FAMILY PRACTICE INSULIN THERAPY IN TYPE 2 DIABETES

A
S U P P L E M E N T
T O
THE J O U R N A L OF
CME
1 credit
hour
FAMILY
PRACTICE
J U N E
2 0 0 5
INSULIN THERAPY IN
TYPE 2 DIABETES
Louis Kuritzky, MD
Clinical Assistant Professor
University of Florida College of Medicine
Gainesville, Florida
Scott E. Nelson, MD
Family Medical Clinic
Cleveland, Mississippi
More Than Just
Improved Glycemic
Control
Jointly sponsored by the University of Medicine & Dentistry of New Jersey
Center for Continuing and Outreach Education (CCOE) and Thomson Interphase
Introduction
Eighteen million persons have diabetes mellitus in the United
States, with an estimated 1.3 million cases of new-onset diabetes diagnosed each year.1 Diabetes is characterized by hyperglycemia resulting from impaired insulin secretion and insulin
resistance.2 Proper diet, regular exercise, weight loss, and maintaining near-normal glycemia and healthy lipid levels are integral
to successful treatment of diabetes—goals that should be
emphasized at diagnosis and throughout the course of the disease. Treatment tailored to the patient can help achieve these
goals;3 however, when the goals are unmet, oral antidiabetic
agents are typically added to antidiabetic regimens to decrease
insulin resistance and enhance pancreatic insulin secretion.
More than half of patients with type 2 diabetes will require additional therapies within 6 years of diagnosis to maintain fasting
plasma glucose levels < 6.0 mmol/L.4 When 2 or more oral antidiabetic agents fail, patients may require insulin therapy to
maintain intensive glycemic control. Insulin therapy often is
unnecessarily delayed because of misconceptions that it has
detrimental effects on blood pressure and lipid profiles and that it
exacerbates insulin resistance and causes weight gain. Because
patients with diabetes are at increased risk for macrovascular
complications, it also is important to consider the nonglycemic
effects of insulin and its effect on endothelial function.
This supplement reviews historical misconceptions associated with the use of insulin and the effects of insulin on endothelial function, atherosclerosis, and inflammation.
References
1. American Diabetes Association. National Diabetes Fact Sheet 2002.
2. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes
Care. 2004;27:S5-S10.
3. American Association of Clinical Endocrinologists. Medical guidelines for the management
of diabetes mellitus: The AACE system of intensive diabetes self-management—2002
Update. Endocrine Practice. 2002;8:40-82.
4. Wright A, Burden ACF, Paisey RB, et al. Sulfonylurea inadequacy: efficacy of addition of
insulin over 6 years in patients with type 2 diabetes in the UK Prospective Diabetes Study
(UKPDS 57). Diabetes Care. 2002;25:330-336.
Supported by an educational grant from Aventis Pharmaceuticals, a member of the sanofi-aventis Group
INSULIN THERAPY IN
TYPE 2 DIABETES
Jointly sponsored by the University of Medicine & Dentistry
of New Jersey Center for Continuing and Outreach Education
(CCOE) and Thomson Interphase
Released: June 1, 2005
Expiration date for credit: June 30, 2006
Grantor acknowledgment
This activity is supported by an educational grant from Aventis Pharmaceuticals, a
member of the sanofi-aventis Group.
More Than Just
Improved Glycemic
Control
Scott E. Nelson, MD, has received grant/research funding from and is a consultant for Aventis Pharmaceuticals.
Field testers
Sumon Agarwala, MD, reports no significant financial interests or other relation-
ships to disclose.
Sheri Gillis Funderbunk, MD, reports no significant financial interests or other
relationships to disclose.
Off-label usage disclosure
This continuing medical education (CME) activity has been developed for primary care physicians.
This activity contains information on commercial products/devices that are unlabeled for use or for investigational uses of products not yet approved. Product(s)
is/are not included in the labeling approved by the FDA for the treatment of type
2 diabetes.
Learning objectives
Disclaimer
Target audience
Upon completion of this activity, participants should be able to:
• Understand the common controversies of insulin therapy
• Describe the effects that insulin has on endothelial function
• Explain the anti-inflammatory and antiatherogenic effects of insulin
Method of instruction
Participants should read the learning objectives and review the activity in its
entirety. After reviewing the material, complete the posttest consisting of a series
of multiple-choice questions.
The activity is complemented with references that contain the rationale for
the correct answer to each question as well as a description identifying the section of the activity that contains the correct answer, allowing participants to
review the material as needed, thus finalizing their educational participation.
Upon completing this activity as designed and achieving a passing score
of 70% or more on the posttest, participants will receive the test answer key and
a CME credit letter awarding AMA/PRA Category 1 credit. These will be sent 4
weeks after receipt of the posttest, registration, and evaluation materials.
Estimated time to complete this activity as designed is 1 hour.
Accreditation
This activity has been planned and implemented in accordance with the Essential
Areas and Policies of the Accreditation Council for Continuing Medical Education
(ACCME) through the joint sponsorship of UMDNJ–Center for Continuing and
Outreach Education and Thomson Interphase. UMDNJ–Center for Continuing and
Outreach Education is accredited by the ACCME to provide continuing medical
education for physicians.
UMDNJ–Center for Continuing and Outreach Education designates this
educational activity for a maximum of 1 category 1 credit toward the AMA
Physician’s Recognition Award. Each physician should claim only those credits
that he/she actually spent in the activity.
The activity was prepared in accordance with the ACCME Essentials.
This activity was reviewed for relevance, accuracy of content, balance of
presentation, and time required for participation by Stephen H. Schneider, MD;
Sumon Agarwala, MD; and Sheri Gillis Funderbunk, MD.
Disclosure
In accordance with the disclosure policies of UMDNJ and to conform with
ACCME and Food and Drug Administration (FDA) guidelines, all program faculty
are required to disclose to the activity participants: 1) the existence of any financial interest or other relationships with the manufacturers of any commercial
products/devices or providers of commercial services that relate to the content
of their presentation/material, or the commercial contributors of this activity, that
could be perceived as a real or apparent conflict of interest; and 2) the identification of a commercial product/device that is unlabeled for use or an investigational use of a product/device not yet approved.
