOUS INSULIN
INFUSION (CSII)
M. Cokolic1, M. Krajnc1, A. Zavratnik1
1
Department of Endocrinology and Diabetology Internal Clinic,
University Clinical Centre Maribor, Maribor, Slovenia
Aim: Insulin pump with continuous subcutaneous insulin
infusion (CSII) is nowadays the most modern method of type 1
diabetes treatment. We evaluate metabolic control, maternal
and fetal outcomes in our group of pregnant type 1 diabetic
(DM1) patients treated with CSII. Patients and methods: In the
last 5 years we treated 17 pregnant women with DM1 on insulin
pump and we evaluate metabolic control, maternal and fetal
outcomes.
Results: HbA1c in the first trimester was 6,1% (4,6–7,3%), in
the third trimester 6,4% (5,0–7,8%), in the postnatal period was
7,1% (5,7–8,0%). The average age at childbirth was 27,7 years (22–
31). 41% of the children were born by Caesarean section, of which
59% boys, on average at 37 (35–40) week of pregnancy. The average newborn weight was 3460 g (2260–4500 g), length 49,56 cm
(46–54 cm), only 2 (11%) were weighing more than 4000 g (4500
and 4400 g), of which one mother was less metabolically regulated
(HbA1c 7,5%), while the other not (HbA1c 5,8%).
Conclusion: All pregnancies ended successfully. Only 11% of
newborns were overweight, without other complications, deliveries
were at 37 week. Women with diabetes are more likely to have a
large baby, which can cause problems around birth. Early elective
A-52
delivery (labour induction or Caesarean section) aims to avoid
these complications, so 41% were completed by Caesarean section.
Metabolic arrangement during pregnancy was good, after giving
birth the loss of motivation was apparent. Insulin pump is a safe
treatment in pregnant women with DM1.
P-134
BOTH NIGHTTIME AND DAYTIME GLUCOSE
VARIABILITIES ARE REDUCED AFTER SWITCHING
TYPE 1 DIABETIC PATIENTS TO CSII
L. Crenier1
1
Endocrinology, Hôpital Erasme-ULB, Brussels, Belgium
Background: We used Poincaré plot (PCP) derived metrics
for studying glucose variability (GV) in type 1 diabetic patients
switching to CSII.
Methods: PCP metrics (Dt = 30 and 120 minutes) including
daytime (08-22) and nighttime (22-08) partial indices and
classical GV measures were computed from CGMs of 13
patients, before and six months after CSII. PCP-derived SD1
and SD2 represent short- and long-term GV (panel A). Area of
the fitting ellipse (AFE = pxSD1xSD2) is a marker of diabetes
instability.
Results: CV (49.1 – 8.7 vs 42.5 – 5.0 on CSII; p < 0.030) and
other classical indices were reduced but number of hypoglycemic
events did not change significantly on CSII. SD1-30, SD2-30, SD1120 and SD2-120 decreased significantly as AFE-30 (p < 0.005) and
AFE-120 (p < 0.004). The daytime reductions of AFE-30 and AFE120 were of 29.3% (p < 0.01) and 36.3% (p < 0.008). Nighttime
AFE-30 and AFE-120 decreased from 42.3% (p < 0.006) and 43.2%
(p < 0.004). See figure for absolute numbers.
Conclusions: CSII reduced both nighttime and daytime GVs.
The absolute value of night GV and its reduction was as impressive when measured by both AFE-30 and AFE-120. The
apparent GV degradation when Dt increases from 30 to 120
minutes is thus due to not only daytime post-meal peaks but is
also linked to intrinsic variability.
P-135
TECHNICAL DETERMINANTS OF DIABETES
CONTROL IN INSULIN PUMP THERAPY IN
CHILDREN AND ADOLESCENTS
A. Deeb1, S. Abu-Awad2, S. Abood1, M. El-Abiary2,
J. Al-Jubeh2, H. Ibrahim1, L. AbdulRahman1, A. Al-Hajeri1,
H.U.D.A. Mustafa3
1
Paediatric Endocrinology, Mafraq Hospital, Abu Dhabi,
United Arab Emirates
2
Paediatric Endocrinology, Shaikh Khalifa Medical City,
Abu Dhabi, United Arab Emirates
3
Endocrinology, Shaikh Khalifa Medical City, Abu Dhabi,
Insulin pumps (IPs) are equipped with advanced functions.
However, intensive training and adherence are required for optimum use of the technology. We aim to assess the association of
various key elements in IP functions on blood glucose (BG)
control. Patients with T1DM on IP therapy were enrolled. IPs
were downloaded (Care-link 3) and data over 8–12 weeks were
collected. Patients were grouped, based on HbA1c of £ 8% and
> 8% into controlled (G1) and uncontrolled (G2) respectively.
Variables studied are; use of sensors and duration, frequency of BG
monitoring, bolus wizard (BW) use, frequency of correction boluses and frequency of cannula changing. 60 patients were enrolled. Age range was 2.3–17.1 with a median of 12 years. 25
patients were in G1 and 35 in G2. Median BG checks were 4.4 (2–
11.4) and 3.2 (0.5–7.9) for G1 and G2 respectively (P < 0.021).
Frequency of BW use showed a median of 6 (3.9–12.9) and 4.15
(0.6–9) for G1 and G2 respectively (P < 0.001). 8 (30%) of G1 and
14 (40%) of G2 used sensors. G1 used sensors for longer (5 vs 2.9
days/week). G1 did more corrections than G2 (3.9 vs 2.5). There
was no difference in the frequency of changing the infusion cannula in both groups (3.5 days). We conclude that the frequency of
BG monitoring and bolus wizard use have a favorable correlation
with glycemic control. Our data shows that patients with better
control tend to bolus more for correction and wear sensors for
longer.
P-136
RELATIONSHIP BETWEEN BASAL INSULIN
REQUIREMENT AND BODY MASS INDEX IN CHILDREN
AND ADULTS WITH TYPE 1 DIABETES USING
INSULIN PUMP THERAPY
A. Deeb1, S. Abu-Awad2, S. Abood1, M. El Abiary2,
J. Al-Jubeh2, M. Tomy1, S. Abu-Samhadanah1, R. Hazaimeh1,
H.U.D.A. Mustafa3
1
Paediatric Endocrinology, Mafraq Hospital, Abu Dhabi,
2
Paediatric Endocrinology, Shaikh Khalifa Medical City,
Abu Dhabi, United Arab Emirates
3
Endocrinology, Shaikh Khalifa Medical City, Abu Dhabi,
It is recommended that basal insulin (BI) for children and adolescents to be between 30–50% of the insulin total daily dose
(TDD) which is lower than the adults’ basal requirement. As patients with higher body mass index (BMI) are more insulin resistant, we hypothesize that they might require higher BI compared to
those with normal BMI. We aim to examine the correlation between BMI and BI requirement in paediatric and adult patients.
Patients with type 1 diabetes on insulin pump (IP) therapy
were enrolled. Subjects were categorized to normal weight
(NWt) and overweight (OvWt) based on BMI. IP were downloaded and data over 8–12 weeks’ period were collected. BI
requirement is considered high if it exceeded 50% of TDD. Selected variables included; HbA1c, insulin TDD, and daily carbohydrate consumption.
72 patients were enrolled (50 children). Median (range) was
12 (2.5–17.2) and 30 (20–48) for children and adults. 14 children
and 9 adults were NWt while 36 and 13 were OvWt. There was
no difference in the number of NWt and OvWt with BI over 50%
in the children or the adult groups (P = 0.86, 0.80). However, a
positive correlation was seen between BMI and BI in older
children (P < 0.03).
We found no correlation with BMI and BI requirement in young
children and adults regardless of the insulin TDD, HbA1c or
carbohydrate consumption. Nonetheless, older children showed a
higher requirement for BI. We hypothesize that pubertal factor has
an impact on BI requirement regardless of the BMI.
P-137
IMPACT OF INSULIN PUMP THERAPY IN CHILDREN
AND ADOLESCENTS WITH TYPE 1 DIABETES
ON LONG-TERM METABOLIC CONTROL
N. Elbarbary1
1
Department of pediatrics, Ain Shams University, Cairo, Egypt
Objectives: This study was designed to assess the impact of
CSII in children with type 1 diabetes (T1DM) on long-term
metabolic control and acute diabetic complications at initiation
of pump therapy and after one year of follow-up.
Methods: A total of 21 patients (12M/9F) with T1DM mean
age 12.78 – 2.31 years (4–18 years) and disease duration of
5.2 – 1.9 (3 months–14 years) participated in the study. Insulin
pumps (Minimed 722 Paradigm Real time and Minimed 712)
were used administering short–acting insulin analogue.
Results: After 1 year CSII, a significant reduction in HbA1c
levels was observed (8.9 – 1.6% to 7.6 – 0.9%, P = 0.01) from CSII
initiation. Total insulin dose required decreased in all patient from
A-53
1.2 – 0.4 to 0.8 – 0.26 U/kg/day, p = 0.00). The frequency of significant hypoglycemia during CSII were less than initiation (4.8 – 3.5
to 1.6 – 1.9, P = 0.007), hyperglycemic attacks was lower especially
episodes exceeding 300 mg/dl (P = 0.00). One patient had an attack
of DKA due to catheter trouble, non had mechanical troubles or skin
problems. Rate of post-prandial hyperglycemia decreased (P = 0.09)
as a result of adequate insulin bolus on each food intake using Bolus
Wizard calculator. The rate of hospitalization due to acute events
was less (P = 0.03). Patients were satisfied with decreasing the frequency of injections (one per three to four days).
Conclusion: This study revealed the importance of CSII
therapy in sustaining good metabolic control and blood glucose
stability for one year follow-up.
P-138
COMPARISON DAILY DOSE INSULIN BETWEEN
CONTINUOUS SUBCUTANEOUS INSULIN INFUSION
AND MULTIPLE DAILY INJECTIONS IN CHILDREN
WITH ONSET TYPE 1 DIABETES MELLITUS
E. Evsyukova1, I. Colomina1, L. Samsonova2, O. Latyshev2
1
Endocrinology, Tushino City Children’s Hospital, Moscow,
Russia
2
Endocrinology, Russian Medical Academy for Postgraduate
Education, Moscow, Russia
Background: The purpose of this study was to investigate
potential benefit of using continuous subcutaneous insulin infusion from onset diabetes type 1 in children.
Methods: In the study were included 72 children with first
diagnosed type 1 diabetes during 4 weeks after diagnosis. All
patients were with good glycemic control. The patients were
divided in two groups. The children from the first group (n = 54,
mean age 9.85 – 3.12, diabetic ketoacidosis 51.8%) were treated
by multiple daily injections. The patients from the second group
(n = 18, mean age 9.89 – 3.29, diabetic ketoacidosis 44.4%) were
treated by subcutaneous insulin infusion.
Results: In the first group the mean daily dose of insulin was
0.4 – 0.2 U/kg, the rate of basal insulin - 43.64 – 10.3%. In the
second group the mean daily dose of insulin was 0.36 – 0.16 U/kg
(p = 0.4), the rate of basal insulin - 38.99 – 10.42% (p = 0.1).
Conclusion: The mean daily dose of insulin and rate of basal
insulin is similarly in two groups. The result highlights the potential benefit of subcutaneous infusion in diabetes care in children at the beginning of treatment.
P-139
INSULIN PUMPS AND CONTINUOUS GLUCOSE
MONITORING IN CHILDREN WITH TYPE 1
DIABETES: A LONG-TERM FOLLOW-UP OF
PATIENTS AND THEIR DEVICES
R. Rigamonti1, F. Meschi1, G. Frontino1, V. Favalli1,
C. Bonura1, R. Battaglino1, G. Ferro1, C. Rubino1,
F. Pedrini1, R. Bonfanti1
1
Pediatrics, IRCCS Ospedale San Raffaele, Milan, Italy
The aim was to perform a long-term retrospective evaluation of
type 1 diabetes (T1DM) pediatric patients treated with insulin
pumps (CSII) and continuous glucose monitoring (CGM) at our
clinic. Patients (n = 156) were included if treated with CSII for at
least 12 months from year 2007, were interviewed and their
A-54
medical records reviewed. Mean age: 12.9 yrs – 4.29. Mean age at
diabetes onset: 5.71 yrs – 3.65. Mean diabetes follow-up:
3.16 yrs – 2.04. All commercially available CSII and CGM devices
in Italy were used. HbA1c was measured with DCA2000. Control
group: 500 patients in multidrug injection therapy (MDI) matched
for age, sex and follow-up. CSII use was 48.7%, 30.7% and 20.6%
in patient ages 7–12 yrs, 0–6 yrs, and 13–18 yrs respectively. Mean
age of CSII initiation: 8.9 yrs – 4,12 (range: 9 months to 18 years).
Of our study cohort only 4.5% suspended CSII. Mean HbA1c:
7.27% – 0,47 and 7.3% – 1.4 in CSII and MDI groups respectively.
Mean HbA1c reduction: 0.1% and 0.2% in the 7–12 years and 13–
18 years respectively when comparing CSII vs MDI. Diabetic
ketoacidosis in the CSII group was 1.28/100 patients/year (no
significant difference vs MDI group). Pumps were replaced in 50%
of cases (55% for malfunction). Of the patients using CGM, 72.7%
suspended its use for invasiveness (28.4%) or imprecise readings
(8%). Our data confirms that CSII enables to achieve adequate
glucose control in all ages during an average follow-up period of 3
years. Furthermore, this is accomplished safely and without increasing the risk of acute complications compared to MDI.
P-140
THE MANDATORY REQUIREMENT FOR SENSOR
AUGMENTED INSULIN PUMP THERAPY IN INFANTS
WITH ILLUSTRATION OF THE PITFALLS WITHIN
THIS AGE GROUP
K. Karabouta1, S. Cheney1, M.A. Balapatabendi1, J. Greening1
1
Paediatric Diabetes, University Hospitals of Leicester,
Leicester, United Kingdom
Background: Diabetes in an infant ( < 12 months) is rare
most cases are monogenic either transient or permanent.
Diabetes management is complex due to patients size, insulin
sensitivity and feeding patterns.
Case series: We report 2 infants, one 11 days old female term
(IUGR) with permanent neonatal diabetes and a pre-term 11
month male with type 1A diabetes. The female presented with
failure to thrive whereas the male had polyuria and poydypsia,
neither were in Diabetic Ketoacidosis(DKA) but had glycosuria.
Diagnosis was confirmed via random laboratory glucose of
19 mmol/l/342 mg/d]l and 26.7 mmol/l/481 mg/dl respectively.
Both required Intravenous rehydration and IVI insulin infusion to
stabilise glycaemic control. Transition onto CSII(continuous
subcutaneous insulin infusion) via a sensor augmented pump
occurred between day 18 and 7 respectively. Glycaemic control
proved extremely difficult with marked glucose variability/
protracted hypoglycaemia with emergency management. which
occurred secondary to insulin sensitivity, demand feeding via
breast, bottle and solids. We used a modified insulin regime
which required. No boluses, Suspension of the basal rate with
cannula reinsertion and prolonged hypoglycaemia, delivered via
the glucose sensor as well as manual suspension. Use of the
temporary basal rates, higher than recommended (ADA) glycaemic ranges (6–14 mmol/l) for the first month from diagnosis.
We identified and addressed issues with cannula insertion due to
lack of subcutaneous fat with Sensor malfunction/calibration;
Training of parents, ward staff and the parental psychological
fear of hypoglycaemia and its treatment.
Conclusion: The patients demonstrated extreme insulin sensitivity, unpredictable hypoglycaemia with need for accurate
insulin titration. It is our experience that this was only achieved
with a sensor augmented insulin pump despite its pitfalls.
P-141
EXAMINING GLYCAEMIC CONTROL AND
VARIABILITY UTILISING THE MEDTRONIC
CONTINUOUS GLUCOSE MONITORING SYSTEM
(CGMS) IN PRE AND POST CSII THERAPY
M. Harrison1, C. Marriott1, J. Shaw2
1
School of Pharmacy & Biomolecular Sciences, University of
Brighton, Brighton, United Kingdom
2
Biomedicine, University of Newcastle, Newcastle upon Tyne,
United Kingdom
Introduction: Currently measures of glycaemic variability
(Standard Deviation, Mean and MAGE) all fail to fully highlight
the extent of blood glucose variability so there is a need for
improved measures of glycaemic variability.
Aim: To utilise clinical data produced using CGMS to
develop and validate a clinically-relevant novel measure
of glycaemic variability and to use it to compare CSII with
MDI.