Activity director
Stephen H. Schneider, MD, has received grants/research funding from Aventis
Pharmaceuticals, Merck & Company Inc, Novo Nordisk, and Pfizer Inc.
Authors
Louis Kuritzky, MD,
is a member of the speakers’ bureaus for Aventis
Pharmaceuticals, Bayer, Bristol-Myers Squibb Company, Eli Lilly and Company,
GlaxoSmithKline, Novartis Pharmaceuticals Corporation, Pfizer Inc, Pharmacia,
and Upjohn.
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The views expressed in this activity are those of the faculty. It should not be
inferred or assumed that they are expressing the views of Aventis
Pharmaceuticals, a member of the sanofi-aventis Group; any other manufacturer of pharmaceuticals; UMDNJ; Thomson Interphase; or THE JOURNAL OF
FAMILY PRACTICE.
The drug selection and dosage information presented in this activity are
believed to be accurate. However, participants are urged to consult the full prescribing information on any agent(s) presented in this activity for recommended
dosage, indications, contraindications, warnings, precautions, and adverse
effects before prescribing any medication. This is particularly important when a
drug is new or infrequently prescribed.
© 2005 Dowden Health Media and UMDNJ–Center for Continuing and
Outreach Education. All rights reserved including translation into other languages. No part of this activity may be reproduced or transmitted in any form or
by any means, electronic or mechanical, including photocopying, recording, or
any information storage and retrieval systems, without permission in writing from
Dowden Health Media and UMDNJ–Center for Continuing and Outreach
Education.
This supplement to THE JOURNAL OF FAMILY PRACTICE was supported by
a grant from Aventis Pharmaceuticals, a member of the sanofi-aventis Group,
and submitted by Thomson Interphase. It has been edited and peer-reviewed by
THE JOURNAL OF FAMILY PRACTICE.
Contents
Assessing the controversies
of insulin therapy in patients
with type 2 diabetes mellitus
................
3
Beneficial effects of insulin on endothelial
function, inflammation, and atherogenesis
and their implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Insulin therapy in primary care:
Practical issues for clinicians . . . . . . . . . . . . . . 10
Posttest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
CME registration/evaluation
S U P P L E M E N T T O T H E J O U R N A L O F F A M I LY P R A C T I C E
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12
THE J O U R N A L OF
FAMILY
PRACTICE
Assessing the controversies
of insulin therapy in patients
with type 2 diabetes mellitus
Louis Kuritzky, MD
University of Florida College of Medicine, Gainesville, Florida
Scott E. Nelson, MD
Family Medicine Clinic, Cleveland, Mississippi
n type 2 diabetes improved glucose values result in
improved microvascular outcomes pertinent to
retinopathy, nephropathy, and neuropathy. Quality-oflife studies also demonstrate the benefits of good longterm glucose management. Despite the evolution of
excellent oral agents such as thiazolidinediones, sulfonylureas, alpha-glucosidase inhibitors, and
biguanides, many patients do not achieve appropriate
therapeutic goals. Attaining glucose treatment goals
should be a fundamental objective for diabetes
patients; at all stages of therapy insulin is a rational
choice as foundation therapy or in combination with
oral agents. Still, insulin is underused. The use of
insulin has been hampered by concerns surrounding:
• The relationship between insulin, blood pressure
(BP), and dyslipidemia because early data suggested a potential for increasing atherosclerotic risk by
insulin treatment
• The relationship between insulin therapy and
insulin resistance, which is a major feature of diabetic pathogenesis
• Concerns about insulin treatment producing counterproductive weight gain
Clinicians need practical information to assess the
appropriateness of insulin treatment at all stages of
diabetes and provide patient education about the
importance of achieving glycemic goals.
major coronary heart disease (CHD), which was largely independent of other cardiovascular (CV) disease
risk factors, including blood glucose values, cholesterol
and triglyceride (TG) levels, BP, indices of obesity and
fat distribution, smoking, and physical activity.
Although the ability to predict risk based on insulin levels declined as follow-up time increased, the suggestion
that hyperinsulinemia and adverse outcomes were associated was disquieting.1
When other epidemiologic studies supported an
association between high insulin levels and increased risk
of CHD, confounders such as age2,3 and inclusion of
patients at baseline higher risk for CHD events4 may
have received insufficient attention. Including elderly
patients in such studies can result in a survival bias.
Moreover, including high-risk patients results in a relatively higher incidence of baseline insulin resistance.5
Despite the inclusion of confounding factors, these types
of studies have contributed to the theory that high insulin
levels increase the risk of CHD. Even if hyperinsulinemia
were consistently associated with adverse CV outcomes,
it would remain uncertain whether hyperinsulinemia
simply reflects underlying insulin resistance or actually is
a mediator of CHD events. These controversies have
influenced many physicians’ perceptions. In this article,
we review the controversies and provide the evidence to
support or refute them.
Risks of insulin use: fact or fiction?
CONTROVERSY 1
Early epidemiologic studies contributed to the development of controversies associated with the use of
insulin. A study of nondiabetic, healthy, middle-aged
men (N=970) followed over 22 years found an association between hyperinsulinemia and increased risk of
Insulin increases blood pressure
and causes lipid abnormalities
I
Blood pressure elevation and insulin
Several studies have found a correlation between
S U P P L E M E N T T O T H E J O U R N A L O F F A M I LY P R A C T I C E •
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Insulin therapy for type 2 diabetes
insulin resistance and elevated BP. A multivariate
analysis that simultaneously accounted for gender, age,
body mass, and fasting insulin showed mean BP was
inversely correlated with insulin sensitivity. In other
words, independent of body size, individuals with
insulin resistance were predicted to have higher mean
BP than insulin-sensitive individuals.6 The theory
behind insulin’s effect on BP has been based on the
purported ability of insulin to increase sodium reabsorption and activate the sympathetic nervous system
(SNS), either of which has the potential to increase BP.
DeFronzo and colleagues were among the first to
describe the effect of insulin on sodium reabsorption.