Methods: 20 participants (6 months pre and post CSII) with
24 hr CGM data sets were analysed. Glucose variability Rating
(GVR) was calculated in three steps including change in sensor
reading at 5 minute intervals which were then squared and averaged to obtain GVR (mmol/L) 2/hr. GVR was plotted, area
under curve (AUC) calculated and pre vs. post-CSII GVR
compared. Time series analysis was also investigated to try and
identify specific periods with increased variability. A comparison of the percentage change in GVR vs the change in HbA1c
value in pre vs post-CSII was also analysed to identify correlation between these two measures.
Results: GVR was applied to pre and post-CSII CGM data;
75% of participants showed < 20% reduction of GVR post-CSII
vs. MDI. The group also showed a significant reduction in GVR
(p < 0.003) post-CSII (vs MDI).
Conclusions: Results indicate a reduction in glucose variability with CSII and highlight the limitations of HbA1c, as well
as the useful potential of GVR to highlight specific time periods
where intervention is required to control blood glucose
variability.
P-142
HBA1C AND WEIGHT DEVELOPMENT ONE YEAR
AFTER INITIANTION OF CONTINUOUS
SUBCUTANEOUS INSULIN INJECTION THERAPY
IN ADULT SUBJECT
E. Hommel1, H.U. Andersen2, H.C. Andersen2,
J.N. Christensen2, K. Rytter2, A. Hougaard2,
A. Grynnerup2, M. Ridderstråle2
1
2
Diabetes, Steno Diabetes Center, Gentofte, Denmark
Diabetes, Steno Diabetes Center, Gentofte, Denmark
Aims: We performed a retrospective analysis in Type 1 diabetes patients initiating continuous subcutaneous insulin injection (CSII to evaluate the effect on hba1c and weight).
Materials and methods: All subjects initiating CSII after
year 2002 were analyzed for age, HbA1c, weight, total insulin
dose prior to and one year after pump initiation.
Results: 505 (184 males/ 321 females) entered into the analysis; at CSII initiation age: 40 – 0.6 years, weight: 82.9 – 1.1 and
70.0 – 0.8 kg for males and females, respectively (p 312 – 2.5
days) HbA1c (mmol/mol) 62.6 – 0.9 in males vs 60.6 – 0.6 in
females (p < 0.01).
Conclusion: From MDI to CSII in type 1 diabetes patients the
HbA1c decrease is relatively greater in females with a marginal
increase in weight.
P-143
TO DISCUSS OUTCOMES AND CONTROL IN 21
PREGNANCY EPISODES IN TWO GROUPS
OF WOMEN WITH TYPE 1 DM, USING CSII
M. Karamat1, M. Ahmed1, J. Hand1, A. Field1, D. Brewer1,
P. Dyer1, A. Tahrani1, A. Syed1
1
Diabetes, Heartlands Hospital, Birmingham, United Kingdom
Methods: In 9 pregnancies, CSII was started during pregnancy (first group), while in 12 CSII was started before pregnancy (second group).
HbA1c, DR, ACR data were reviewed in the pregnancies that
went through the 3 trimesters.
Results: In the first group, 8 pregnancies had successful outcome compared to 11 on the second group.
In the first group mean HbA1c was 53 mmol/l, first trimester,
45, second trimester & 44 mmol/mol, third trimester. Change
from 57 to 51 at the upper bound, 49 to 37 at the lower bound.
In the second group mean HbA1c was 50 mmol/l first trimester
& 47 mmol/mol second & third trimesters. Change from 54 to 53
at the upper bound, 46 to 41 at the lower bound.
In first group; 4 (50%) patients progressed to STDR compared
to 3 (30%) the second group, while 5 (62%) patients progressed
to maculopathy compared to 4 (40%) the second group.
Any DR progression; 7 (87.5%) patients first group, compared
to 7 (70%) the second group.
ACR values were normal in all patients in both groups.
Conclusions: When CSII was started during pregnancy,
HbA1c values started higher & ended lower compared to pregnant women who had CSII before pregnancy. Both groups had
DR progression, but progression was worde in the patients who
started pump during pregnancy.
CSII appears to provide a safe method of glycaemic control in
pregnant women with Type 1 diabetes.
Starting CSII before pregnancy would allow enough time to
acclimatise to the insulin pump suggesting clear importance of
preconception care in women with Type 1 DM.
P-144
ESTIMATED GLOMERULAR FILTRATION RATE
IS THE DETERMINANT OF EXTENDED BOLUS
INSULIN DURATION TIME OF INSULIN PUMP
A. Kuroda1, T. Kondo2, M. Tamaki1, I. Endo2, K. Aihara2,
T. Matsumoto2, M. Matsuhisa1
1
Diabetes Therapeutics and Research Center, The University
of Tokushima, Tokushima, Japan
2
Department of Medicine and Bioregulatory Sciences,
The University of Tokushima, Tokushima, Japan
Backgrounds: Extended insulin bolus time of insulin pump
(square-wave bolus insulin) might be a beneficial option for
patients who have postprandial hypoglycemia followed by
hyperglycemia. It has not been investigated the clinical characteristics of the patients who use square-wave bolus insulin.
A-55
The objective is to investigate the clinical characteristics and
extended bolus insulin time of the patients who use squarewave bolus insulin.
Methods: Fifty-three patients with type 1 diabetes, who use
insulin pump, were investigated during 2–3 weeks of hospitalization. Each meal omission was done to confirm basal insulin
rate. The amount and duration time of each bolus insulin was
adjusted to set blood glucose to 100 and 150 mg/dL before and 2
hours after meal, respectively. Insulin pump setting and clinical
characteristics, which contributed the average duration time of
bolus insulin was investigated.
Results: Total daily insulin dose (TDD) (p < 0.001), the percent of daily basal insulin rate to TDD (p < 0.05), average
carbohydrate-to-insulin ratio (p < 0.001), retinopathy score
(p < 0.01), and estimated glomerular filtration rate (eGFR)
(p < 0.001) were significantly correlated with average bolus insulin duration time. According to multiple regression analysis,
eGFR (F = 10.10) was the independent determinant for bolus
insulin duration time.
Conclusions: Extended bolus insulin time should be considered in patients who have kidney dysfunction.
P-145
LESSONS LEARNED FROM SUCCESSFUL
RECRUITMENT TO A PUMP/CGM TRIAL
M.L. Lawson1, J. Courtney2, A. Hill3, M. Watson4, S. Datwani5,
K. Sahota6, B. Bradley2, JDRF Canadian Clinical Trial
Network CCTN1101 Study Group7
1
Endocrinology and Metabolism, Children’s Hospital of
Eastern Ontario, Ottawa, Canada
2
Diabetes Research Group, Children’s Hospital of Eastern
Ontario Research Institute, Ottawa, Canada
3
Endocrinology and Metabolism, McMaster Children’s
Hospital, Hamilton, Canada
4
Endocrinology and Metabolism, London Children’s Hospital,
London, Canada
5
Pediatrics, Markham-Stouffville Hospital, Toronto, Canada
6
Endocrinology and Metabolism, Hospital for Sick Children,
Toronto, Canada
7
Canada
Background: Recruitment failures and delays threaten the
success and resources of clinical trials, with more than 80% of
trials failing to reach recruitment targets.
Objective: To determine whether lessons learned from a pilot
study improved recruitment in the multicenter trial.
Method: Pilot study recruitment rates and strategies were
compared to those of the multicenter CGM TIME Trial.
Results: The pilot study and TIME Trial had the same eligibility criteria and design other than longer trial duration for the
TIME Trial (12 vs. 4 months). The pilot study required 24
months to recruit 20 patients through 2 sites, whereas the TIME
Trial exceeded its required sample size, recruiting 144 patients
through 5 sites within the 21 months. In the pilot study, 25% of
patients met eligibility criteria vs. 43% in the TIME Trial. 20/41
(48.7%) patients eligible for the pilot study consented to participation vs. 144/152 (94.7%) for the TIME Trial. 25% of pilot
study subjects terminated the study prematurely vs. 5.6% of the
TIME Trial. The TIME Trial incorporated a research recruitment tool, modeled after patient decision aids, comparing the
pros and cons of participating vs. not participating in the Trial
which was provided to eligible families along with the consent
A-56
form in 3/5 sites. Six of 8 refusals to the TIME Trial and 5/8
early terminations came from the 2 sites not using the recruitment tool.
Conclusion: Use of a research recruitment decision tool
which addresses family preferences and perceptions of trial
participation may improve trial recruitment and retention.
P-146
HEALTH RISKS OF YOUNG ADULT TRAVELERS
Y. Levy Shraga1, U. Hamiel1, M. Yaron2, O. Pinhas-Hamiel1
1
Pediatric Endocrine and Diabetes Unit Edmond and Lily Safra
Children’s Hospital, Sheba Medical Center, Tel Hashomer,
Israel
2
Juvenile Diabetes Center, Maccabi Health Care Services,
Raanana, Israel
Objective: International travel has become a popular mode of
travel among young adults. We evaluated the rate and characteristics of travel-associated health risks among young adults
with type 1 diabetes mellitus (T1DM) compared to healthy sameaged individuals.
Methods: A retrospective study of 47 young adults with
T1DM and 48 without (controls). Structured questionnaires
accessed information regarding 154 international trips that
occurred during the preceding 5 years and that lasted 7 days and
longer.
Results: Mean – SD ages of the diabetic and control groups
were 26.6 – 5.0 and 26.9 – 2.6 years respectively. Mean trip durations were 80.0 (range 7.0–390.0) and 87.6 days (range 7.0–395.0)
respectively. The number of trips per person was 1.5 – 0.6 and
1.7 – 0.8, and the proportion of trips to developing countries 64%
and 61%, respectively. There was no difference in travel-related
diseases that required medical consultation between the groups
(11% vs. 15% for all trips, p = 0.25). No patient sought medical
attention due to acute diabetes complications. Prior to 71% of the
trips to developing countries, respondents with diabetes consulted
their diabetes physician; Prior to 26% of the trips they switched
from an insulin pump to injections; during 41% they increased
glucose monitoring; and for the period of 11% they defined their
metabolic control as poor. Mean reported HbA1c levels before and
after trips were 7.65 – 1.45% and 7.81 – 1.23 respectively (p = 0.42,
paired T test).
Conclusions: Young adults with diabetes did not report more
travel-related diseases than did healthy individuals. Glycemic
regulation during the trip was manageable, without severe consequences.
P-147
CSII AND SAP VALUABLE TOOLS IN THE
TREATMENT OF DIABETES; A SWEDISH HEALTH
TECHNOLOGY ASSESMENT
R. Hanas1, A. Lindholm Olinder2, P.O. Olsson3,
U.B. Johansson4, S. Jacobson5, E. Heintz5, S. Werko5,
M. Persson2
1
Clinical Sciences Sahlgrenska Academy, University of
Gothenburg, Gothenburg, Sweden
2
Clinical Science and Education Södersjukhuset, Karolinska
Institutet, Stockholm, Sweden
3
Internal Medicine, Central Hospital, Karlstad, Sweden
4
Clinical Sciences Danderyd Hospital, Karolinska Institutet
Sophiahemmet University, Stockholm, Sweden
5
LIME, Karolinska Institutet SBU, Stockholm, Sweden
Continuous subcutaneous insulin infusion (CSII) is used by approximately 20% of adults and 50% of children with Type 1 diabetes in Sweden.
This report aims to present a systematic review to establish
available evidence on effects of CSII and SAP (sensoraugmented pump) in adults (A), Children (C) and Pregnant women
(P) compared to MDI (multiple daily injections) with mealtime
insulin analogs and SMBG (self-monitored blood glucose).
Methods: The literature search included PubMed, Cochrane
Library, Cinahl and PsychINFO until November 2012. Two reviewers independently assessed each included study for quality by
using the SBU checklists. The quality of evidence was rated by
using the GRADE system.
Results: Of 1130 identified abstracts, 11 studies on CSII were
included for quality assessment; 8 had low quality (5C + 3P), 2
moderate (1C + 1P) and 1 high (C). On SAP, 10 studies were
included; 3 had low quality (1C + 2A), 6 moderate (2C + 4A) and
1 high (C). For adults, 1 systematic review on CSII of high
quality was included.
There was a lack of high quality research in both areas. Shortterm HbA1 was slightly improved by CSII, more so by SAP.
Patients with SAP reported higher treatment satisfaction. Limited information was available on the frequency of severe hypoglycemia and ketoacidosis. Calculations of intervention costs
demonstrated an increased cost of 1189 EUR for CSII and 3026
EUR for SAP.
Conclusion: Compared with MDI, CSII and SAP demonstrate short-term benefits including a reduced Hb1c level,
which if sustained will reduce the risk of long-term diabetes
complications.
P-148
EVALUATION OF PATIENT ACCEPTANCE
OF THE CELLNOVO INSULIN INFUSION PUMP
R. McDonagh1, S.D. Luzio2, J. Davies2, Q.T.H. Anjum2,
L. Bastin3, C. Fagan3, S.C. Bain2
1
Clinical Dept, Cellnovo, Swansea, United Kingdom
Diabetes Research Group, Institute of Life Science, Swansea,
United Kingdom
3
Joint Clinical Research Facility, Institute of Life Science,
Swansea, United Kingdom
2
Introduction: ‘Patch pumps’ have a pump controller which
communicates with an infusion component attached to the skin
directly instead of via a catheter. The Cellnovo System is a CE
marked insulin delivery system, comprising of mobile connected Handset, Pump and online web-based Management
System.
Aim: This was a single-site pilot study designed for investigation of the acceptance of end-users’ of the study devices.
Methods: Subjects (n = 3) aged >18 years with Type 1 diabetes and already on insulin pump therapy for at least 12 months
and compliant with their therapy were recruited. After a
screening visit, subjects stayed within a clinical research facility
over a period of 3 (24 h) days for training and use of the Cellnovo
System. Following this they used the system at home for 7 days.
At the end of the study visit, subjects returned to complete a
questionnaire and return to their previous insulin pump.
Results: All subjects successfully completed the study. Subjects
were successfully trained to use the pumps during the 3 in-patient
days and managed with minimal support during the 7 days at home.
Insulin requirements were reduced in two of the subjects and in the
third subjects the rates were adjusted more appropriately throughout
the day. User feedback recorded by questionnaire was very positive
for all subjects. There were no adverse events that resulted in professional medical intervention.
Discussion: User feedback was very positive and all three
subjects expressed a preference to continue using the Cellnovo
System in preference to their previous pumps.
P-149
THE ASSOCIATION BETWEEN THE FREQUENCY
OF SMBG ASSESSED BY DATA MANAGEMENT
SOFTWARE AND THE GLYCAEMIC CONTROL
IN T1DM PATIENTS
T. Murata1, H. Okada2, J. Kishi1, K. Yamada1, N. Sakane2
1
Diabetes Center, NHO Kyoto Medical Center, Kyoto, Japan
Division of Preventive Medicine Clinical Research Institute,
NHO Kyoto Medical Center, Kyoto, Japan
2
We investigated the association between the frequency of
self-monitoring of blood glucose (SMBG) and the glycaemic
control in type 1 diabetes mellitus (T1DM) patients at NHO
Kyoto Medical Center.
Method: We recruited 148 adult T1DM patients (48.5 – 17.0
years old, male 43%, mean BMI 21.6 – 2.6 kg/m2, mean diabetes duration 12.6 – 11.3 years, mean HbA1c 8.1 – 1.4%,
continuous subcutaneous insulin infusion [CSII] 28%), of
whom SMBG records were uploaded to MEQNETTM SMBG
Viewer software (Arkray, Inc., Kyoto, Japan). Subjects younger
than 20 years old were excluded. The mean SMBG frequency
for 30 days was calculated from uploaded data, and the HbA1c
was compared between those ‡ 3.5 times/day vs. < 3.5 times/
day using Fisher’s exact test. SMBG frequency, mean blood
glucose (BG) and HbA1c were examined by Pearson correlation coefficient analysis.
Results: The mean SMBG frequency was 3.5 – 1.7 times/day
(range: 0.0–7.1 times/day). The mean HbA1c was significantly
lower in those ‡ 3.5 times/day compared to < 3.5 times/day
(7.7% vs. 8.4%, P = 0.006). Subjects on CSII demonstrated
similar results (7.3% vs. 8.2%, P = 0.002), however subjects on
multiple daily injections (MDI) did not (8.0% vs. 8.4%,
P = 0.172). There was significant negative correlation between
mean SMBG frequency and mean BG (r = - 0.222, P = 0.007),
and between mean SMBG frequency and HbA1c (r = - 0.219,
P = 0.008).
Conclusion: In this cohort, the higher SMBG frequency was
associated with better glycaemic control.
This study was supported by Grant-in-Aid from NHO.