In a small study conducted on 6 subjects, the
researchers demonstrated that acute insulin infusion
over 240 minutes causes sodium excretion to decline
(as a result of increased sodium reabsorption).7
Subsequent animal studies, however, showed that this
acute effect was only transient, ie, by day 7 total
peripheral resistance and mean arterial pressure (MAP)
had actually declined slightly.8 Whether investigators
chose insulin-resistant obese animals9 or animals fed
high-sodium diets,10 insulin infusion over 7 to 28 days
did not result in elevated BP despite the transient initial
increase in sodium reabsorption.
Insulin’s ability to activate the SNS is also debatable. Although an early study by Rowe and colleagues
demonstrated insulin infusion-induced SNS activation,11
Rowe’s results may not apply in diabetes because the
study was conducted under nonphysiologic conditions
and extremely high levels of insulin were infused. Hall
and colleagues studied the effect of insulin infusion on
noradrenergic SNS activation in healthy dogs. Under the
chronically hyperinsulinemic conditions of the study, no
evidence supported an insulin-mediated potentiation of
norepinephrine’s MAP effects.12
A possible hypothesis?
Why then would hyperinsulinemia be associated with
elevated BP? An alternative hypothesis suggests that in
healthy subjects one physiologic function of insulin is
actually vasodilation. In the same way that diverse tissue
compartments reflect insulin resistance in different ways
(skeletal muscle resistance resulting in hyperglycemia,
hepatic resistance resulting in inappropriate glycolysis,
adipose compartment resistance resulting in inappropriate fatty acid production), vascular wall insulin resistance would be reflected as increased vascular resistance,
especially in those with a tendency toward development
of hypertension, and hence might be a primary contributor to elevated BP in type 2 diabetes.
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Numerous studies confirm this concept. Forearm
blood flow increases continuously in a dose-dependent
manner in response to insulin infusion.13 When leg
blood flow is analyzed under physiologic insulin concentrations, it approximately doubles in lean insulinsensitive individuals compared with baseline. In obese
subjects and those with diabetes, however, a relative
resistance to the vasodilative action of insulin is
demonstrated.14 Diabetes patients with better glucose
disposal (ie, better insulin sensitivity) are more likely to
be normotensive than hypertensive (P < .0001).15 For
these reasons, insulin resistance, not hyperinsulinemia,
appears to be the primary correlate with elevated BP.
Lipid abnormalities and insulin administration
Insulin is necessary for the essential functions of lipoprotein lipase, which include degradation of very low density lipoprotein (VLDL) into high density lipoprotein
(HDL) and VLDL disposal. It is commonplace in
patients with diabetes to see the combination of high TG
levels as a result of impaired ability of insulin to promote
lipoprotein lipase (LPL) activity, coupled with low HDL
levels, since VLDL is not converted effectively into HDL
without sufficient LPL activity, which is, in turn, dependent upon an adequate supply and activity of insulin.16 It
appears then that insulin resistance results in decreased
LPL mass and LPL activity, which ultimately results in
decreased VLDL TG removal.17
Insulin resistance in the adipose compartment is
reflected by a decreased ability of insulin to inhibit
lipolysis, demonstrated by increased plasma fatty acids
and increased free fatty acid (FFA) delivery to the liver.
These excessive FFAs serve as substrate for hepatic TG
synthesis, resulting in increased TG levels. Normally
one would anticipate an increase in fatty acids when
glucose supply is insufficient and fat is being mobilized.
The increased fatty acids appear to signal the liver that
more hepatic glucose production is needed. Hence, a
diabetic patient, despite elevated glucose levels, may be
signaling his liver to produce still more glucose through
glycolysis. An approximate 50% decrease in VLDL1
apoB production (P < .05) is observed when normal
subjects are given an insulin infusion, but it is not replicated when the same infusion is given to patients with
type 2 diabetes.18 Consistent with this, clinical trials
have confirmed that the use of intensive insulin therapy
in patients with type 2 diabetes improves TG levels,19,20
refuting the notion that insulin causes hypertriglyceridemia. Lipoprotein lipase activity also is generally
lower in patients with type 2 diabetes but increases with
normalized glycemia.21
S U P P L E M E N T T O T H E J O U R N A L O F F A M I LY P R A C T I C E
THE J O U R N A L OF
FAMILY
PRACTICE
CONTROVERSY 2
FIGURE 1
Odds Ratios for Ischemic
Heart Disease (IHD): TC/HDL-C
6.0
Odds ratios for IHD
The importance of small LDL particles
Small dense LDL particles, a hallmark of diabetic dyslipidemia, are associated with endothelial dysfunction.22-25 In
vivo studies have linked small LDL particle size and
hypertriglyceridemia to impaired endothelium-dependent
vasodilation in healthy men and insulin-resistant
patients.26 In addition, patients with small dense LDL are
more likely to have insulin resistance, hyperglycemia,
hyperinsulinemia, hypertriglyceridemia, lower HDL levels, and higher BP.27 Good glycemic control in diabetes has
been shown to favorably affect the balance toward lighter,
less dense, and less atherogenic LDL.