P-150
DIFFERENT TYPES OF BOLUSES IN CSII THERAPY
FROM PATIENTS’ AND PHYSICIANS’ POINTS OF
VIEW
L. Goncharova1, E. Patrakeeva1, A. Zalevskaya1
1
Endocrinology, Saint-Petersburg Medical University,
Saint-Petersburg, Russia
A-57
Background: Using variable boluses can be a great opportunity for better postprandial replacement and can make control of
diabetes tighter. However precise recommendations about situations when patient should use variable boluses still not exist.
Subjects and methods: We gave for 30 endocrinologists
(mean age 37 – 9 years) and for 30 CSII patients with type 1
diabetes (T1DM) (mean age 27 – 11 years, mean diabetes duration 12 – 6 years, CSII duration 3 – 1,5 years) questionnaire about
situations when variable boluses should be used. It was an open
test with several answer options of using variable boluses and
also responders could propose their answers.
Results: 100% of patients and 90% of doctors answered that
using of variable boluses influenced on glycaemic control. Using
variable boluses helps to manage diabetes better and makes
feel more confident about not getting high glucose blood level
(70% vs. 60%), allows to make diet more wide. 20% of patients
and 10% of doctors answered that they still don’t understand
when variable boluses should be used. Furthermore younger
doctors revealed more knowledge about using insulin pump.
Among patients whose with close to target HbA1c level (< 7,0%)
gave more full answers and showed more optimistic attitude to
variable boluses.
Conclusions: Our results show that there is still no clear understanding of the variable boluses using among patients and
doctors. Repeated theoretical and practical educational courses
about prandial replacement in CSII therapy is essence not only
for patients but also for doctors.
P-151
COPING STYLES AND DIABETES OUTCOME
IN PATIENTS ON CONTINUOUS SUBCUTANEOUS
INSULIN INFUSION THERAPY
M. Pereira1, L. Pinheiro2, C. Neves1, C. Esteves1, D. Coelho3,
D. Carvalho1
1
Endocrinology Diabetes and Metabolism, Centro Hospitalar
S.João, Porto, Portugal
2
Endocrinology Diabetes and Metabolism, University of Minho,
Braga, Portugal
3
Psyquiatry, Centro Hospitalar S.João, Porto, Portugal
Introduction: Coping strategies are key components in the
management of chronic diseases like diabetes. The way that
patients cope in several demanding treatment situations severely
influenciates their psychological balance and therefore could
affect quality of life outcomes.
Aims: To analyse the differences in coping styles and other
psychological aspects in diabetic patients on Continuous Subcutaneous Insulin Infusion treatment (CSII).
Patients: We gathered a sample of 21 type 1 diabetic subjects,
66.7% females, with a mean age of 30.4 – 7.1 (18–46) years.
Methods: We applied the following instruments 9 months
after the CSII placement: A general biographical questionnaire,
the Diabetes Health Profile (DHP), the Problem Areas in Diabetes Scale (PAIDS), and the Problem Solving Inventory (PSI).
Results: We noticed that the coping styles more often used by
these patients were: problem confrontation and active resolution
followed by strategy planification. The least used were: internal/
external agressivity and emotion control strategies. We found a
correlation between the total health profile and problem areas in
diabetes (r = 0.84; p £ 0.001). We also found that people who
don’t let problems interfere with daily activities have less psychological distress (r = - 0.56; p = 0.01).
A-58
Conclusion: In this sample, we found that patients adopt
confrontation strategies more often, in order to solve their diabetes related problems. On the other hand, patients demonstrate
less emotional control skills that studies shown to be a major
factor in diabetes outcome. These results attest that it is important
to investigate coping styles to be able to help the diabetes outcome in patients on CSII.
P-152
SUCCESSFUL DESENSITIZATION IN TYPE 2
DIABETIC PATIENT WITH AN INSULIN ALLERGY
WITH GLARGINE AND INSULIN PUMP: A CASE
REPORT
G. Petrovski1, M. Zivkovic1, I. Ahmeti1, T. Milenkovic1,
S. Subeska1, I. Bitovska1
1
Center for Insulin Pump, University Clinic of Endocrinology,
Skopje, Macedonia
Introduction: Insulin allergy are rare but they can occur occur
in patients starting insulin therapy. There are different insulin
desensitization protocols where insulin is diluted and given to the
patient in small doses in a period of couple of days. We are presenting case report in type 2 diabetic patient with insulin allergy,
where desensitization was performed using insulin pump (Medtronic Minimed Veo) with glargine.
Case presentation: A 54-year-old man with 8 year history of
type 2 diabetes, BMI 27.8 kg/m2 was used metformin (2 gr) and
glymepiride (4 gr). His average Hba1c was 9.2 – 0.3% in the last
year. In a period of 1 month, different insulin preparation (NPH
insulin, glargine, detemir and biphasic insulin aspart/NPH) were
used, but patient developed pruritic plaques (3–8 cm) at the injection sites that persisted for several days. Allergologic testing
revealed positive reactions against every insulin preparation, with
smaller reaction on insulin glargine. Insulin desensitization with
glargine was performed using insulin pump (Medtronic Minimed
Veo), where insulin was given as basal dose of 4 hour every day in
the next 2 weeks, starting with daily dose of 0.1 units and slight
increase up to 16 units at day 14th. During the two weeks, there was
no reaction at the infusion site. After 2 weeks, the patient continued with insulin glargine using insulin pen (Sanofi Solostar)
with titration algorithm (2–4 units increase) for fasting glycaemia
of 5.6 mmol. Hba1c decreased to 6.2% in the next 6 months with
insulin dose 36 units of glargine and 2 gr of metformin.
Conclusion: As reported in this case, desensitization for long
acting insulin (such as glargine) can be successfully performed
using insulin pump and may present an easy form of therapy that
is successful within a few days.
P-153
PILOT STUDY FOR THE ASSESSMENT OF
TOLERABILITY OF PROLONGED CATHETER USE
IN INSULIN PUMP THERAPY
A. Pfützner1, C. Forkel2, M. Grenningloh2, L. Johannesen3,
R.A.B.I. Gharabali3, D. Klonoff4
1
Diabetes Research Center, IKFE Services - Institute for
Clinical Research and Development, Mainz, Germany
2
Clinical Research, ClinLogix Europe, Mainz, Germany
3
Unomedical, Convatec, Roskilde, Denmark
4
Diabetes, Mills Peninsula Healthcare Services, San Mateo,
USA
Use of insulin infusion sets in insulin pump therapy is recommended for two to three days. However, many patients use
the catheters even longer for economical reasons risking adverse events and skin reactions. This study was performed to
investigate the tolerability of regular catheter use (two days)
with extended use (four days) in a real world setting. Here we
report on an interim analysis which was performed with 12
patients (4 men, 8 women, age 47 – 11 years, BMI:
27.4 – 3.2 kg/m2), who participated in a prospective open randomized cross-over study with 2 · 3 month observation periods
using the infusion sets for 2 days and 4 days, respectively. The
number of treatment related adverse events was 189 with 2 day
use vs. 201 with 4 day use (n.s.). The number of catheter related
events was 42 with 2 day use vs. 130 with 4 day use (p < 0.001).
The combination of catheter related and treatment related was
significantly favorizing 2 day use (231 vs. 331, p < 0.001).
Several patients reported a major increase in infusion site
problems when extending the usage time to 4 days. Glycemic
variabiity was also less favorable with extended use (e.g. hypoglycemic events: 238 vs. 341 events, p < 0.001). In conclusion, using the infusion sets for a longer than recommended
usage period of 2 days resulted in a clinically relevant increase
in treatment-related tolerability problems and impaired glycemic control. Patients should be encourage to not use insulin
pump infusion sets for a longer then recommended time period.
P-154
CARBOHYDRATE COUNTING AND INSULIN PUMP
THERAPY HELP CHILDREN WITH TYPE 1 DIABETES
TO BETTER COPE WITH DIETARY REGIMEN
D. Tinti1, A. Scaramuzza2, S. Giorda1, G. Ignaccolo1,
F. Cerutti1, I. Rabbone1
1
Department of Pediatrics University of Turin, AO Città della
Salute e della Scienza di Torino, Torino, Italy
2
Department of Pediatrics University of Milan, Sacco Hospital,
Milano, Italy
To investigate the effect of carbohydrate counting (carbsC) on
metabolic control and dietary habits in type 1 diabetes children
treated using multiple daily injections (MDI) or continuous
subcutaneous insulin infusion (CSII). We enrolled 50 children
(mean age 9.2 – 4.3 yrs) with type 1 diabetes for more than 6
months, using MDI (n = 31) or CSII (n = 19). Patients using MDI
were trained in carbsC (n = 8) or not (n = 23), while CSII patients
were all trained in carbsC. Each subject filled a 7-day dietary recall, subsequently evaluated by a skilled registered dietitian. BMI, HbA1c, insulin requirement, self-monitoring blood
glucose/day were recorded in each patient. No difference has
been observed in BMI, HbA1c, insulin requirement and number
of glucose testing in patients using carbsC vs patients not using it.
However, number of insulin boluses in carbsC patients was
higher than in patients not using carbsC (p < 0.01). Moreover,
stratifying carbsC users according therapy, Hba1c was significantly higher in MDI than in CSII patients (p < 0.05), while
number of boluses was significantly less (p < 0.01). Patients not
using carbsC were more likely to be less flexible regarding dietary regimen (OR 2.333, IC 0.721–7.547) than patients using it,
and were more worried when they had to eat outside the home
(OR 2.619, IC 0.799–8.588).
CarbsC increases flexibility in dietary regimen, improving
dietary habits and CSII seems to favor a even better metabolic
control.
P-155
THE IMPACT OF INSULIN INFUSION RATE
VARIABILITY ON GLYCAEMIC VARIABILITY
IN ADULTS WITH TYPE 1 DIABETES
M. Reddy1, N. Oliver1, P. Herrero2, P. Georgiou2, S. Misra1,
M. El Sharkawy2, P. Pesl2, N. Jugnee1, C. Toumazou2,
D. Johnston1
1
Division of Diabetes Endocrinology and Metabolism, Imperial
College London, London, United Kingdom
2
Centre for Bio-inspired Technology Institute of Biomedical
Engineering, Imperial College London, London, United
Kingdom
Objective: Improving glycaemic variability (GV) may reduce
long-term diabetes related complications and quality of life.
Continuous subcutaneous insulin infusion (CSII) and long-acting
basal analogue insulins improve HbA1c and reduce the frequency
of hypoglycaemia. CSII does this with variable basal rates and
analogues by providing stable basal insulin concentrations. We
aimed to assess the impact variable insulin infusion rates have on
GV, and in particular hypoglycaemia and risk of hypoglycaemia.
Method: Subjects wore a Medtronic iPro2 retrospective
continuous glucose monitor (CGM) for 5 days. GV measures
including LBGI, LI, ADDR and % time in hypoglycaemia were
calculated using the EasyGV version 9.0 software. We then
performed a linear regression analysis to evaluate the relationship between GV and insulin infusion rate variability
(measured as standard deviation of insulin/hour).
Results: 20 adult subjects with type 1 diabetes (T1DM) were
included in the study (55% male, mean (SD) age 44 (10) years,
duration of diabetes 22 (12) years, duration of CSII 3.4 (4) years,
HbA1c 7.4 (0.7) %, body mass index 25 (4) kg/m2). There were
no significant associations between insulin infusion rate variability and GV or hypoglycaemia: LBGI (R2 = 0.02, p = 0.55), LI
(R2 = 0.06, p = 0.32), ADDR (R2 = 0.03, p = 0.45) and % time in
hypoglycaemia (R2 = 0.04, p = 0.41).
Conclusion: The results suggest, surprisingly, that insulin
infusion rate variability has no impact on hypoglycaemia risk or
% time spent in hypoglycaemia in adults with T1DM on pump
therapy. Further work is needed to understand how CSII and
multiple daily injections affect glycaemic quality.
P-156
GLYCAEMIC VARIABILITY AND QUALITY OF LIFE
IN SUBJECTS WITH TYPE 1 DIABETES MELLITUS –
IS THERE A CORRELATION?
M. Reddy1, N. Oliver1, P. Herrero2, P. Georgiou2,
M. El Sharkawy2, P. Pesl2, N. Jugnee1, H. Thomson1,
C. Toumazou2, D. Johnston1
1
Division of Diabetes Endocrinology and Metabolism,
Imperial College London, London, United Kingdom
2
Centre for Bio-inspired Technology Institute of Biomedical
Engineering, Imperial College London, London,
United Kingdom
Objective: Hypo- and hyperglycaemic excursions have been
associated with oxidative stress and vascular risk. Glycaemic
variability has been associated with reduced quality of life in
subjects with type 2 diabetes. We aimed to evaluate if there is a
correlation between glycaemic variability and quality of life in
subjects with type 1 diabetes (T1DM) on insulin pump therapy.
A-59
Method: Subjects wore a Medtronic iPro2 retrospective
continuous glucose monitor (CGM) for 5 days and completed the
diabetes quality of life questionnaire (DQOL) and diabetes
treatment satisfaction questionnaire (DTSQ). Glycaemic variability measures (SD, CONGA, LI, JINDEX, LBGI, HBGI,
GRADE, MODD, MAGE, ADDR, MVALUE, MAG) were
calculated using the EasyGV version 9.0 software. We then
calculated Pearson’s correlation coefficient and linear regression
to assess whether there was a correlation between glycaemic
variability, diabetes treatment satisfaction and quality of life.
Results: 20 adult subjects with T1DM (55% male, mean
(SD) age 44 (10) years, duration of diabetes 22 (12) years,
duration of insulin pump therapy 3.4 (4) years, HbA1c 7.4
(0.7) %, body mass index 25 (4) kg/m2) participated in the
study. None of the glycaemic variability metrics showed
significant correlation with diabetes treatment satisfaction or
quality of life outcome measures (p-values > 0.05).
Conclusion: Contrary to findings in type 2 diabetes, our study
suggests that increased glycaemic variability does not impact
overall or subscale quality of life in adults with T1DM. A larger
scale study is needed to validate these findings.
P-157
IN TYPE 1 DIABETES INSULIN PUMP TREATMENT
IS ASSOCIATED WITH REDUCED ARTERIAL
STIFFNESS
S. Rosenlund1, S. Theilade1, T.W. Hansen1, P. Rossing1
1
Complication research, Steno Diabetes Center, Gentofte,
Denmark
Aim: Insulin pump (CSII) treatment is associated with reduced glucose variability and in small improvements in glycaemic control. This might reduce development of vascular
complications. We investigated the relationship between arterial
stiffness, evaluated by pulse wave velocity (PWV), and CSII
treatment, and examined if this association was dependent of
glucose control.
Methods: Cross-sectional study, from 2009–2011, including
639 patients with type 1 diabetes. PWV measurements (SphygmoCor, AtCorMedical, Australia) were available in 58 patients
with CSII (35 with albuminuria) and 542 (274 with albuminuria)
treated with multiple daily injections (MDI). ANCOVA compared groups and adjusted linear regression examined the association between PWV, HbA1c and treatment groups.
Results: CSII vs. MDI treated patients were 48% vs. 57%
men, 51 – 11 vs. 54 – 13 years old, 33 – 11 vs. 32 – 16 years diabetes duration and HbA1c 62 – 10 vs. 64 – 13 mmol/mol
( p > 0.08 for all). PWV was lower in CSII vs. MDI (9.3 – 2.8 vs.
10.4 – 3.4 m/s; p = 0.02). This difference remained significant
( p = 0.003) after adjustment for gender, diabetes duration, eGFR,
urine albumin excretion rate, HbA1c, total-cholesterol, smoking,
mean arterial pressure, heart rate and BMI.
In patients with albuminuria, PWV was lower in CSII vs. MDI
(9.3 – 2.5 vs. 11.3 – 3.4 m/s; adjusted p = 0.002).
In adjusted regression analysis, treatment with CSII was significantly ( p = 0.003) associated with lower PWV, while HbA1c
was not ( p = 0.95).
Conclusion: CSII treatment was independently associated
with reduced arterial stiffness, while HbA1c was not. Although
glucose variability was not assessed, our results suggest that
glucose variability and not HbA1c-level affects arterial stiffness.
This needs confirmation in randomised prospective studies.
A-60
P-158
A RETROSPECTIVE COMPARISON: PREGNANCY
OUTCOME AND GLYCEMIC CONTROL WITH CSII
OR MDI TREATMENT
B. Saboo1, P. Talaviya1, S. Joshi2, H. Chandarana1
1
Diacare Research, DiaCare - Diabetes Care & Hormone
Clinic, Ahmedabad, India
2
Joshi Clinic, Joshi Clinic, Mumbai, India
Aim: Aim of present study was to assess glycemic control and
maternal-fetal outcome in pregnant type 1 diabetic patient treated with continuous subcutaneous insulin infusion (CSII) or
multiple daily injections of insulin (MDI).
Patients and Methods: A retrospective observational study
included thirty-four pregnant type 1 diabetic patients. Patients
were divided into two groups, CSII treated group (n = 24) and
MDI treated group (n = 35). The HbA1c level and maternal-fetal
outcome were evaluated in both the treatment group. Outcome
parameters such as glycemic control (HbA1c), hypoglycemic
events, time and mode of delivery and labour results (Abortion,
premature labour, perinatal mortality, neonatal weight, Apgar
score, neonatal hypoglycaemia, presence of congenital abnormalities) were analyzed.
Results: Pregnancy outcome and glycemic control in pregnant type 1 diabetic patients treated with CSII and MDI were
evaluated and compared. Two groups were compared for their
epidemiological parameters, although patients on CSII treatment
had longer duration of diabetes compared to MDI treated group.
Reduction in HbA1c level was higher in CSII treated patients at
first (CSII: 1.2% Vs MDI: 0.58%), second (CSII: 1.81% Vs MDI:
0.99%) and third trimester (CSII: 1.82% Vs MDI: 1.31%) of
pregnancy compared to MDI treated patients. Duration of pregnancy and new born baby weight were founded similar in both
group. Moreover, the rate of abortion, preterm labour, caesarean
section and hypoglycemia in new born were founded less in CSII
treated group compared to MDI treated group and apgar score
was significantly (p < 0.05) higher in CSII treated group compared to MDI treated group.
Conclusion: Results of present study revealed that the CSII
gives better glycemic control and pregnancy outcome in pregnant type 1 diabetic patients compared to MDI treatment. CSII
also decreases the daily insulin requirement compared MDI.
Keywords: Abortion, CSII, HbA1c, MDI, Type 1 Diabetes
P-159
CORRECTION BOLUS FOR PREPRANDIAL
HYPERGLYCEMIA IN CHILDREN WITH TYPE 1
DIABETES USING INSULIN PUMP THERAPY:
TO SEPARATE OR NOT TO SEPARATE?
A. Scaramuzza1, A. Bosetti1, E. Giani1, F. Redaelli1,
A. Gazzarri1, A. De Palma1, M. Macedoni1, M. Ferrari1,
V. Comaschi1, G.V. Zuccotti1
1
Pediatrics, University of Milan, Milano, Italy
Objective: Type 1 diabetes (T1D) is often characterized by high
glycemic variability. When it happens before meals, especially for a
hyperglycaemic value, may be challenging to inject the right insulin
dose at the right time to gain postprandial euglycaemia. The aim of
the present study was to evaluate the best correction strategy for each
value > 160 mg/dl in children and adolescents with T1D, using insulin pump therapy (CSII).
Methods: One-hundred-sixty-three young patients (87
males), aged 13.7 – 3.4 years, with T1D since 9.1 – 4.8 years
(BMI 21.6 – 4.9 kg/m2, insulin requirement 0.84 – 0.24 U/kg/
day; HbA1c 7.6 – 1.6%), using CSII therapy, were randomly
allocated to one or more of the following experimental arms:
simultaneous injection of correction and pre-prandial bolus
given 20 min (arm A), 40 min (arm B), or 60 min (arm C) before
meal; arm D provided a correction bolus injected 20 min before a
pre-prandial bolus, given 15 min before meal.
Results: Results are summarized in Figure 1. The best strategy
seems to be when correction bolus and pre-prandial bolus are
injected separately. Arm D (n = 83): - 60 min: 223 – 32 mg/dl,
- 40 min: 204 – 44 mg/dl, - 20 min: 187 – 32 mg/dl, 0 min: 163 –
43 mg/dl, + 60 min: 153 – 52 mg/dl, + 120 min: 136 – 47 mg/dl,
+ 180 min: 120 – 40 mg/dl (p = 0.004 among arms by ANOVA;
p = 0.009 intra arm D by paired t-test).
Conclusions: To separate the correction bolus, injecting it
20 min before the pre-prandial bolus, seems the best strategy to
quickly recover from a hyperglycaemia and to maintain a postprandial euglycaemic state in children with T1D using CSII.
P-160
NEONATAL HYPOGLYCEMIA IN SIBLINGS OF
WOMEN WITH TYPE 1 DIABETES ON CONTINUOUS
SUBCUTANEOUS INSULIN INFUSION VERSUS
MULTIPLE DAILY INJECTION THERAPY
Z. Mouslech1, I. Zografou2, M. Somali1, C.H. Daramilas3,
C.H. Sampanis2
1
Endocrinology, National Organization for Health Care
(EOPYY), Thessaloniki, Greece
2
Diabetes Centre, 2nd Propedeutic Department of Internal
Medicine Aristotle University of Thessaloniki Hippocratio
Hospital, Thessaloniki, Greece
3
Department of Biology, Faculty of Sciences Aristotel
University, Thessaloniki, Greece
Introduction: An uneventful pregnancy with an optimal
outcome in women with type I diabetes (DM) is strictly dependent on tight glycemic control during pregnancy.
Objective: Two treatments, multiple daily insulin injections
(MDI) and continuous subcutaneous infusion insulin therapy
(CSII) were implemented in women with type 1 DM during
pregnancy with the aim to compare glycemic control.
Material and Methods: Twenty-six (26) women with type 1
DM, eleven (11) on MDI and fifteen (15) on CSII were studied.
Body Mass Index (BMI), HbA1c before pregnancy and before
delivery, rate and severity of hypoglycemia, duration of pregnancy,
newborn birth weight and neonatal hypoglycemia were recorded.
Results: For women on MDI, mean age was 35 – 4.8 years,
BMI 23.75 – 2.34 before pregnancy and 27.08 – 2.1 before delivery (p = 0.005). For women on CSII, mean age was 32 – 4.84
years, BMI 23.78 – 2.85 and 26.12 – 3.07 before pregnancy and
before delivery respectively (p = 0.001). There was also no difference regarding the duration of pregnancy, the weight of the
newborn and the incidence of hypoglycemia of the mother between the two study groups. A higher rate of neonatal hypoglycemia was observed in the MDI group compared to the CSII
group; the difference was statistically significant (p = 0.02).
Conclusion: CSII seems to be more effective than MDI in
achieving a lower incidence of neonatal hypoglycemia although
there was no statistically significant difference between the two
study groups regarding glycemic control during the pregnancy,
the duration of the pregnancy and the weight of the newborn.
P-161
BODY WEIGHT CHANGES DURING THE
CONTINUOUS SUBCUTANEOUS INSULIN INFUSION
(CSII) THERAPY IN ADULT TYPE 1 DIABETES
PATIENTS
E. Szymanska-Garbacz1, K. Michalska1, A. Trzeciak1, J. Loba1,
L. Czupryniak1
A-61
1
Internal Medicine and Diabetology Dept., Medical University
of Lodz, Lodz, Poland
Clinical observation suggests that CSII therapy in adult type 1
diabetes patients leads to a significant weight loss in some of
them. We conducted an observational study aiming at assessing
body weight changes during first 6 months of CSII therapy at our
centre. Non-pregnant subjects with at least 1 year duration of
diabetes, normal thyroid function, not participating in any weight
loss programmes were enrolled into the study. The group comprised 27 subjects (21 women, mean age 27.4 – 9.5 years, diabetes duration 9.5 – 8.2 years, CSII duration 3.1 – 3.4 years, body
weight 71.1 – 13.9 kg, BMI 24.6 – 3.7 kg/m2, HbA1c 8.3 – 1.7%,
blood glucose 161 – 68 mg/dl), who were followed for 6 months.
The patients were seen at least every 6 weeks; all necessary
adjustments to basal rate, normal and dual-wave bolus instructions were made during this period. After the follow-up 14
subjects (52%) lost (mean – SD) 2.6 – 1.7 kg (3.7 – 2.4%)
(weight reduction group, WR), whilst the others gained
0.7 – 1.0 kg (p < 0.01) (comparator group, C). WR patients were
older (30.4 – 7.6 vs. 24.2 – 5.4 years, p < 0.05) and had longer
duration of diabetes (5.4 – 9.7 vs. 2.8 – 3.2 years, p < 0.01). No
change in hypoglycaemia rates was noted in any of the subgroups. No major differences in CSII parameters were found
between the groups, however WR subjects showed tendency of
decreasing insulin basal rate and increasing use of prandial boluses.
Detailed changes in metabolic and CSII parameters are presented
in the table. In conclusion, CSII therapy may lead to body weight
reduction in adult type 1 diabetes subjects, particularly those with
longer diabetes duration.
A-62
P-162
AN OBSERVATIONAL STUDY OF PEDIATRIC
INSULIN PUMP THERAPY IN KAZAKHSTAN:
PRELIMINARY RESULTS
G. Abduakhassova1, R. Bazarbekova2, A. Muratalina3,
A. Salahi4, M. Liu4, J.B. Welsh4, L. Yedigarova4,
F.R. Kaufman4
1
Diabetes, National Research Center of Maternal and Child
Health, Astana, Kazakhstan
2
Diabetes, National Institute for Postgraduate Education,
Almaty, Kazakhstan
3
Diabetes, Medtronic Inc., Almaty, Kazakhstan
4
Diabetes, Medtronic Inc., Northridge, USA
Background: Large-scale introduction of advanced diabetes
technologies to improve glycemic control may be facilitated by
partnerships between national health services and industry. Such a
partnership was used to introduce insulin pump therapy (CSII) to
children in Kazakhstan.
Methods: Pediatric endocrinologists from all 17 regions of
Kazakhstan were identified and trained by experts in CSII from
Medtronic Diabetes. Children age 5–15 with type 1 diabetes and
their families received pumps and training beginning in February
2012. Baseline A1C measurements were obtained. Clinic visits
at 3-month intervals included A1C measurements, pump data
uploads to CareLink, review of CareLink reports, and therapy
adjustments as needed.
Results: As of 8/19/2013, 635 children had enrolled with
per-site enrollments ranging from 11 to 135. Most children
(N = 442, 69.6%) had baseline A1C values ‡ 7.5. In a subgroup
of 313 children who had completed baseline and 12-month
visits, the A1C range at 12 months was 4.3% to 14.0%, and for
those with baseline A1C ‡ 7.5% (N = 221, 70.6%), mean A1C
decreased by 0.85 – 3.07%. Mean daily blood glucose values
(averaged over 4 weeks) for this group fell from 12.28 – 3.99 to
10.45 – 2.47 mmol/L, a mean 1.83 – 4.52 (14.9%) mmol/L decrease. A report from the Kazakhstan Ministry of Health
documented decreases in both severe hypoglycemic events and
DKA during calendar year 2012.
Conclusions: Children adopting CSII in the context of government-industry collaborations, particularly those with baseline
A1C ‡ 7.5%, may realize significant glycemic benefits. The
Kazakhstan/Medtronic collaboration provides a model for other
initiatives that require rapid deployment and/or massive enrollment for introduction of CSII.
P-163
CONTINUES GLUCOSE MONITORING SYSTEM
AS A TOOL FOR MANAGEMENT IN TYPE 2
DIABETES ON BIPHASIC INSULIN DURING
RAMADAN: CASE REPORT
I. Ahmeti1, G. Petrovski1, T. Milenkovic1, I. Bitoska1,
B. Jovanoska1
1
University Clinic of Endocrinology Diabetes and Metabolic
Disorders, Clinical Campus Mother Theresa, Skopje,
Macedonia
Introduction: Fasting during the holy month of Ramadan is
an important spiritual practice in Muslims. The Quran states that
groups of people who do not have to fast like children, pregnant
or breastfeeding women. Diabetic patients using insulin have to
discuss with their health care professionals about insulin titration
and possibility risks.
Case presentation: A 57-year-old woman with 5 year history
of type 2 diabetes, BMI 28.4 kg/m2 was used biphasic insulin
analogue with Hba1c 7.1%. Her insulin dose was 38 units in the
morning and 30 units at evening (0.9 U/kg). During the first week
of Ramadan, blinded continuous glucose monitoring (CGM) for
7 days was performed with Medtronic Ipro2. CGM revealed
hypoglycemic episodes during the day and hyperglycemic periods during the nights. According the CGM, insulin was given as
20 units in the morning and 34 units at evening (0.72 U/kg).
Another blinded CGM was performed which confirmed the
switch of the morning and evening dose with satisfactory glucose
profile.
Conclusion: CGM can be used as a tool for management of
insulin regime in type 2 diabetic patients during Ramadan to
decrease potential glucose variations.
Key words: Ramadan, CGM, glucose variations, switching
dose
P-164
ACCURACY, PRECISION, AND USER
PERFORMANCE EVALUATION OF THE
CONTOUR NEXT LINK 2.4 BLOOD GLUCOSE
MONITORING SYSTEM
T. Bailey1, L.J. Klaff2, J.F. Wallace3, C. Greene3,
S. Pardo3, D. Brown3, B. Pflug3
1
AMCR Institute, Inc., Escondido CA, USA
Rainier, Clinical Research Center, Renton WA, USA
3
Bayer HealthCare LLC, Diabetes Care, Tarrytown NY, USA
2
Objective: Two studies were conducted, in the laboratory and
in the clinical setting, to evaluate the accuracy of the CONTOUR NEXT LINK 2.4 blood glucose monitoring system
(BGMS).
Methods: In the laboratory study, fingerstick samples from
100 subjects were tested in duplicate using 3 test strip lots
and assessed per ISO 15197:2003 section 7 and ISO 15197:
2013 section 6.3 accuracy criteria. In the clinical study, 219
subjects with diabetes enrolled at 2 clinical sites. Subjects
naive to the BGMS tested capillary blood from their fingertips and palms; BGMS glucose results were compared
with YSI reference method. Subjects in the clinical setting
completed questionnaires on ease of use and diabetes management.
Results: In the laboratory study, 100% of results met ISO
15197:2003 section 7 and ISO 15197:2013 section 6.3 accuracy
criteria. Also, 99% (594/600) of results were within –10 mg/dL
(0.6 mmol/L) or – 10% of the YSI reference method. Regression
analysis demonstrated a high degree of agreement between
BGMS and reference (R2 = 0.9926). In the section 8 clinical
study, 100% of subject fingerstick and 99.1% of palm results met
ISO 15197:2003 accuracy criteria; 98.6% of subject fingerstick
and 97.2% of palm results met ISO 15197:2013 section 8 accuracy criteria. Questionnaire results showed most subjects found
the BGMS easy to use.
Conclusion: The CONTOUR NEXT LINK 2.4 BGMS,
which wirelessly communicates with Medtronic devices,
exceeded ISO 15197:2003 sections 7 and 8 and ISO
15197:2013 sections 6.3 and 8 accuracy criteria in analytical accuracy evaluations and in the hands of untrained
lay users.
P-165
COMPARATIVE EVALUATION OF CONTOUR NEXT
USB BLOOD GLUCOSE MONITORING SYSTEM
USING ISO 15197:2013 ACCURACY CRITERIA
AND MARD
J.L. Bedini1, T. Petruschke2, S. Pardo3
1
Laboratorio Core, Hospital Clinic, Barcelona, Spain
Medical Clinical & Scientific Affairs, Bayer Vital GmbH,
Leverkusen, Germany
3
Bayer HealthCare LLC, Bayer HealthCare LLC, Tarrytown,
USA
2
Objectives: Study purpose was to test primarily the performance of a Bayer Blood Glucose meter (BGM) and secondly in
comparison with two additional BGMs versus hexokinase
method.
Method: Accuracies of Contour NEXT USB (Bayer),
FreeStyle InsuLinx (Abbott), One Touch Verio IQ (Lifescan)
were evaluated with two test strip lots each. Left-over venous
blood samples of 204 subjects were measured. Results were
compared to Dimension EXL (Siemens) hexokinase method data
to determine whether results are within either –15 mg/dL of
the corresponding Dimension result, when Dimension result
< 100 mg/dL, or within – 15% of corresponding Dimension result
when it is ‡100 mg/dL.
Furthermore, Mean Absolute Relative Differences (MARD)
from hexokinase reference results were compared for each of the
three BGMs.
Parkes Error Grid and BGM precision were analyzed.
Results: Overall, 99,75% of CONTOUR NEXT USB
BGMS results met the more stringent ISO 15197:2013 accuracy
criteria, compared with 97,55% of FreeStyle InsuLinx results
and 97,55% of OneTouch Verio IQresults. ANOVA indicated
that differences in MARD between meters were statistically
significant. MARD (%): Contour NEXT USB (3,44%); Freestyle
Insulinx (4,23%) and One-Touch Verio IQ (5,17%). For Contour
NEXT USB all results were in Parkers Error Grid zone A and in
zones A or B for the other BGMs.