Small dense LDL is an independent predictor of
CHD. The plasma concentration of small dense LDL
particles is directly associated with intima-media thickness of the common carotid artery.28 Further, prospective
results from the Quebec Cardiovascular Study suggest
that the presence of small dense LDL particles predicts a
greater risk for ischemic heart disease in men (FIGURE 1).29
5.0
P = .001
4.0
3.0
2.0
1.0
1.0
0.0
1.7
1.2
4.9
≤25.64 nm ≤25.64 nm
≥6.0
<6.0
>25.64 nm >25.64 nm
≥6.0
<6.0
TC/HDL-C
LDL Peak Particle Diameter
TC = total cholesterol; HDL-C = high-density lipoprotein cholesterol;
LDL = low-density lipoprotein
The smaller the LDL peak particle diameter and the greater the TC/HDLC ratio, the higher the risk for the development of ischemic heart disease
Insulin aggravates insulin resistance
CONTROVERSY 3
Insulin therapy and its association
with weight gain
Although weight gain is indeed commonplace with
insulin therapy, in large clinical trials like the UKPDS,
FIGURE 2
Effects of Insulin on
Basal Hepatic Glucose Output
(HGO) and Glucose Uptake19
700
1800
*P < .001
*P < .05
µmol/m2/min
600
µmol/m2/min
While clinicians have theorized that insulin therapy
worsens insulin resistance, multiple data have shown
different outcomes. Glucose toxicity is seen when pancreatic beta cells fail to respond to a glucose load with
appropriate insulin output. Apparently, beta cells that
have been persistently exposed to sustained glucose
levels over 140 mg/dL become sluggish in their insulin
output, both in timing of insulin delivery and total
insulin output; ultimately, beta cells exposed to chronic supraphysiologic levels of glucose undergo early
apoptosis, leading to a decline in the absolute number
of beta cells left to produce insulin.30,31
In type 2 diabetes, insulin therapy improves beta
cell function; glucose disposal rates are improved in
patients who receive insulin, presumably because
insulin reverses the component of insulin resistance
consequent to glucotoxicity.32 This leads to better glucose uptake, as has been demonstrated with the use of
intensive insulin therapy (FIGURE 2 )19,33 and basal
insulin therapy in patients with type 2 diabetes.34 These
data indicate that the use of insulin therapy results in
improved insulin sensitivity rather than increased
insulin resistance.
500
400
1600
1400
300
200
1200
Basal HGO
Before Insulin Therapy
Glucose Uptake
After Insulin Therapy
all treatment groups (oral agents and insulin) gained
some weight over the trial study period.35 Weight gain
can be minimized when using insulin in diabetes
patients. Because weight gain is associated with worsening insulin resistance, increased BP, and adverse lipid
profiles, treatment of type 2 diabetes must counterbalance the intensity of glucose control with the negative
consequences of weight gain. Each 5% increase in
weight over the reported weight at age 20 is associated
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Insulin therapy for type 2 diabetes
9. Hall JE, Brands MW, Zappe DH, et al. Hemodynamic and renal responses to
chronic hyperinsulinemia in obese, insulin-resistant dogs. Hypertension.
1995;25:994-1002.
FIGURE 3
Mean Body Weight Gain Over
28 Weeks With Insulin Glargine vs
Neutral Protamine Hagedorn37
11. Rowe JW,Young JB, Minaker KL. Effect of insulin and glucose infusions on sympathetic nervous system activity in normal man. Diabetes. 1981;30:219-225.
12. Hall JE, Brands MW, Kivlighn SD. Chronic hyperinsulinemia and blood pressure.
Interaction with catecholamines? Hypertension. 1990;15:519-527.
13. Utriainen T, Malmstrom R, Makimattila S, et al. Methodological aspects, doseresponse characteristics and causes of interindividual variation in insulin stimulation of limb blood flow in normal subjects. Diabetologia. 1995;38:555-564.
1.4
Mean body weight
increases (kg)
10. Hall JE, Coleman TG, Mizelle HL, et al. Chronic hyperinsulinemia and blood pressure regulation. Am J Physiology. 1990;258:F722-731.
1.2
14. Steinberg HO, Baron AD. Vascular function, insulin resistance and fatty acids.
Diabetologia. 2002;45:623-634.
1
15. Pollare T, Lithell H, Berne C. Insulin resistance is a characteristic feature of primary
hypertension independent of obesity. Metabolism. 1990;39:167-174.
0.8
16. Maheux P, Azhar S, Kern PA, et al. Relationship between insulin-mediated glucose
disposal and regulation of plasma and adipose tissue lipoprotein lipase.
Diabetologia. 1997;40:850-858.
0.6
17. Miyashita Y, Shirai K, Itoh Y, et al. Low lipoprotein lipase mass in preheparin
serum of type 2 diabetes mellitus patients and its recovery with insulin therapy.
Diabetes Res Clin Pract. 2002;56:181-187.
0.4
0.2
P = .0007
0
18. Malmström R, Packard CJ, Caslake M, et al. Defective regulation of triglyceride
metabolism by insulin in the liver in NIDDM. Diabetologia. 1997;40:454-462.
Type of Insulin
Insulin Glargine
Neutral Protamine Hagedorn
with nearly a 20% greater risk of developing insulin
resistance by age 53 after adjustment for age and
height.36 Although all insulins can produce weight gain,
amongst the basal insulins, the use of insulin glargine
has been associated with modestly less weight gain
compared with NPH (neutral protamine Hagedorn):
0.4 vs 1.4 kg, P = .0007 (FIGURE 3 ).37
19. Henry RR, Gumbiner B, Ditzler T, et al. Intensive conventional insulin therapy for
type II diabetes. Metabolic effects during a 6-mo outpatient trial. Diabetes Care.
1993;16:21-31.
20. Taskinen MR, Kuusi T, Helve E, et al. Insulin therapy induces antiatherogenic
changes of serum lipoproteins in noninsulin-dependent diabetes. Arteriosclerosis.
1988;8:168-177.
21. Syvänne M, Taskinen MR. Lipids and lipoproteins as coronary risk factors in noninsulin-dependent diabetes mellitus. Lancet. 1997;350:S120-S123.
22. Tan KCB, Ai VHG, Chow WS, et al. Influence of low density lipoprotein (LDL)
subfraction profile and LDL oxidation on endothelium-dependent and independent vasodilation in patients with type 2 diabetes. J Clin Endocrinol Metab.
1999;84:3212-3216.
23. Skyrme-Jones RA, O'Brien RC, Luo M, et al. Endothelial vasodilator function is
related to low-density lipoprotein particle size and low-density lipoprotein vitamin
E content in type 1 diabetes. J Am Coll Cardiol. 2000;35:292-299.
24. O’Brien SF, Watts GF, Playford DA, et al. Low-density lipoprotein size, high-density lipoprotein concentration, and endothelial dysfunction in non-insulin dependent
diabetes. Diabet Med. 1997;14:974-978.
Conclusion
25. Mäkimattila S, Liu ML, Vakkilainen J, et al. Impaired endothelium-dependent
vasodilatation in type 2 diabetes. Diabetes Care. 1999;22:973-981.
Insulin does not appear to be responsible for elevated BP
and dyslipidemia in type 2 diabetes. Although hyperinsulinemia is a compensatory marker of insulin resistance, it does not mediate changes in BP or lipid levels.