Conclusion: Analyses showed that all three meters exceeded
the more stringent ISO 15197: 2013 accuracy requirements, but
Contour Next USB had a significantly lower MARD than either
Freestyle Insulinx or One-Touch Verio IQ.
P-166
COMPARISON OF CONTOUR NEXT STRIPS USED
WITH THREE DIFFERENT BAYER BLOOD
GLUCOSE METERS
J.L. Bedini1, J. Alcaraz1, B. Morales1, A. Royo1, M. Parra1,
N. Rico1
1
Laboratorio Core, Hospital Clinic, Barcelona, Spain
Introduction: In the recent years Bayer has developed three
different blood glucose meters (BGM), Contour XT, Contour Next
and Contour Next USB that uses the same strip, Contour NEXT,
for glucose measurement. Each of these three BGM presents different characteristics and specifications and are intended to be used
by different types of patients.
Objective: To evaluate BGM precision. To compare the results obtained with these three BGM and to determine if they are
exchangeable. To determine if results obtained with the three
BGM fulfil ISO 15197:2013 criteria.
A-63
Methods: 100 venous blood samples were measured with
each of the three meters as well as by a Dimension EXL chemistry analyzer (Siemens) that uses hexokinase method for serum
glucose measurement.
Results: Imprecision for the three meters, measured at three
different glucose concentration levels, is below 2%. Comparison,
using Passing-Bablok method, demonstrated that results are totally exchangeable between the three meters, since in all the
linear equations 95% confidence interval always include 1 for the
slope and 0 for the intercept. All three meters fulfil the ISO
15197:2013 criteria with percentage of measurements with accuracy compliance close to 100%.
Discussion: For each of the BGM, operating and technical
specifications are different, making each of them more recommendable for certain types of situations and patients. Despite
these differences, all the meters use the same strips and provide
the same results, allowing doctors to choose the best BGM for
each patient, situation and clinical condition without putting
quality at risk.
P-167
A CHIP-BASED NEAR INFRARED SENSOR
FOR CONTINUOUS GLUCOSE MONITORING
L. Ben Mohammadi1, S. Sigloch1, I. Frese1, K. Welzel1,
M. Goeddel1, T. Klotzbuecher1
1
Microstructuring and Sensors, Institut für Mikrotechnik Mainz
GmbH, Mainz, Germany
In this work we present the concept and in vivo results of a
minimally invasive, chip-based near infrared (NIR) sensor,
combined with microdialysis, for continuous glucose monitoring. The sensor principle is based on difference absorption
spectroscopy in the 1st overtone band of the near infrared
spectrum, using a multi-emitter near infrared LED at wavelengths of 1300, 1450 and 1550 nm. The LED’s together with
two InGaAs-Photodiodes are located on a single electronic
board (non-disposable part) which is connected to a personal
computer via Bluetooth. The disposable part consists of a chip
containing the fluidic connections for microdialysis, two fluidic
channels acting as optical transmission cells and total internally
reflecting mirrors for in- and out-coupling of the LED light to
the chip and to the detectors. The sensor is combined with an
intravascular microdialysis to separate the glucose from the
cells and proteins in the blood and operates without any chemical consumption.
In vivo measurements on 10 patients showed that the NIRCGM sensor data reflects the blood reference values adequately, if a proper calibration and signal drift compensation is
applied. The MARE (mean absolute relative error) value taken
over all patient data is 13.8%. The best achieved MARE value is
at 4.8%, whereas the worst is 25.8%, with a standard deviation
of 5.5%.
P-168
COMPARISON OF CROSS-CALIBRATED SENSORS
AND STANDARD FINGERSTICK-CALIBRATED
SENSORS: FEASIBILITY OF UNIVERSAL
CALIBRATION
E. Budiman1
1
Diabetes Care, Abbott, Alameda, USA
A-64
Background: Subcutaneously inserted glucose monitoring
systems require sensor specific calibration. Ideally, universal
calibration allows for any calibration factor valid for one sensor
to be valid for other sensors, without subject specific information. This analysis compares a hypothetical cross-calibration
method to a standard fingerstick-calibration method.
Methods: A total of 33 subjects with diabetes were enrolled to
wear four sensors simultaneously. Sensors from a lot with low
in vitro sensitivity CV ( = 2.9%) were used in the study. A constant calibration factor is determined on three randomly selected
sensors from the study data. The median is used to cross-calibrate
the other sensors. To evaluate the potential variability introduced
by the random cross-calibrator sensor selection, this virtual study
is repeated 1000 times. Per-sensor MARD distribution of the
cross-calibrated sensors is compared against the same sensors
under standard fingerstick-calibration schedule of five fingersticks over the 5 day wear duration.
Results: Within the 1000 virtual studies, the mean of the persensor MARD in the cross-calibrated system averages at 13.6%
with a standard deviation of 0.9%. The standard method achieves
a similar 13.1% mean (of per-sensor MARD). The mean of the
90th percentile MARD in the cross calibration averages at 18.1%,
with a standard deviation of 1.7%. The 90th percentile MARD in
the standard method is 19.2%.
Conclusions: Mean and 90th percentile per-sensor MARD
comparisons of cross-calibrated sensors against standard fingerstick-calibrated sensors, in subjects with diabetes using sensors with low in vitro sensitivity CV, suggest the feasibility of
non-subject-specific universal calibration.
P-169
OFFLINE CONTINUOUS GLUCOSE MONITORING:
DOES IT MATTER?
H.W. de Valk1, A.B. Grijzenhout1
1
Background: Offline continuous glucose monitoring
(OCGM) offers the possibility to improve glycaemic control by
comparing nutrition and activities with glucose profiles registered blindly. Little is known about the effect of using OCGM in
daily practice on glycaemic control. We assessed retrospectively the effect of OCGM on HbA1c as measure of glycaemic
control.
Patients and Methods Patients with type 1 diabetes (DM1)
and insulin-requiring type 2 diabetes mellitus (DM2) who were
assessed with OCGM during 2009–2011 were identified. OCGM
were re-analysed blindly and divided in those with mainly hyperglycaemia and those with mainly hypoglycaemia. HbA1c
before and maximally 4 months after OCGM were recorded.
Results 100 patients were identified: 79 with hyperglycaemiarelated indication (46% male, age 48.4 – 15.5 years, DM1 61.5%,
HbA1c 71.8 – 16.1 mmol/l) and 21 with hypoglycaemia-related
indication with comparable baseline characteristics (62% male,
age 42.3 – 10.8, DM1 76%) with HbA1c being significantly
lower (52.8 – 12.4 mmol/mol, p < 0.001). After OCGM decreased with 4.8 – 11.7 mmol/mol (p < 0.001) in the hyperglycaemia-group with no significant change ( + 1.4 – 6.2 mmol/mol)
in the hypoglycaemia-group (p = 0.32).
Conclusion OCGM improved glycaemic control as assessed
by HbA1c in patients in the mainly hyperglycaemia-group with
no change in the mainly hypoglycaemia-group. Assessing the
effect of OCGM depends on the reason to do OCGM.
P-170
NATIONAL REGISTRATION PROGRAMME REAL
TIME CONTINUOUS GLUCOSE MONITORING
IN THE NETHERLANDS: THE ‘‘TRACING’’-STUDY
(REGISTRATION CONTINUOUS GLUCOSE
MONITORING IN THE NETHERLANDS)
H. de Valk1, B. Sivius1, X. TRACING Study Group1
1
Background: Real-time-continuous glucose monitoring (RTCGM) may to improve glycaemic control in patients with type 1
diabetes. Patient selection is an important issue taking into account
self-management, compliance and use of sensors > 70–75% of the
time. Prediction of success is important in view of costs of RTCGM. In the Netherlands, RT-CGM is nationally reimbursed for
children, pregnant women and adults on CSII with HbA1c ‡ 64
mmol/mol, with locally other indications. A national registration
programme has started to assess nationwide use and results of RTCGM. We report preliminary results on the adult groups.
Patients and Methods: Hospitals in the Netherlands were
approached to participate. Participation required providing baseline
data of patients starting RT-CGM including quality of life assessment (EQ5D, 0-100) and follow-up data such as HbA1c, severe
hypoglycaemia, hospital admissions and use of sensors during the
first year. Data were sent to the coordinating centre (University
Medical Centre Utrecht). Here we report preliminary results.
Results: 50 major hospitals already participate with inclusion
of 302 patients. Indications: adults HbA1c ‡ 64 mmol/mol 55%,
pregnancy 12%, other indications 33%, mainly hypoglycaemiarelated or unstable glucose profiles; 88% on CSII. Mean age
42.5 – 13.9 years, 67% female, mean EQ5D 65 – 15; mean
HbA1c 59 – 11 mmol/molmol. Study is on-going with growing
number of participants.
Conclusion: A national registry on RT-CGM has been set up
in the Netherlands. Initial results suggest use also outside nationally set indications, especially hypoglycaemia. Results will
help to optimise use of RT-CGM. Such a registry can be used as
template in the implementation of other innovations.
P-171
THE DEADLY MOTHER INSTINCT
H.W. de Valk1, L.B.E.A. Hoeks1, G.H.A. Visser2
1
2
Obstetrics, UMC Utrecht, Utrecht, Netherlands
Background: Realtime-continuous glucose monitoring (RTCGM) has shown in non-pregnant patients to be associated with
improved glycaemic control. Less experience is available in
pregnant women with type 1 diabetes. These women differ from
non-pregnant women in that glycaemic control is often already
quite good and hypoglycaemia an important problem. Analysis
of individual patients may provide important clinical findings
and guidance. We would like to present a case analyse illustrating a particular behavioural pattern in pregnancy.
Case description: She is a 35-year-old well-educated woman
with type 1 diabetes for 31 years without organ complications.
Preconceptional HbA1c level was 34 mmol/mol. She used RTCGMS from the moment of positive testing. During the first 12
weeks she experienced very frequent severe hypoglycaemias,
several times requiring ambulance assistance with also her first
ever epileptic fit. RT-CGM clearly could not protect her from
severe hypoglycaemia but even possibly contributed to them because direct questioning and analysis of glucose profiles and insulin administration, showed that she so much focused on her
glucose values that she impatiently administered insulin for each
elevated glucose value, not taking insulin accumulation into account and even gave insulin bolus when glucose levels were already falling. This fetus-protecting mother instinct, with care for
herself coming second after that for her child, can be very dangerous and potentially lethal.
Conclusion: The many and accurate glucose data can be associated with unrestrained insulin administration in pregnant
women with type 1 diabetes and aggravate severe hypoglycaemia. We have coined this the ‘‘deadly mother instinct’’.
P-172
A NEAR FIELD COMMUNICATION (NFC)
SMARTPHONE INTERFACE TO A FULLY
IMPLANTABLE GLUCOSE SENSOR
C. Long1, X. Wang1, B. Raisoni1
1
Product Development, Senseonics Incorporated, Germantown,
USA
This abstract presents the development of a convenient interface to the Senseonics subcutaneous fluorescent based glucose
sensor which enables users to have an on demand glucose
reading without a body worn transmitter. The fully implantable
sensor is targeted at 180 day insertion duration. The project
utilizes an application running on an NFC capable smartphone,
which provides the hardware and system level support, for remote powering of an otherwise dormant sensor using the extended command set of ISO 15693. The antenna used for NFC
communication is embedded inside currently available, off-theshelf smartphones. The phone used for this development work is
the Samsung Galaxy SIII. Figure 1 shows the NFC Sensor Interface App running on the NFC enabled Smartphone with capability for on-demand readings of the fully implanted sensor.
Current clinical testing of the sensor is targeted at upper arm and
abdomen insertion sites. Visual, audible, or haptic feedback can
be used for alignment on upper arm, which is shown in Figure 1,
or abdomen insertion sites. Further testing of the long-term implantable sensor is targeted to include both sites as this use case
continues to be developed.
A-65
P-173
A WEARABLE CONTINUOUS GLUCOSE
MONITORING SYSTEM WITH BUILT-IN ACTIVITY
TRACKING
R. Rastogi1, S. Rajaraman1, A. Dehennis1
1
Product Development, Senseonics Incorporated, Germantown,
USA
This abstract presents the development of a single, wearable
device that enables both continuous glucose monitoring (CGM)
and activity tracking. The Transmitter for the Senseonics’ CGM
System, when paired with the Mobile Medical Application, can
facilitate individuals with diabetes to extend the measured physiologic parameters with user-entered information, such as insulin
and meal boluses, caloric consumption, and exercise regimen. The
Transmitter hardware incorporates a low-power, tri-axial accelerometer enabling near-continuous activity tracking. This system
is currently being used in feasibility study clinical testing. The data
from this study, which is 4 subjects for 180 days duration, has been
analyzed to segment four activity levels; sedentary, light, moderate and intense. Further, the activity monitoring information was
fused with the continuous glucose measurements to assess correlation between the two sets. Figure 1 shows a nighttime hypoglycemic episode that was preceded by extended durations of
activity, which is similar to approximately 8% of the hypoglycemic sessions in the total data set. In these cases, subjects could
show benefit from the real time feedback of the cumulative day
activity levels. Overall, incorporation of activity tracking technology into our base CGM system can enable more information to
the subject in managing their therapeutic regimens.
P-174
DEVELOPMENT OF A NOVEL MICROPROBE ARRAY
CONTINUOUS GLUCOSE SENSOR FOR TYPE 1
DIABETES: INTERFERENCE STUDIES
A. El-Laboudi1, S. Sharma2, N. Oliver1, T. Hussein2,
D. Patel2, D. Johnston1, T. Cass2
FIG. 1.
1
Diabetes Endocrinology & Metabolic Medicine,
Imperial College London, London, United Kingdom
2
Department of Chemistry & Institute of Biomedical
Engineering, Imperial College London, London,
United Kingdom
A-66
Background: Invasiveness, pain and reduced accuracy limit the
use and effectiveness of continuous glucose monitors (CGM). We
have developed an electrochemical microprobe biosensor for
painless, accurate continuous monitoring of interstitial fluid (ISF)
glucose. The solid microprobes are 1000 lm in length and 15 lm tip
and are fabricated from SU8 epoxy metalized with gold and functionalized with glucose oxidase. They are finally coated with a PU
(polyurethane) membrane, limiting interference and reducing glucose diffusion to enhance selectivity and maintain enzyme activity.
Aim: To optimize the PU membrane thickness and assess its
ability to resist interference from ascorbic acid, uric acid or
acetaminophen.
Method: Metalized microprobes were conformally covered
with PU membrane of variable thickness by adjusting the duration of dip coating (5,10,20 seconds). They were then assessed
using chronoamperometry. Interference studies were performed
by polarizing the metal electrode at 0.7 V or 0.53 V in the
presence of uric acid, ascorbic acid and acetaminophen.
Results: From chronoamperometry the optimum PU membrane thickness was obtained by dip coating for 15 s. For microprobes dip coated for more than 10 seconds, interference was seen
only at 0.7 V with acetaminophen concentrations higher than
0.1 mM (therapeutic concentration 0.03–0.13 mM). However at
0.53 V no interference was seen from any of the three interferents.
Conclusion: In vitro sensor optimization showed the optimum
PU membrane thickness to resist interferents was obtained by dip
coating for 15 seconds with no interference from ascorbic acid,
uric acid or acetaminophen at 0.53 V. Further In vitro tests to
assess glucose sensitivity at these parameters are planned.
P-175
HYPOGLYCEMIA-INDUCED EEG CHANGES IN TYPE
1 DIABETIC SUBJECTS
1
1
2
3
C. Fabris , M. Rubega , A.S. Sejling , J. Duun-Henriksen ,
L.S. Remvig3, C.B. Juhl3, G. Sparacino1, C. Cobelli1
1
Padova, Italy
2
Department of Cardiology Nephrology and Endocrinology,
Nordsjællands Hospital, Hillerød, Denmark
3
Hyposafe, Hyposafe, Lyngby, Denmark
Background: Hypoglycemic events have been proven to
be associated with EEG changes, especially in the low
frequency bands, suggesting the possible role of the brain
as a biosensor to detect hypoglycemia in real-time. Many
indices can be extracted from the EEG, in particular in
time, frequency, and time-frequency domains, but the set
of the most sensitive to hypoglycemia is not completely
established.
Methods: EEG recordings and sparse blood glucose (BG)
concentrations were collected in parallel in 18 T1D subjects
during an insulin-induced hypoglycemia experiment. P3-C3 (P4C4) and P3-T3 (P4-T4) EEG recordings were assessed by linear
spectral analysis (in canonical as well as in individualized
bands), variability of EEG power modulation, and nonlinear
complexity indices. Statistical significance of the changes of
EEG indices during the transition from eu- to hypo-glycemic
conditions has been evaluated.
Results: In all the domains of analysis, statically significant
differences in the EEG signal by passing from eu- to hypoglycemia have been observed. For instance, an increase of the
power spectral density in both theta and alpha bands (in particular in the left brain channels), a significant decrease in
EEG complexity measured by Approximate Entropy, and an
increase of the variability of the reactivity index in theta band
were noted.
Conclusion: Remarkable changes of some EEG indicators
measurable in real-time in time, frequency, and timefrequency domains have been shown to occur during insulininduced hypoglycemia. Possible use of these indicators in the
real-time detection of hypo-events will be a matter of future
investigations.
P-176
LONG-TERM OUTCOMES OF CONTINUOUS
GLUCOSE MONITORING IN YOUNG CHILDREN
WITH TYPE 1 DIABETES UNDERGOING INSULIN
PUMP THERAPY: A RETROSPECTIVE EVALUATION
G. Frontino1, A. Rigamonti1, D. Tinti2, D. Ignaccolo2,
R. Favalli1, C. Bonura1, R. Battaglino1, I. Rabbone2,
G. Chiumello1, R. Bonfanti1
1
Department of Pediatrics, IRCCS Ospedale San Raffaele,
Milan, Italy
2
Department of Pediatrics, University of Turin, Turin, Italy
To evaluate the long-term outcomes of continuous glucose
monitoring (CGM) use in young children with type 1 diabetes
mellitus (T1DM). We retrospectively evaluated 36 (19 males, 17
females) young children (mean age: 5.9 – 1.5 years) who had
undergone insulin pump therapy for at least 5 months (mean
treatment time: 2.2 years). Average HbA1c before CGM placement: 7.6%. Height, weight, BMI, and HbA1c were evaluated at
5 – 4 and 17 – 8 months of CGM follow-up. CGM was worn daily
in 85% of patients for an average 17 – 8 months. CGMS use was
interrupted only in 10 cases due to poor child compliance (n = 7),
skin reactions (n = 2), sensor malfunction (n = 1). HbA1c and
BMI after CGM use were analogous at the end of follow-up
(HbA1c - 0.2%) However, a statistically significant difference
was found in those with HbA1c > 7.5% at the beginning of follow-up: - 0.7% at 6 months (p < 0.05). Furthermore this reduction in HbA1c was maintained at a mean follow-up period of
15 – 6 months (p < 0.05). In the population with HbA1c < 7.5%,
metabolic control did not differ at the end of follow-up. No
severe hypoglycemic events were documented. Our data confirm
that long-term daily use of CGM is feasible in preschool children
with T1DM. A significant reduction can be achieved in those
who start CGM with HbA1c above target and HbA1c may be
maintained stable in those who start CGM with adequate HbA1c.
Further studies involving larger cohorts are necessary to eventually establish age-specific behavioral algorithms, which may
aid in reducing glycemic excursions associated to preschool age.
P-177
CLINICAL IMPACT OF SENSOR-AUGMENTED
INSULIN PUMP (SAP) THERAPY IN TYPE 1
DIABETES LONG-TERM RELATED
COMPLICATIONS IN COLOMBIA
A. Gomez1, R. Alfonso-Cristancho2, D. Prieto-Salamanca3,
J.E. Valencia4, J.E. Valencia4, P. Lynch5, S. Roze6
A-67
1
Colombia
2
Medical Information and Biomedical Informatics, University
of Washington, Seattle, USA
3
Costs, RANDOM foundation, Bogotá, Colombia
4
Reimbursement, Medtronic Latinamerica Inc., Bogotá,
Colombia
5
Diabetes, Medtronic, Tolochenaz, Switzerland
6
Health Economics, Heva, Lyon, France
Background: Sensor Augmented Pump Therapy (SAP) is
more effective than multiple daily injections (MDI) achieving a
good metabolic control in patients with Type 1 Diabetes (T1D)
and has a positive clinical impact.
Objective: To show the impact of SAP Therapy in life
expectancy and long-term complications related to Type 1
Diabetes in comparison to multiple daily injections (MDI), in
Colombia.
Methods: In order to project the incidence and associated
costs of diabetes-related complications over a lifetime, a Core
Diabetes Model was adapted to Colombian population. It is an
internet-based, validated, simulation model developed to determine the long-term health outcomes and economic consequences
of diabetes interventions(1). The inputs were taken from a Colombian real life clinical study(2) of 217 T1D on SAP therapy,
which reported -1.47% reduction in HbA1c levels and a significant reduction in severe hypoglycemic events (5.22 events/
year vs. 0.37 with SAP; p = 0.0009).
Results: Life expectancy of patients with SAP was increased
by 3.51 years and diabetes complications were delayed on average by 1.74 years. The relative reduction in long-term complications including, proliferative diabetic retinopathy (PDR)
42%, Severe Vision Loss (SVL) 20%, End Stage Renal Disease
(ESRD) 46% and Amputations (AMP) 12%, as well as the average delay in their onset (4.9 years, 4.0 years, 3.8 years, 3.7
years, respectively).
Conclusions: SAP therapy, in comparison to MDI, increased
the life expectancy by 3.51 years, delayed the related complications by 1.74 years on average and had a relative risk reduction
in T1D related long-term complications.
A-68
P-178
POSTPRANDIAL GLYCEMIC PROFILES IN NON
DIABETIC SUBJECTS: PRELIMINAR RESULTS
FROM A POPULATION-BASED STUDY
M. González1, M. Pazos1, J.M. Garcı́a1, J. Rivero de Aguilar2,
M. Fernández3, F. Gude2
1
Endocrinology, Universitary Hospital Santiago de
Compostela, Santiago de Compostela, Spain
2
Clinical Epidemiology, Universitary Hospital Santiago de
Compostela, Santiago de Compostela, Spain
3
A Estrada Health Center, Sergas, Santiago de Compostela,
Spain
Objectives: The present study aimed to depict postmeal glucose profiles and to assess the effects of macronutrient intake on
postprandial glycemic responses in non diabetic subjects who
consumed their foods without any restrictions.
Methods: 22 males and 20 females, non previously diagnosed
of diabetes. Participants wore a continuous glucose monitor and
simultaneously kept a food diary for 6 days. We calculated
postprandial glycemic profiles for each dinner (from starting the
meal up to 8 hours), glucose AUCs and glucose concentrations.
Results: Median total energy taken per dinner was 691 (interquartile range, 460, 902) kcal, carbohydrates 67 (46, 96) g,
proteins 30 (19, 46) g, and lipids 25 (13, 37) g. Mean age was 47
years; BMI, 29.0 kg/m2; fasting glucose, 89 mg/dL; HbA1c,
5.4%
Postprandial glucose profiles are shown for the 156 dinners
corresponding to the 42 subjects (Figure 1).
When the subjects were divided into three groups according
to calories intake levels (1000 Kcal), the average glucose level, postprandial peak glucose level, and AUCs increased
steadily (Figure 2). Multivariate analysis showed that carbohydrates intake was the only significant variable at predicting higher glucose levels (p < 0.05).
Conclusions: There is a great variability in postprandial
glucose profiles between subjects. Postprandial glycemic responses are related to the total amount of calories intake. As
regards the macronutrients intake, only the absolute amount of
carbohydrates intake seems to have effect on postmeal glycemic
response.
Acknowledgements: Grants by Spanish Ministry of Health
(FIS PI11/02219, RD12/0005/0007) and Medtronic Inc.
P-179
INFLUENCE OF GLUCOSE VARIABILITY
IN A1C INTERPRETATION
D. Guelho1, L. Barros1, C. Baptista1, I. Paiva1, J. Saraiva1,
C. Moreno1, L. Cardoso1, N. Vicente1, F. Carrilho1
1
Department of Endocrinology, Hospitais da Universidade de
Coimbra, Coimbra, Portugal
Introduction: While A1C remains the standard reference to
assess mean glycaemia, the variations of glucose at cellular level
only are evaluated by direct measuring of interstitial glucose.
Under physiological conditions there is a strong correlation between glycaemia and interstitial glucose; however, in periods of
rapid glucose fluctuations the reliability of this correlation could be
affected. This study aimed to evaluate whether glucose variability
(GV) influences the A1c interpretation.
Methods: Continuous glucose monitoring, using CGMS
system, was performed in 130 T1D patients with diabetes duration of 17,1 – 8,6 years, in intensive insulin therapy
(49.8 – 17.9 UI). Mean interstitial glucose (in mg/dL) and GV
measured by SD of mean interstitial glucose (in mg/dL) were
assessed. HbA1c was simultaneous measured. Statistical analysis was performed using SPSS, version 21.0.
Results: Mean – SD for A1C was 8,2 – 1,4% and for mean
interstitial glucose (MG) was 161 – 34,8 mg/dl. GV was correlated with mean interstitial glucose and A1C (r = 0,58 and
r = 0,29, p = 0,05).
Conclusions: T1D patients with poor glycemic control had
higher GV, and this, per se, impairs the correlation of A1C with
mean interstitial glucose. The combination of GV with A1C may
be a more reliable indicator of blood glucose control than A1C
alone.
A-69
Background: The original FDA approved GlucoWatch presented a number of difficulties including skipped readings due to
movement and perspiration, and skin irritation due to proximity
with the skin of hydrogen peroxide generating sensors.
Method: The CGM Watch is a device that has been developed
by Nemaura Pharma Limited, currently undergoing clinical
studies for CE approval.
Results: During bench trials 12 healthy volunteers (56 paired
data points) were tested over 6 hr duration. 92.86% of the data
points were in Clark Error Grid A zone, i.e. clinical accurate
(Fig.1). Skipped readings were not observed during the study,
and only one subject showed slight redness on the skin after the
study, which disappeared within 2 hours after removal of the
patch.
P-180
COMPARATIVE PERFORMANCE BETWEEN THE
FORMER GLUCOWATCH AND AN IMPROVED NONINVASIVE CONTINUOUS GLUCOSE MONITORING
WATCH (CGM WATCHTM)
Y. Han1, F. Chowdhury1
1
Diagnostic Devices, Nemaura Pharma Ltd, Leicestershire,
United Kingdom
Table 1. CGM WatchTM Improvements over Glucowatch
Feature
Glucowatch Biographer
Nemaura CGM-Watch
Benefit
Skin Contact Material
Hydrogel with Phosphate
buffer (20 ul), impregnated
with Glucose Oxidase
Phosphate Buffer Solution
(pH = 7, 300 ul)
Electro-Chemistry
GOx immobilised in Hydrogel
User Interface Screen
Character LCD
Cross-linked GOx covered
with Zirconia/Nafion
membrane
Graphic LCD
Iontophoresis Drive
Control Sensor for
Interference
reduction
DC
No
Higher Frequency DC
Yes
- Eliminate the swelling
effect of Hydrogel
- Reduced oxygen deficiency
problem due to the increase
of buffer volume
- Reduction in H2O2
concentration more than
10 fold, leading to
reduced/absent skin
irritation
Increased GOx stability
by cross-linking, increased
sensor shelf life
Permits viewing of trends
on device
Reduces Parasthesia (tingling)
Reduces interfering effect
of extraneous substances
such as uric acid and drugs
A-70
P-181
CALIBRATION SCHEMES OF A TRULY NONINVASIVE GLUCOSE MONITOR FOR VARIETY
OF DIABETICS
A. Gal1, I. Harman-Boehm2, A. Drexler3, E. Naidis1,
Y. Mayzel1, N. Goldstein1, K. Horman1
1
R&D, Integrity Applications Ltd., Ashkelon, Israel
Internal Medicine and the Diabetes Unit, Soroka University
Medical Center, Beer-Sheva, Israel
3
Division of Endocrinology Diabetes and Hypertension, David
Geffen School of Medicine University of California, Los
Angeles, USA
2
Calibration is an essential process in Non-Invasive (NI) blood
glucose (BG) monitors. This process minimizes the impact of
individual quasi-stable factors and sets a baseline for individual
detection of physiological change. Previous publications about
GlucoTrack, a NI glucose monitoring device (CE-mark approved), proposed a calibration process that increases BG level,
in order to track physiological changes. However, in order to
have a utilizable process available to all users, an additional
scheme of glucose level decrease was evaluated.
Calibration of GlucoTrack requires an overnight fasting beforehand. During calibration, BG is changed, so that user’s upper and
lower BG levels are reached (with some degree of flexibility at the
edges). However, in some cases, fasting values do not always represent the user’s lower BG values. Therefore, two calibration
schemes are applied: depending on the user’s fasting BG value, the
calibration is performed at either glucose increase or decrease mode.
The calibration schemes’ robustness was evaluated in clinical
trials. 87 out of 139 participants were calibrated in glucose increase
mode, the rest, mostly insulin treated subjects, were calibrated by
BG decrease mode.
Clarke Error Grid analysis for BG increase and decrease
modes shows that 96.9% and 94.6% of the points are in the
clinically acceptable A + B zones, respectively. Mean Absolute
Relative Differences are 30.0% and 31.6%, correspondingly.
The two calibration schemes yield similar GlucoTrack accuracy. The new calibration scheme can therefore be used when BG
fasting level deviates from subject’s lower level. The two calibration modes create an approachable process, which overcomes
inappropriate user’s initial BG level, thus enables more flexibility in the calibration process.
P-182
USABILITY OF A TRULY NON-INVASIVE GLUCOSE
MONITOR IN HOME USE
A. Gal1, I. Harman-Boehm2, A. Drexler3, E. Naidis1,
Y. Mayzel1, N. Goldstein1, K. Horman1
1
R&D, Integrity Applications Ltd., Ashkelon, Israel
Internal Medicine and the Diabetes Unit, Soroka University
Medical Center, Beer-Sheva, Israel
3
Division of Endocrinology Diabetes and Hypertension, David
Geffen School of Medicine University of California, Los
Angeles, USA
2
Glucose monitoring adherence is considered essential for
achieving tight glycemic control in diabetic patients. Non-invasive (NI) glucose monitoring is expected to encourage frequent
self-monitoring by overcoming pain and complexity involved in
invasive measurements. To motivate contributive utilization, a
NI device should be user friendly and simple-to-manage at home
and home-alike environment.
GlucoTrack is a NI, CE Marked glucose monitoring device.
GlucoTrack suitability for home use was tested by 50 educated
subjects (high-school and higher) based on device accuracy and
user feedback analyses. First trial day included individual calibration and brief training by a proficient team. 42 subjects conducted
the measurements by themselves for three more days. 8 more
participants used the device at home for 5–7 days after calibration.
Clarke Error Grid analysis shows 96.2% of the points in the
clinically accepted A + B zones. Mean Absolute Relative Difference
of 30.5% was observed. 82% of all subjects expressed willingness to
use the device regularly. 78% were generally pleased with the device. GlucoTrack display appeared clear and understandable to 89%
of the participants. The operating instructions were clear to 81% of
the high-school-educated and to 84% of the higher-educated participants. 64% and 61% claimed the device is easy to use among
high-school and higher-educated, respectively.
GlucoTrack yields fair accuracy and is user friendly regardless
of education level. These advantages, along with its painless
nature of measuring and competitive long-term cost of use,
suggest GlucoTrack as utilizable device for enhanced blood
glucose monitoring and tighter glycemic control.
P-183
THE STATSTRIP GLUCOSE MONITOR IS SUITABLE
FOR USE DURING HYPERINSULINEMIC
EUGLYCEMIC CLAMPS IN A PEDIATRIC
POPULATION
K.A. Lindquist1, K. Chow2, A. West3, L. Pyle3, T.S. Isbell4,
J.A. DuBois4, M. Cree-Green3, K.J. Nadeau3
1
Medicine, University of Massachusetts Medical School,
Worcester, USA
2
Medicine, Rosalind Franklin University of Medicine and
Science, North Chicago, USA
3
Pediatric Endocrinology, University of Colorado Denver
Children’s Hospital Colorado, Denver, USA
4
Medical and Scientific Affairs, Nova Biomedical, Waltham, USA
The hyperinsulinemic euglycemic clamp is the gold standard
for assessment of insulin resistance, and requires frequent, accurate measurements of blood glucose concentrations, typically
utilizing the YSI 2300 STAT Glucose Analyzer (YSI Incorporated, Yellow Springs, OH). Despite its accuracy, the YSI
has several limitations, including: cost, lengthy run time, need for
trained personnel, frequent maintenance, and large blood volumes. Simpler hospital-grade handheld glucose meters are now
available, but have not been validated for use in pediatric clamp
settings. This study evaluated the accuracy, precision, and reliability of the StatStrip (SS) Hospital Glucose Meter (Nova Biomedical, Waltham, MA) relative to the YSI 2300 STAT Glucose
Analyzer in a pediatric hyperinsulinemic euglycemic clamp setting. 460 blood specimens were drawn from 11 pediatric patients
undergoing hyperinsulinemic euglycemic clamps and were simultaneously analyzed by SS and YSI. The imprecision of SS and
YSI were measured and the bias of SS relative to YSI was calculated. The SS showed a slight mean positive bias of 0.75 mg/
dl – 2.83 mg/dl vs. the YSI. Coefficients of variance for SS and
YSI were 9.53% and 9.25%, respectively. Using a Bland-Altman
plot, the limits of agreement were – 5.7 mg/dl. The coefficient of
repeatability for SS was 6.63; the coefficient of individual
agreement between the YSI and SS was 0.995. The SS is a
suitable replacement for the YSI in pediatric hyperinsulinemic
euglycemic clamp studies and is more cost effective, faster, requires less blood and is easier to use. Future euglycemic clamp
studies can consider utilizing this methodology.