Insulin therapy improves insulin sensitivity, probably by
decreasing glucotoxicity and lipotoxicity. ■
26. Vakkilainen J, Makimattila S, Seppala-Lindroos A, et al. Endothelial dysfunction in
men with small LDL particles. Circulation. 2000;102:716-721.
References
1. Pyorala M, Miettinen H, Laakso M. Hyperinsulinemia predicts coronary heart disease risk in healthy middle-aged men: the 22-year follow-up results of the Helsinki
Policemen Study. Circulation. 1998;98:398-404.
2. Welin L, Eriksson H, Larsson B, et al. Hyperinsulinemia is not a major coronary
risk factor in elderly men. The study of men born in 1913. Diabetologia.
1992;35:766-770.
3. Ferrara A, Barrett-Connor EL, Edelstein SL. Hyperinsulinemia does not increase
the risk of fatal cardiovascular disease in elderly men or women without diabetes:
the Rancho Bernardo Study, 1984-1991. Am J Epidemiol. 1994;140:857-869.
4. Orchard TJ, Eichner J, Kuller LH, et al. Insulin as a predictor of coronary heart disease: interaction wtih Apolipoprotein E phenotype. A report from the Multiple
Risk Factor Intervention Trial. Ann Epidemiol. 1994;4:40-45.
27. Reaven GM, Chen Y-DI, Jeppesen J, et al. Insulin resistance and hyperinsulinemia
in individuals with small, dense, low density lipoprotein particles. J Clin Invest.
1993;92:141-146.
28. Skoglund-Andersson C, Tang R, Bond MG, et al. LDL particle size distribution is
associated with carotid intima-media thickness in healthy 50-year-old men.
Arterioscler Thromb Vasc Biol. 1999;19:2422-2430.
29. Lamarche B, Tchernof A, Moorjani S, et al. Small, dense low-density lipoprotein
particles as a predictor of the risk of ischemic heart disease in men: prospective
results from the Quebec Cardiovascular Study. Circulation. 1997;95:69-75.
30. Kaiser N, Leibowitz G, Nesher R. Glucotoxicity and beta-cell failure in type 2 diabetes mellitus. J Pediatr Endocrinol Metab. 2003;16:5-22.
31. Rhodes CJ. Type 2 diabetes—A matter of beta-cell life and death? Science.
2005;307:380-384.
32. Garvey WT, Olefsky JM, Griffin J, et al. The effect of insulin treatment on insulin
secretion and insulin action in type II diabetes mellitus. Diabetes. 1985;34:222-234.
33. Scarlett JA, Gray RS, Griffin J, et al. Insulin treatment reverses the insulin resistance
of type II diabetes mellitus. Diabetes Care. 1982;5:353-363.
34. Vehkavaara S, Makimattila S, Schlenzka A, et al. Insulin therapy improves
endothelial function in type 2 diabetes. Arterioscler Thromb Vasc Biol. 2000;20:
545-550.
5. Haffner SM, Miettinen H. Insulin resistance implications for type II diabetes mellitus and coronary heart disease. Am J Med. 1997;103:152-162.
35. Wright A, Burden F, Paisey RB, et al. Sulfonylurea inadequacy: efficacy of addition
of insulin over 6 years in patients with type 2 diabetes in the UKPDS. Diabetes
Care. 2002;25:330-336.
6. Ferrannini E, Natali A, Capaldo B, et al. Insulin resistance, hyperinsulinemia, and
blood pressure. Hypertension. 1997;30:1144-1149.
36. Everson SA, Goldberg DE, Helmrich SP, et al. Weight gain and the risk of developing insulin resistance syndrome. Diabetes Care. 1998;21:1637-1643.
7. DeFronzo RA, Cooke CR, Andres R. The effect of insulin on renal handling of sodium, potassium, calcium, and phosphate in man. J Clin Invest. 1975;55:845-855.
37. Rosenstock J, Schwartz SL, Clark CM, et al. Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin.
Diabetes Care. 2001;24:631-636.
8. Brands MW, Mizelle HL, Gaillard CA. The hemodynamic response to chronic
hyperinsulinemia in conscious dogs. Am J Hypertens. 1991;4(2 Pt 1):164-168.
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S U P P L E M E N T T O T H E J O U R N A L O F F A M I LY P R A C T I C E
THE J O U R N A L OF
FAMILY
PRACTICE
Beneficial effects of insulin on endothelial
function, inflammation, and atherogenesis
and their implications
Louis Kuritzky, MD
University of Florida College of Medicine, Gainesville, Florida
Scott E. Nelson, MD
Family Medicine Clinic, Cleveland, Mississippi
ith 221 million people predicted to have diabetes
by 2010,1 increasing numbers of patients will
require insulin to maintain glycemic control. Patients
with type 2 diabetes are at increased risk for cardiovascular (CV) mortality2 independent of classic risk factors
such as smoking, dyslipidemia, and hypertension.
Despite not having the problem of severe insulin resistance, patients with type 1 diabetes are also at increased
risk for coronary artery disease (CAD). Clearly, this
would suggest that hyperglycemia plays a more fundamental role in worsening CV risk than insulin resistance
in patients with diabetes.
Inflammation is considered to be a significant contributor to the pathogenesis of atherosclerosis and ultimately to adverse CV events. The recent REVERSAL
study demonstrated that progression of coronary atherosclerosis was decreased in patients with CAD who
received an intensive regimen of atorvastatin (80
mg/day). This outcome may be a result of atorvastatin’s
combined effects on atherogenic lipoproteins and
inflammation (reflected by C-reactive protein, a nonspecific marker of inflammation).3 Because of these
results and the increased risk for CV mortality seen in
patients with type 2 diabetes, the effect of insulin on
atherogenesis is also important. In fact, insulin has also
been studied to determine its possible anti-inflammatory and antiatherogenic roles.
W
The effects of insulin
resistance on platelets
Insulin resistance has also been shown to affect
platelets. Normally, insulin prevents platelet adherence
to collagen; insulin resistance reduces insulin’s effect on
platelets and contributes to a potentially atherogenic
state. This interaction has been studied in vitro after in
vivo exposure of platelets to insulin in insulin-sensitive
(nonobese) and insulin-resistant (obese) patients.
Following in vivo insulin infusion, insulin inhibited
platelet deposition upon collagen in insulin-sensitive
individuals (P < .05), but failed to do so in patients with
insulin resistance.4 Insulin resistance, then, favors an
atherothrombotic status, by adversely affecting platelet
function (ie, enhancing aggregability).
Notably, in patients with type 2 diabetes, platelets
are hyperactive, resulting in a provasoconstrictive and
proaggregation state. The progressive nature of this
process is clearly depicted in FIGURE 1. Moreover, the fibrinolytic side of normal hemostasis may also be
impaired in patients with type 2 diabetes. Patients with
type 2 diabetes demonstrate hypofibrinolysis.5 In fact, a
recent study demonstrated altered structures of fibrin
clots obtained from patients with type 2 diabetes, and
those alterations were related to an individual’s
glycemic control. These structural differences might
increase resistance to fibrinolysis in the setting of
thrombosis and also contribute to increased CV risk in
the setting of type 2 diabetes.6
Endothelium vasodilation:
CV risk and effect of insulin
Endothelial dysfunction, which results in pathologic
coagulant, inflammatory, and vascular growth patterns,
is often demonstrated by measuring impaired endothelium-dependent vasorelaxation resulting from a loss of
nitric oxide (NO) bioactivity in the vessel wall.7
Endothelial cells produce a variety of vasodilators,
NO being the most important. NO is produced from Larginine in a reaction catalyzed by endothelial nitric
S U P P L E M E N T T O T H E J O U R N A L O F F A M I LY P R A C T I C E •
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2005
S7
Progressive Nature
of Atherosclerosis
FIGURE 1
Atherosclerosis begins with endothelial dysfunction, specifically, increased
endothelial permeability, leukocyte migration, endothelial adhesion, and
leukocyte adhesion.
Leukocyte
Adhesion
Leukocyte
Migration
Endothelial
Permeability
Following maturation, monocytes become macrophages and increase their
lipid concentrations to become foam cells forming an early fatty streak.
Adherence and
Aggregation of
Platelets
T-cell Activation
Smooth-muscle
Migration
Adherence and
Entry of Leukocytes
Macrophages continue to accumulate, enabling the fatty streak to progress
to intermediate and advanced atherosclerotic lesions.
Fibrous-cap
Formation
Studies of the effect of chronic insulin use on endothelial
function in patients with type 2 diabetes have demonstrated that insulin enhances ACh-induced vasodilation.13-15 A Finnish study assessed the effect of chronic
insulin glargine therapy on endothelial function in
patients with type 2 diabetes. Eleven insulin-naïve
patients with diabetes (aged 59 ± 2 years) had insulin
glargine added to their oral hypoglycemic therapy for 3.5
years. Compared with baseline, significant improvements in blood flow response to high-dose ACh were
demonstrated at 0.5 years and 3.5 years, with an 86%
improvement in blood flow at 3.5 years.16
Vasodilatory, anti-inflammatory, and
antiatherogenic effects of insulin
Formation of
Necrotic Core
Macrophage
Accumulation
Adapted with permission from Ross R. N Engl J Med. 1999;340:115-126.
oxide synthase (eNOS). It then diffuses to the vascular
smooth-muscle cells and stimulates guanylate cyclase to
catalyze the production of cyclic guanosine monophosphate (cGMP)—a potent vascular smooth-muscle
relaxing agent—resulting in vasodilation and increased
blood flow. Endothelial function can be studied using
agents such as acetylcholine (ACh); ACh stimulates
parasympathetic receptors to increase eNOS in an
endothelium-dependent manner, the impact of which
may be quantified by measuring forearm blood flow.
Blunted increments of forearm blood flow indicate
endothelial dysfunction. In a study of patients with
JUNE
essential hypertension, the blunted production of NO
in response to ACh predicted CV events;8 similar results
were seen in patients with CAD.9
Insulin mediates the production of potent vasodilators
including NO (FIGURE 2 ). In vitro insulin has stimulated
the production of eNOS and NO in a receptor kinasemediated manner.10 Clinical studies have substantiated the
acute activation of endothelium-dependent vasodilation in
subjects by either regular human insulin or insulin
glargine, as long as the vasculature is healthy.11 However,
in diabetic subjects or others with vascular disease there is
consistent blunting of endothelial blood flow in response
to ACh.12 Ultimately, insulin treatment may improve
endothelial function in patients with diabetes (see below).
The effect of chronic insulin therapy
on endothelial function
Foam-cell Formation
S8
Insulin therapy for type 2 diabetes
2005
•
The vasodilatory, anti-inflammatory, and antiatherogenic effects of insulin have been studied. In vitro,
insulin induces a dose-dependent increase in NO synthase production in the endothelium.17 Insulin was
administered to norepinephrine-constricted veins in 10
healthy subjects and resulted in an immediate and significant vasodilation when compared with baseline (P <
.05). Methylene blue, a known inhibitor of guanylate
cyclase and NO synthase, inhibits insulin-induced
vasodilation. Thus, the vasodilatory effect of insulin on
vessels is likely cGMP- and NO-dependent.18 There is a
dose-dependent insulin effect on NO production in
healthy individuals,19 but that vasodilatory response is
absent when the same experiment is conducted in
patients with type 2 diabetes. Confirming that this vascular dysfunction is indeed due to lack of endothelial
production of NO, vasodilation does occur in diabetic
patients when their vasculature is exposed to sodium
S U P P L E M E N T T O T H E J O U R N A L O F F A M I LY P R A C T I C E
THE J O U R N A L OF
FAMILY
PRACTICE
FIGURE 2
Insulin Stimulates eNOS Activation
and Subsequent NO Production10,12,22
Insulin
▲
L-arginine
eNOS
▲
NO
Endothelial Cell
▲
GTP
Guanylyl
Cyclase
▲
nitroprusside, an endothelium-independent NO donor.