P-184
THE BENEFIT OF CONTINUOUS GLUCOSE
MONITORING SYSTEM(CGMS-IPRO2) IN REDUCING
A1C IN SUBOPTIMALLY CONTROLLED TYPE 2
DIABETES
J. Kannampilly1, A. Paleri1, A. Valsan1
1
Diabetology, Lakeshore Hospital & Research Centre Ltd,
Ernakulam District, India
Aim: To study the benefit of short-term blinded continuous
glucose monitoring (CGM) studies in conjunction with therapy
intensification with respect to A1C reduction.
Materials and Methods: Fifty-five patients with type 2 diabetes were selected from the outpatient diabetes service at Lakeshore Hospital & Research Centre Ltd, Kochi. Initial A1C values
ranged from 7.5% to 12.6%. A blinded 3-day CGM study (iPro2,
Medtronic) was conducted in each patient and data were retrospectively analyzed by physicians; results were shared with patients
and areas for therapy intensification and behavioral/dietary adjustments were discussed. Therapy intensification options included
addition of oral hypoglycemic agents (OHA), multiple daily injections (MDI), OHA + MDI, adjustments to insulin dose, OHA + adjustments to insulin dose, and addition of an insulin pump. After 3–6
months, patients returned to the clinic for A1C determination.
Results: All 55 patients experienced an A1C reduction. The
average A1C reduction was 2.12% (range, 5.2% to 0.1%). The
number of patients with A1C < 7.5% increased from 0 (0%) to 36
(65.45%). The number of hypoglycemic events decreased during
the post-iPro2 interval.
Conclusion: Results of iPro2 studies can provide clinicians
with insights to guide effective therapy intensification efforts
in patients with type 2 diabetes with suboptimal control. With
iPro2 as a tool in the management of diabetes mellitus, most
patients can achieve A1C reductions and reach the goal of
A1C < 7.5% without any severe hypoglycemic events. Further
studies of the effects of iPro2 studies on patient motivation
and adherence to treatment regimens are warranted.
P-185
MODY3 IN CHILDHOOD: DIAGNOSIS AND
TREATMENT WITH CONTINUOS GLUCOSE
MONITORING
I. Kántor1, Z.S. Gaal2, I. Balogh3
1
Pediatrics, Szabolcs-Szatmar-Bereg County Hospitals and
University Hospital, Nyiregyhaza, Hungary
2
Internal Medicine 4th Dep., Szabolcs-Szatmar-Bereg County
Hospitals and University Hospital, Nyiregyhaza, Hungary
3
Department of Laboratory Medicine, University of Debrecen
Medical and Health Science Center, Debrecen, Hungary
Background and aims: MODY3 (also known as HNF1AMODY) is caused by mutation of the HNF1alfa, a homeobox gen
on chromosme 12. Beside MODY2 this is the most common type
of MODY in pupolations with Europena ancestry, accounting for
about 70% of all cases in Europe. HNF1alfa is a transcriptional
A-71
faktor (TCF1) that is thought to controll a regulatory network
important for differentiation of beta-cells. In mature beta-cells
takes part in the transcriptional process of insulin gen. Mutations
of this gene lead to reduced beta-cell mass as well as impaired
beta-cell function, reduced insulin releasing capacity. About
70% of people develope MODY3 diabetes by age 25 years.
Materials and methods: Our patient had the genetic diagnosis
of MODY3 by age 6 years (following her mother’s genetic diagnosis). During her follow-up (beside OGT) we peformed CGM to
monitor her beta-cell function, when developing diabetes. Even the
first OGT result proved to be diabetic, according to diagnostic
criteria. HbA1c was in normal range. She was treated with life-style
modification and diet. Her metabolic dysfunction was worsening,
repeated OGT result showed deterioriation. She was started on
sulfonilurea: glibenclamid 7,5 mg daily. The treatment was followed by CGM- as to prevent hypoglycemia and to titrate the dose.
Results: Our patients blood-glucose returned within normal
limits despite unsatisfactory life-style and diet.
Conclusion: CGM is a useful tool to help decision making:
initiation of treatment, to adjust dose of medication: to achive
normal BG without hypoglycemia in this special sulfonilurea
sensitiv and limited number patients.
P-186
EFFECT OF CGM SENSOR TIME DELAY ON MARD
AND PARD PERFORMANCE MEASURE
H. Kirchsteiger1, V. Lodwig2, E. Ramstetter2,
G. Schmelzeisen-Redeker2, M. Schoemaker2, L. Del Re1
1
Design and Control of Mechatronical Systems, Johannes
Kepler University, Linz, Austria
2
Roche Diagnostics GmbH, Mannheim, Germany
The clinical and laboratory standards institute document
POCT05-A, performance metrics for continuous glucose monitoring (CGM) suggests to report theinherent lag times of the
sensors. In this study, the effect of two approachesfor lag time
estimation on the MARD and PARD (mean and precision absoluterelative deviation) between continuous and reference glucose measurements isanalyzed.
Methods: Data from 12 patients wearing 6 CGM sensors (two
FreeStyle NavigatorTM, two MiniMedGuardian REAL-Time with
Enlite sensor and two DexComTM SevenPlus) inparallel (Freckman et al., J. of Diabetes Science and Technology 7(4), pp. 842–853)
were analyzed. Sensor lag was estimated by cross-correlationanalysis using CGM data and interpolated reference measurements and
by choosinga time delay between paired CGM data and reference
measurements which resultsin the minimum MARD.
Results: Estimated timedelays by the cross-correlation method
are (mean – SD): SevenPlus 9.24 min – 2.66, Navigator 14.23 min –
6.96 and Guardian 13.83 min – 4.87. Time delays found byminimizing the MARD are: SevenPlus 9.05 min – 3.26, Navigator
12.23 min – 3.37 and Guardian 14.33 min – 1.94. Both methods give
comparable results consistent with previouslypublished ones.
On average (12 patients), MARD is reduced relatively by
9.7% (SevenPlus), 17.7% (Navigator) and 20.9% (Guardian)
when taking the time delay into account. Minimum/maximum
reductions are 1%/19% (SevenPlus), 3%/37% (Navigator)
and1%/40% (Guardian). PARD is not substantially affected, even
if the delaybetween two sensors of same type is not identical.
Conclusions: Both methods give accurate results for lag time.
Time delay has asignificant effect on the MARD and should be
considered in performanceassessments. Effect on PARD is insignificant.
A-72
P-187
INFLUENCE OF LONG DISTANCE RUNNING ON
CGMS VALUES CORRELATION WITH CAPILLARY
GLUCOSE IN PATIENTS WITH DIABETES
R.N. Lamounier1, G.L.C. Mendes2, A.S. Silva1, E.S. Oliveira3,
A.H. Silva3, T.M. Ferreira1, D. Giannella-Neto4
1
Endocrinology, Belo Horizonte Diabetes Center (CDBH), Belo
Horizonte, Brazil
2
Diabetes Education and Technology, Belo Horizonte Diabetes
Center (CDBH), Belo Horizonte, Brazil
3
Physical Trainning, Belo Horizonte Diabetes Center (CDBH),
Belo Horizonte, Brazil
4
Endocrinology, Nove de Julho University (UNINOVE), Sao
Paulo, Brazil
Aim: To evaluate the correlation of sensor (SG) and capillary
glucose (CG) and the impact of long distance running on this
correlation.
Methods: 301 CGMS procedures were analyzed, 80 done
in Type 1 Diabetes runners. Overall SG and CG correlation
was obtained and compared with the correlation within 36 h
around running long distance (RUN), and during resting
time (REST). Clark’s Errors Grid Analysis (EGA) was
performed.
Results: The whole sample (ALL) included 5946 paired
points, with 688 points in RUN and 558 in REST periods respectively. Average SG and CG were 163*# – 73 mg/dL,
164 – 70 mg/dL (ALL); 153* – 72 mg/dL, 156 – 72 mg/dL
(RUN) and 155# – 66 mg/dL, 154 – 66 mg/dL (REST), respectively. There was no difference within each group. ALL had
higher average SG than both RUN (*p = 0.001) and REST
(#p = 0.007). SG and CG correlation were R2 = 0.77; R2 = 0.76;
and R2 = 0.64 for ALL, REST and RUN, respectively. (p = 0.005,
for RUN versus both ALL and REST). EGA showed 95.5%, 96%
and 92% of paired points in A and B zones, for groups ALL,
REST and RUN respectively. While 1.1%, 3.2% and 0.3% in C,
D and E zones in group ALL, 0.9%, 3% and 0.2% in group REST
and 3%, 5% and 0%, in group RUN. None of the 80 distance runs
were interrupted by hypoglycemia.
Conclusion: In this sample, SG showed good correlation with
CG. This correlation was modified by exercise, but this difference did not affect error chance.
P-188
CGMS IN 67 TYPE 1 DIABETES ATHLETES DURING
AN 18 KM DISTANCE RUN
R.N. Lamounier1, G.L.C. Mendes2, A.S. Silva1, E.S. Oliveira3,
A.H. Silva3, T.M. Ferreira1, D. Giannella-Neto4
1
Endocrinology, Belo Horizonte Diabetes Center (CDBH), Belo
Horizonte, Brazil
2
Diabetes Education and Technology, Belo Horizonte Diabetes
Center (CDBH), Belo Horizonte, Brazil
3
Physical Trainning, Belo Horizonte Diabetes Center (CDBH),
Belo Horizonte, Brazil
4
Endocrinology, Nove de Julho University (UNINOVE), Sao
Paulo, Brazil
Aims: The project ‘‘Volta Monitorada’’ prepares and empowers T1DM subjects to participate in long distance run events
in Brazil. We evaluated their glucose profile during an 18 km run.
Methods: 67 T1DM athletes and 10 controls completed the 18
km run with CGMS. According to their previous treatment, they
were divided in three groups: CSII, n = 17; Basal analogs (BA),
n = 34; NPH, n = 16.
Results: Average age was 28.8 – 8.3 years and time for
completing 18 km was 139.9 – 33.6 min. HbA1c was 7.6 –
1.32%, and similar among the three groups. C peptide was
higher in NPH vs CSII (0.5 vs 0.1; p = 0.02). CGM time was
4431.6 – 108.3 min, with 886.32 – 357.06 readings. Average
sensor glucose was 152.09 – 23.6 mg/dL, similar between groups
and different from CT, 96.7 – 7.8 mg/dL; p < 0.0001. Hypo and
Hyperglycemia exposition was similar between groups with 5%
of values below 70 mg/dL. Run speed inversely correlated with
HbA1c (RR: - 0.32; P < 0.001) and sensor AUC (RR - 0.31;
P < 0.002). Glucose variability (GV) was similar among diabetes
groups. CT had maximum glucose value of 138 mg/dL vs
342 mg/dL in T1DM runners (p < 0.0001). Glucose decrease
correlated positively with glucose value at start (RR - 0.49;
P < 0.0001). After run Lactate correlated positively with maximum glucose value and GV.
Conclusion: In this study GV was similar among different treatments, but NPH group had higher C peptide values
than CSII. Better fitness was related to better glycemic control, while higher glucose values related to higher post run
lactate.
P-189
DEVELOPMENT OF A STANDARDIZED APPROACH
TO INITIATING CONTINUOUS GLUCOSE
MONITORING IN A MULTICENTRE PEDIATRIC STUDY
M.L. Lawson1, C. Richardson1, J. Muileboom2, K. Evans3,
A. Landry4, L. Cormack5, JDRF Canadian Clinical Trial
Network CCTN1101 Study Group6
1
2
3
London, Canada
4
5
Toronto, Canada
6
Canada
Objective: To evaluate a standardized approach to education
and device setting options for continuous glucose monitoring
(CGM) in children and adolescents with type 1 diabetes (T1D)
starting pump therapy with simultaneous or delayed CGM initiation.
Method: All participants are part of the CGM TIME Trial, a
multicentre 5-site RCT of pump naı̈ve 5–18 year olds with
T1D > 1 year who were randomized to simultaneous initiation of
pump (Medtronic Veo) and CGM (Enlite) or to standard pump
therapy with delayed CGM introduction 6 months later. Prior to
the trial, diabetes educators at the 5 participating centers critically reviewed published and unpublished education materials
and approaches to initiating CGM.
Results: A standardized approach to CGM education and
settings was developed and implemented study-wide along with
A-73
a novel study-specific algorithm for trend arrow adjustments. All
sites utilized the standardized CGM settings and education materials, resulting in a consistent and step-wise approach to initiating CGM amongst the 144 subjects participating in the trial.
Analysis of CGM adherence and effectiveness, and their relationship to participants’ use and frequency of alarms will begin in
July 2014.
Conclusion: The CGM TIME Trial successfully developed
and standardized a step-wise approach to CGM education
and settings. Its conclusions will enhance our understanding of optimal CGM settings for simultaneous and delayed
CGM initiation, and offer guidelines to support other centers in
best practices to improve CGM adherence and effectiveness.
P-190
TIMING OF INITIATION OF CONTINUOUS
GLUCOSE MONITORING IN ESTABLISHED
PEDIATRIC DIABETES: RECRUITMENT AND
BASELINE CHARACTERISTICS IN THE CGM
TIME TRIAL
M.L. Lawson1, B. Bradley2, K. McAssey3, C. Clarson4,
S. Kirsch5, J.R. Curtis6, C. Richardson1, J. Courtney2,
T. Cooper1, JDRF Canadian Clinical Trial Network CCTN1101
Study Group7
1
2
Diabetes Research Group, Children’s Hospital of Eastern
Ontario Research Institute, Ottawa, Canada
3
4
London, Canada
5
6
Toronto, Canada
7
Canada
Objective: To determine if initiating continuous glucose
monitoring (CGM) at the same time as starting pump therapy in
pump naı̈ve children and adolescents results in greater CGM adherence and effectiveness compared to delaying CGM introduction by 6 months, and whether this is related to greater readiness
for making behavior change at the time of pump initiation.
Method: Multicentre 5-site RCT of 5–18 year olds with
T1D > 1 year who are starting pump therapy and willing to be
randomized to simultaneous initiation of pump (Medtronic Veo)
and CGM (Enlite) or to standard pump therapy with delayed
CGM introduction 6 months later. Primary outcomes are CGM
adherence and A1C at 6 and 12 months post pump initiation.
Secondary outcomes include glycemic variability and patient
reported outcomes.
Results: Recruitment was completed in 21 months, during
which 353 children started pump therapy. 144 (95%) of the 152
eligible patients were enrolled and randomized (73 simultaneous,
71 delayed; mean age 12.0 + / - 3.3 (SD) years; T1D duration
3.3 + / - 3.0 years; baseline A1C 8.0 + / - 1.0%). Reasons for
exclusions (n = 201) included: not willing to use CGM (20.9%),
< 5 years old (9.0%), < 1 year T1D (7.0%), unwilling to be
randomized to delayed CGM (1.5%), chose non Medtronic pump
[but met other inclusion criteria] (53.2%).
Conclusion: The CGM TIME Trial is the first study to examine
the relationship between readiness for behavior change, timing of
A-74
CGM initiation, and subsequent CGM adherence in pump naı̈ve
children and adolescents. Analysis of 12 month primary outcomes
will begin in July 2014.
P-191
EFFICACY OF BLINDED, 3 DAY CONTINUOUS
GLUCOSE MONITORING IN THE REGULATION
OF POORLY CONTROLLED DIABETES
S.B. Leichter1, B.A. Dennis1, E. Evans1, A. Johnson1
1
Diabetes and Metabolism, Center for Diabetes and
Metabolism, Columbus, USA
As the application of continuous glucose monitoring (CGMS)
evolves, most studies have focused on the long-term placement
of CGMS on individual patients (single-user). The effectiveness
of short term, multi-user professional CGMS has been studied
less extensively with conflicting results. To evaluate short-term
CGMS effectiveness in our Center, we carried out a retrospective
review of 113 consecutive patients. We used a three day, blinded,
multi-user CGMS protocol supplemented by food and activity
diaries. Hemoglobin A1c (Hgb A1c) was measured 6–12 weeks
before the study and 6–12 week after changes in treatment were
implemented, based on the results of the CGMS assessment.
Baseline Hgb A1c in the entire group was 8.81 – 0.14%, and fell
to 8.26 – 0.14% following the testing (p < 0.000002). Hgb A1c in
patients with type 1 diabetes was 8.78 – 0.18% at baseline and
8.36 – 0.17% at follow-up (p < 0.01). Hgb A1c also significantly
declined in patients with type 2 diabetes (8.88 – 0.23% vs
8.07 – 0.24%) (p = 0.000003). Hgb A1c declined significantly in
patients on insulin therapy alone (p = 0.004), and insulin plus
oral hypoglycemics (p = 0.0035). The change in Hgb A1c was
not significant in patients on oral hypoglycemic agents; however, the number of subjects in this group was small (n = 10).
We conclude that use of blinded, short-term, multi-user CGMS
is an effective tool for improving glycemic control in diabetic
patients on insulin therapy, when implemented with supplemental lifestyle data.
P-192
CGM AND SAP ARE VALUABLE TOOLS IN THE
TREATMENT OF DIABETES; A SWEDISH HEALTH
TECHNOLOGY ASSESSMENT
A. Lindholm Olinder1, R. Hanas2, E. Heintz3,
S. Jacobson3, U.B. Johansson4, P.O. Olsson5,
M. Persson1, S. Werko3
1
Clinical Science and education Södersjukhuset, Karolinska
Institut, Stockholm, Sweden
2
Clinical Sciences Sahlgrenska Academy, University of
Gothenburg, Gothenburg, Sweden
3
LIME, Karolinska Institutet SBU, Stockholm, Sweden
4
Clinical Sciences Danderyd Hospital, Karolinska Institutet
Sophiahemmet University, Stockholm, Sweden
5
Internal Medicine, Central Hospital, Karlstad, Sweden
Long-term use of CGM (continuous glucose monitoring) is
used by a few percent of adults and 3–16% of children with Type
1 diabetes in Sweden.
Aim: to present a systematic review to establish available
evidence on effects of CGM and SAP (sensor-augmented pump)
in adults (A), children (C) and pregnant women (P) compared to
SMBG (self-monitored blood-glucose).
Methods: Literature search included PubMed, Cochrane Library, Cinahl and PsychINFO until November 2012. Two reviewers independently assessed the quality of each included
study by using the SBU checklists. Quality of evidence was rated
by the GRADE system.
Results: Of 1130 identified abstracts, 24 CGM studies were
quality assessed; 11 had low quality (6C,1P,4A), 8 moderate
(5C,3A) and 5 high (4C,1A). For SAP, 10 studies were assessed;
3 had low quality (1C,2A), 6 moderate (2C,4A) and 1 high (C).
For adults, 1 systematic review of high quality was included.
There was a lack of high quality research. Short-term HbA1c
was improved by CGM if used ‡ 6 days/week, more so by SAP.
Patients with CGM reported higher treatment satisfaction, especially when using SAP. Limited information was available on
frequency of severe hypoglycemia and ketoacidosis.
Calculations of costs demonstrated an increased cost of 3026
EUR for CGM vs. SMBG and 4216 EUR for SAP vs. MDI and
SMBG.
Conclusion: CGM and SAP demonstrate short-term benefits
including a reduced HbA1c level, which if sustained may reduce
the risk of long-term diabetes complications.
P-193
PERFORMANCE EVALUATION OF FOUR BLOOD
GLUCOSE MONITORING SYSTEMS
M. Link1, G. Freckmann1, A. Baumstark1, C. Schmid1,
S. Pleus1, C. Haug1
1
Institut für Diabetes-Technolgie Forschungs- und
Entwicklungsgesellschaft mbH, - Ulm, Germany
Objective: Self monitoring of blood glucose (SMBG) is used
for therapy adjustment by patients. Therefore, high quality
SMBG systems are required. In this study, system accuracy of
four SMBG systems was evaluated following ISO 15197:2003
and the recently published ISO 15197:2013 criteria. In addition,
measurement performance on 100 native samples with BG
concentration < 70 mg/dl was assessed.
Methods: Four systems were evaluated with three test strip
lots each: Contour XT (Bayer Consumer Care AG), GlucoCheck XL (aktivmed GmbH), Accu-Chek Aviva (Roche
Diagnostics GmbH), GlucoMen LX Plus + (A. Menarini Diagnostics S.r.l). System accuracy evaluation was performed
following the standard ISO 15197:2003/2013. In addition, 100
capillary blood samples of 40 subjects with BG concentrations
< 70 mg/dl (mean 60.1 mg/dl, range 38.5 mg/dl–69.6 mg/dl) were
collected to analyze mean absolute relative differences (MARD)
between system and comparison method results (hexokinase,
cobas c111).
Results: All systems met the ISO 15197:2003 criteria with
95.5% to 100% of measurement results within the respective
limits. When applying the ISO 15197:2013 criteria, three
systems met these criteria (95.5% to 100% of results within
the limits). For native samples < 70 mg/dl SMBG systems
showed MARD of 2.7%, 5.1%, 6.8% and 15.2%, respectively.
Conclusion: All investigated SMBG systems fulfilled
system accuracy criteria of the standard ISO 15197:2003,
whereas only three of them fulfilled the requirements of ISO
15197:2013. These showed only small deviations from the
comparison method in the low glycemic range which is important to detect hypoglycemic events.
P-194
PERFORMANCE ASSESSMENT OF A CONTINUOUS
GLUCOSE MONITORING CALIBRATION
ALGORITHM IN HYPOGLYCEMIA
Z. Mahmoudi1, M. Hasselstrøm Jensen1, M. Dencker Johansen1,
T.F. Christensen1, L. Tarnow2, J.S. Christiansen3,
O.K. Hejlesen1
1
Health Science and Technology, Aalborg University, Aalborg,
Denmark
2
Health, Aarhus University, Aarhus, Denmark
3
Endocrinology and Diabetes, Aarhus University Hospital,
Aarhus, Denmark
Background: The aim of this study was to assess the performance of a new continuous glucose monitoring (CGM)
calibration algorithm.
Method: CGM data from 10 type 1 diabetes patients undergoing insulin-induced hypoglycemia were collected in two sessions using Guardian REAL-Time (RT) (Medtronic Diabetes).
Data from the same CGM sensor were calibrated by two calibration methods: the Guardian RT algorithm, and a new algorithm.
Results: For the new calibration algorithm, the median (mean)
absolute relative deviation of the sensor glucose (SG) readings
from the hypoglycemic plasma glucose (PG) values (PG £ 70
mg/dl) were 35.9% (44.8%), and for the Guardian RT calibration, they were 60.9% (62.8%). Friedman’s analysis of variance,
with algorithm and patient as the two factors and the sessions of
the data collection as the replication indicated that the samplebased hypoglycemia sensitivity of the new algorithm was significantly higher than that of the Guardian RT algorithm (median
sensitivity was 82% for the new calibration and 23% for the
Guardian RT calibration, Friedman’s test, X2(2) = 5.7,
P = 0.0169). The sample-based specificity of the new algorithm
was lower; however the difference was not significant (median
A-75
specificity of 95% for the new calibration vs. 100% for the
Guardian RT calibration, Friedman’s test, P > 0.05).
Conclusions: The results suggest that the new calibration
algorithm may reduce the inaccuracy of Guardian RT CGM in
hypoglycemia; however, thorough evaluation by using a more
varied set of performance metrics and larger datasets is required
to compare the clinical reliability of the two algorithms.
P-195
INITIATION STUDY: A MODEL OF CARE FOR
COMMENCING BASAL/PRANDIAL INSULIN IN T2D IN
PRIMARY CARE WITH ADJUNCT RETROSPECTIVECONTINUOUS GLUCOSE MONITORING
D. O’Neal1, J. Furler2, I. Blackberry2, J. Manski-Nankervis2,
L. Ginnivan2, A. Jenkins3, N. Cohen4, D. Liew5, J.D. Best6,
D. Young7
1
University of Melbourne Dept of Medicine, St Vincent’s
Hospital Melbourne, Melbourne, Australia
2
University of Melbourne Dept of Medicine, Department of
General Practice, Parkville, Australia
3
Clinical Trials Centre, University of Sydney, Sydney, Australia
4
Diabetes, Baker-IDI, Prahran, Australia
5
University of Melbourne Dept of Medicine, Royal Melbourne
Hospital, Parkville, Australia
6
School of Medicine, University of Melbourne, Parkville,
Australia
7
Dept of General Practice, University of Melbourne, Parkville,
Australia
Objective: To evaluate a model of care for T2D insulin initiation in Australian primary care and compare retrospectivecontinuous glucose monitoring (r-CGM) with self-monitoring of
blood glucose (SMBG).
A-76
Methods: Primary care patients commenced glargine with
glulisine added if deemed necessary. Outcomes were benchmarked against ambulatory T2D specialist data. An embedded
randomised-controlled trial compared r-CGM and SMBG. Primary Outcome: Initiation vs benchmark DHbA1c (baseline vs 24
week). Secondary Outcomes: DHbA1c; CGM time in target
range; proportion of patients with glulisine added to glargine in
r-CGM (n = 48) vs SMBG (n = 44).
Results: 92 T2D participants with HbA1c Mean (SD) 10.1
(1.6)%; 55 M/37F; Age (range) 59 (28–77) Y from 20 general
practices commenced insulin. Mean (95%CI) DHbA1c reduction
was - 2.6% ( - 2.9, - 2.2); p < 0.0001 for 88 attending at 24
weeks. 82 T2D patients HbA1c Mean (SD) 9.6 (1.8)%; 51 M/31
F; Age (range) 60 (25–86) Y in specialist care commenced insulin. DHbA1c for 66 patients attending at 24 weeks was - 1.7%
( - 2.1, - 1.3); p < 0.001. HbA1c reduction in Initiation vs
Benhmark Groups: p = 0.0017. Comparing r-CGM with SMBG
there were no differences in major hypoglycaemia (p = 0.17) and
no significant difference in HbA1c reduction (Mean [SD])
r-CGM vs SMBG ( - 2.7 [1.8] vs - 2.4 [1.4] %; p = 0.31) or any rCGM parameters. More r-CGM participants commenced
glulisine (26/48 vs 7/44; p = 0.0001)
Conclusions: Reduced loss to follow-up and outcomes comparable to specialists were obtained in primary care. R-CGM use in
primary care was feasible, enhanced post-prandial hyperglycaemia
recognition, and has potential to improve T2D health-care delivery.
P-196
CONTINUOUS GLUCOSE MONITORING SYSTEM
(CGMS): A USEFUL DEVICE IN METABOLIC
DISEASES AFFECTING CARBOHYDRATES
METABOLISM AS WELL AS IN TYPE 1 DIABETES
A. Tummolo1, F. Ortolani1, M. Vendemiale2, S. Fedele3,
A.M. Dimauro3, C. Grande3, F. Papadia3, L. Cavallo4,
M.F. Faienza4, E. Piccinno1
1
Metabolic Diseases Clinical Genetics and Diabetology,
Pediatric Hospital ‘‘Giovanni XXIII’’, Bari, Italy
2
Clinical Psychology, Pediatric Hospital ‘‘Giovanni XXIII’’,
Bari, Italy
3
Metabolic Disease Clinical Genetics and Diabetology,
Pediatric Hospital ‘‘Giovanni XXIII’’, Bari, Italy
4
Pediatrics University ‘‘Aldo Moro’’, Pediatric Hospital
‘‘Giovanni XXIII’’, Bari, Italy
Background: CGMS is commonly used for detecting hypoglycaemic events in type 1 diabetic patients. In the last years,
the development of more technological CGMS devices has
suggested their potential application in the study of carbohydrates metabolic disorders as well as in Type 1 Diabetes.
Aim: To examine the efficacy of CGMS Medtronic in 20 patients with documented/suspect metabolic disorders: one type 1A
glycogen storage disease (A), one suspect hyperinsulinism (B),
one phospho-fructose isomerase deficit (C), one congenital hyperinsulinism (D), one Wolfram syndrome (E), 15 patients in
follow-up for symptomatic/asymptomatic hypoglycaemic events.
Results: In (A) CGMS demonstrated the importance of small
frequent meals and overnight enteral nutrition in order to avoid
severe hypoglycaemia. In (B) it recorded recurrent asymptomatic
hypoglycaemic events, especially at night, and post-prandial
hyperglycaemic spikes, thus excluding hyperinsulinism. Similar
pattern was noticed in (C). (D) presented a constant hypoglycemic trend without post-prandial spikes and an improvement after
therapy with diazoxide. In (E) we observed post-prandial hyperglycemic spikes. 6 patients presented asymptomatic nocturnal
hypoglycaemic events, 2 tendency to hyperglycaemia, 7 did not
record any significative hypo/hyperglycaemic events. Our results
could allow a correct prophylaxis for avoiding nocturnal hypoglicaemia and identifying a glucose metabolism alteration
which is not caused by a peculiar deficit.
Conclusions: Experimental preliminary evidences suggest that
CGMS could be applied in diagnosis/follow-up process of patients
with suspect/documented carbohydrates metabolic disorders, in
order to evaluate glucose excursions, to identify nocturnal hypoglicaemic events and treat them with more adequate therapy.
P-197
TRANSITORY BENEFICIAL EFFECTS
OF PROFESSIONAL CONTINUOUS GLUCOSE
MONITORING ON THE METABOLIC CONTROL
OF PATIENTS WITH TYPE 1 DIABETES
I. Patrascioiu1, C. Quirós1, P. Rı́os1,
M. Ruı́z1, R. Mayordomo1, I. Conget1, M. Giménez1
1
Diabetes Unit Endocrinology and Nutrition Department,
Background: The benefit of professional continuous glucose
monitoring (PCGM) in the metabolic control of patients with
type 1 diabetes mellitus (T1D) is uncertain.
Methods: This was a retrospective study of all consecutive
T1D patients who underwent a 6 day PCGM in our Diabetes Unit
over the course of 17 months. According to the indication, two
groups were arbitrarily defined: a ‘‘hyperglycemic’’ and a ‘‘hypoglycemic’’ one. Data from medical files and sensor reports were
reviewed. HbA1c was evaluated 2–4 weeks prior to PCGM, as well
as 3–5 and 12 months after PCGM. In the hypoglycemic group, the
number of self-reported mild hypoglycemic episodes (as defined
by the American Diabetes Association) was collected.
Results: Of the 67 patients reviewed, 43 belonged to the hyperglycemic group and 24 to the hypoglycemic one. In the hyperglycemic group, the HbA1c dropped at 3–5 months post-intervention
from 8.45 – 0.72% to 8.04 – 0.9%, the decline being statistically
significant ( - 0.4%, p = 0.001) and positively correlated with the
initial HbA1c value (0.366, p = 0.016). One year after the PCGM
study, the HbA1c tended to return to the initial values: 8.20 – 1.05%
( - 0.24%, p = 0.081). In the hypoglycemic group, HbA1c did not
change neither 3–5, nor 12 months after PCGM, while the percentage of patients in whom the number of mild hypoglycemic
episodes was significantly reduced was 86% (p = 0.001).
Conclusions: Although transiently, PCGM can be useful at
the short term in improving metabolic and clinical profile of
T1D subjects suboptimally controlled including those with
repeated hypoglycemia.
P-198
HOW PEOPLE USE DIRECTION AND RATE OF
CHANGE INFORMATION PROVIDED BY REAL-TIME
CONTINUOUS GLUCOSE MONITORING (RT-CGM)
TO ADJUST INSULIN DOSING
J. Pettus1, D.A. Price2, K.J. Hill2, S. Edelman1
1
Endocrinology, University of California San Diego & Veterans
Affairs Hospital, La Jolla, USA
2
Clinical Affairs, Dexcom Inc., San Diego, USA
There is no published data on how CGM users utilize rate of
change (ROC) arrows for glycemic management. Accordingly,
practitioners are

to - Kenes Group

Transcription

Similar documents

Education

Tim McGraw has a challenge for you.

ARC factsheet Special Research Initiative for Type 1 Juvenile

NIDDK Medical Student Research Program in Diabetes and Obesity

Diabetes, Type 1

High and Low Blood Glucose Levels

Sponsor a Child and Save a Life - International Diabetes Federation

AstraZeneca Mölndal Presentation PDF 13683KB

Equine Metabolic Syndrome (Insulin Resistance)

The Economic Benefit of Public Funding of Insulin Pumps in