In a study conducted in 10 obese insulin-resistant
subjects, insulin was shown to have a potent acute
anti-inflammatory effect. Compared with baseline,
insulin infusion significantly decreased reactive oxygen
species generation (P < .005) and the endogenous anticoagulant plasminogen activator inhibitor (PAI-1) (P <
.001) after 4 hours.20 The data clearly demonstrate that
insulin provides acute anti-inflammatory effects at the
molecular level, which might translate into long-term
antiatherogenic effects.
Finally, one study analyzed the anti-inflammatory
effect of insulin in patients with ST-segment elevation
myocardial infarction (STEMI). In the STEMI study, 32
patients who received reteplase were randomized to
receive infusions of insulin, dextrose, and potassium or
normal saline and potassium for 48 hours. The absolute
increase in C-reactive protein was reduced by 40% in
the insulin group compared with placebo (P < .05); the
absolute increase in PAI-1 also was significantly lower
in the insulin-treated group (P < .05).21
cGMP
Vascular
Smoothmuscle Cell
4. Westerbacka J, Yki-Järvinen H, Turpeinen A, et al. Inhibition of platelet-collagen
interaction. Arterioscler Thromb Vasc Biol. 2002;22:167-172.
5. Erem C, Hacihasanoglu A, Celik S, et al. Coagulation and fibrinolysis parameters in
type 2 diabetic patients with and without diabetic vascular complications. Med Princ
Pract. 2005;14:22-30.
6. Dunn EJ, Ariens RAS, Grant PJ. The influence of type 2 diabetes on fibrin structure
and function. Diabetologia. 2005; April 29. Epub ahead of print.
Conclusion
Insulin and its normal physiologic actions can be considered antiatherogenic. Insulin resistance is associated with
defects in the normal antiatherogenic actions of insulin,
which may help explain why insulin resistance is associated with an increased risk for CV disease. Insulin therapy may, however, reverse or ameliorate many of the consequences of insulin resistance such as diabetic dyslipidemia and endothelial dysfunction.
Atherosclerosis and thrombosis are inflammatory
processes that involve a number of mediators. In addition to insulin’s clear benefits in managing hyperglycemia
of patients with diabetes and its potentially beneficial
effects on endothelial function, insulin appears to be an
anti-inflammatory hormone based on its interactions and
effects on inflammatory mediators. Furthermore, insulin
has been demonstrated to be antiatherosclerotic in animal models. Finally, in patients with acute myocardial
infarction, insulin was shown to have favorable effects
on markers of inflammation, which correlates with
adverse CV outcomes. ■
References
1. Zimmet P, Alberti KG, Shaw J: Global and societal implications of the diabetes epidemic. Nature. 2001;414:782–787.
2. Fuller JH, Shipley MJ, Rose G, et al. Mortality from coronary heart disease and
stroke in relation to degree of glycaemia: the Whitehall study. BMJ.
1983;287:867–70.
3. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071–1080.
7. Cai H, Harrison DG: Endothelial dysfunction in cardiovascular diseases: the role of
oxidant stress. Circ Res. 2000;87:840-844.
8. Perticone F, Ceravalo R, Pujia A, et al. Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation. 2001;104:191-196.
9. Heitzer T, Schlinzig T, Krohn K, et al. Endothelial dysfunction, oxidative stress, and
risk of cardiovascular events in patients with coronary artery disease. Circulation.
2001;104:2673-2678.
10. Zeng G, Nystrom FH, Ravichandran LV, et al. Roles for insulin receptor, PI3-kinase,
and Akt in insulin-signaling pathways related to production of nitric oxide in human
vascular endothelial cells. Circulation. 2000;101:1539-1545.
11. Westerbacka J, Bergholm R, Tiikkainen M, et al. Glargine and regular human
insulin similarly acutely enhance endothelium-dependent vasodilatation in normal
subjects. Arterioscler Thromb Vasc Biol. 2004;24:320-324.
12. Mäkimattila S, Yki-Järvinen H. Endothelial dysfunction in human diabetes. Current
Diabetes Reports. 2002;2:26-36.
13. Gaenzer H, Neumayr G, Marschang P, et al. Effect of insulin therapy on endothelium-dependent dilation in type 2 diabetes mellitus. Am J Cardiol. 2002;89:431-434.
14. Rask-Madsen C, Ihlemann N, Krarup T, et al. Insulin therapy improves insulin-stimulated endothelial function in patients with type 2 diabetes and ischemic heart disease. Diabetes. 2001;50:2611-2618.
15. Vehkavaara S, Makimattila S, Schlenzka A, et al. Insulin therapy improves endothelial function in type 2 diabetes. Arterioscler Thromb Vasc Biol. 2000;20:545-550.
16. Vehkavaara S, Yki-Järvinen H. 3.5 years of insulin therapy with insulin glargine
improves in vivo endothelial function in type 2 diabetes. Arterioscler Thromb Vasc
Biol. 2004;24:325-330.
17. Aljada A, Dandona P. Effect of insulin on human aortic endothelial nitric oxide synthase. Metab. 2000;49:147-150.
18. Grover A, Padginton C, Wilson MF, et al. Insulin attenuates norepinephrine- induced
venoconstriction: an ultrasonographic study. Hypertension. 1995;25:779-784.
19. Zeng G, Quon M. Insulin-stimulated production of nitric oxide is inhibited by wortmannin. J Clin Invest.1996;98:894-898.
20. Dandona P, Aljada A, Mohanty P, et al. Insulin inhibits intranuclear factor kB and
stimulates IkB in mononuclear cells in obese subjects: Evidence for an anti-inflammaotry effect? J Clin Endocrinol Metab. 2001;86:3527-3265.
21. Chaudhuri A, Janicke D, Wilson MF, et al. Anti-inflammatory and profibrinolytic
effect of insulin in acute ST-segment-elevation myocardial infarction. Circulation.
2004;109:849-854.
22. Montagnani M, Chen H, Barr VA, et al. Insulin-stimmulated activation of eNOS
is independent of Ca2+ but requires phosphorylation by Akt at Ser1179. J Biol Chem.
2001;276:30392-30398.
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2005
S9
THE J O U R N A L OF
FAMILY
PRACTICE
Insulin therapy in primary care:
Practical issues for clinicians
Louis Kuritzky, MD
University of Florida College of Medicine, Gainesville, Florida
Scott E. Nelson, MD
Family Medicine Clinic, Cleveland, Mississippi
Importance of glycemic control
lycemic control is paramount to preventing the other-
Gwise inevitable microvascular complications of type 2
diabetes. In the primary care setting, there are opportunities to intervene and improve short- and long-term outcomes for patients at risk for or who have diabetes.
Patients with risk factors (eg, family history, obesity, ethnicity, sedentary lifestyle) can be identified early, and
lifestyle modifications can be initiated prior to developing
overt type 2 diabetes. All patients (including children and
adolescents) should be screened for risk factors. Several
encouraging trials support a role for diet, exercise, metformin, acarbose, or thiazolidinediones in appropriately
selected high-risk patients to prevent diabetes.1
Clinicians should identify therapeutic goals as suggested by current American Diabetes Association
Guidelines.1 Attainment of goals will require lifestyle
modification, diet, and pharmacotherapy for most, if
not ultimately all, patients with type 2 diabetes. Most
patients are tempted to try oral therapies first and are
initially averse to parenteral management. In our opinion, skillful presentation of the value of tight control
(A1C < 7.0%) plus realistic advice on the limitations of
currently available oral agents can set the stage for early
adoption of the most effective therapy as opposed to
the most convenient therapy. Once patients become
facile with insulin management, their improved quality
of life and diabetes control typically foster sustained
endorsement of this methodology.
How to introduce insulin therapy
Once diabetic disease requires insulin to maintain
glycemic control, the primary care practitioner plays an
integral role in educating patients about the value of
insulin therapy. Primary care practitioners can assist
patients in overcoming barriers to the use of insulin therS1 0
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2005
•
apy by presenting it in a positive light, framing goals
appropriately, and addressing patient concerns. Patients
should be asked if they have any preconceptions about
insulin. The clinician can normalize the situation with a
typical inquiry like: “Many patients considering insulin
therapy have some questions, anxieties, or fears about
using insulin. How do you feel about it?” The busy clinician may not have time to personally instruct patients
in insulin administration technique, so referral to
sources for diabetes instruction is appropriate.
Clinicians must inform patients that although they
have a serious health problem, consistent good health
practices, lifestyle changes, and exercise can bring about
meaningful reductions in risk. Glucose control reduces
microvascular disease endpoints; blood pressure (BP) control reduces macrovascular and microvascular risk; lipid
control reduces macrovascular risk. Diet and exercise
enhance the favorable impact of each of the pharmacotherapies. Appropriate goals (A1C, BP, lipids, body
weight, exercise, fasting glucose, postprandial glucose, etc)
should be communicated verbally and in written format
for all patients and/or their caregivers. The therapeutic regimen should be selected first and foremost by likelihood of
achieving therapeutic goals, not by ease or simplicity of
administration. Because the expected decrease in A1C that
can be anticipated from a single oral antidiabetic agent
ranges from 0.3% to 2.0%,2 it is unlikely that a patient
with an initial A1C of 12.8% will achieve an A1C < 7%
with oral medication regimens alone. In our opinion, it
might be appropriate to consider insulin as initial treatment in such cases. Prolonged excursions on oral therapies
that leave patients distant from their goals only expose the
patient to unnecessarily protracted glucotoxicity.
Clinicians should be comfortable describing the likely
attainable reduction in A1C with each class of oral medication, alone and in combination, so that patients with
S U P P L E M E N T T O T H E J O U R N A L O F F A M I LY P R A C T I C E
TABLE
Practical Guide to Administering Insulin
1. Wash hands
2. Mix insulin by rolling between hands or turning bottle slowly up
and down. Do not shake
3. Clean rubber stopper with alcohol swab
4. Pull plunger back to number of units of insulin for dose
When mixing insulins draw up short-acting or rapid-acting insulin
before long-acting or intermediate-acting insulin
5. Holding syringe by the barrel push needle through rubber stopper
and push plunger
6. Leave needle and syringe in place; turn bottle upside down
Tip of needle should always be in the insulin
7. Draw insulin into syringe by quickly pulling plunger past dose
then pushing back to correct dose
8. Before removing syringe from bottle check for air bubbles
9. At correct dose, pull syringe out of bottle by holding onto the barrel
10. Select site and clean skin (rotate sites). Pinch skin into a mound
11. While holding barrel insert needle at 90-degree angle (straight in).
Make sure the needle is all the way in. If you are thin you may need
to inject at a 45-degree angle. Discuss this with your nurse
markedly elevated A1C at the time of diagnosis or substantially elevated A1C despite best efforts at exercise, diet,
and/or oral medications will feel comfortable making the
right therapeutic choice at each stage of type 2 diabetes.
How to address patient misconceptions
Patient fears and misconceptions about insulin may
present barriers to effective therapy. Some patients mistakenly believe that insulin intensifies insulin resistance.
Well-intended practitioners may have inadvertently set
the stage for patient nonreceptivity by portraying insulin
as appropriate therapy for patients who have “failed”
with oral agents. This creates a negative connotation
about insulin. Patients should be taught that insulin therapy is appropriate at any time during the course of diabetes to achieve glycemic goals. It is a rational choice for
initial therapy in some patients and may ultimately prove
to be the only available treatment for patients who have
been unable to attain goals with one or more oral agents.
One way to combat patients’ negative feelings
about insulin therapy is to discuss insulin with patients
at the time of diagnosis to clarify its benefits and preempt misconceptions. For example, the primary care
practitioner can explain to the patient that eventually
insulin might be required because of the progressive
nature of the disease, not because insulin is a last resort
after failed initial antidiabetic treatment. Most people
overestimate the discomfort associated with an injection
from a 32-gauge insulin needle. The authors believe clinicians should suggest at the initial educational encounters that all patients (even those beginning on oral regimens) experience a saline injection with an insulin
syringe to alleviate fears about parenteral therapy (see
TABLE for guide to administering insulin).
Insulin dosing and adjustments
One commonly used method for achieving glycemic
control is to aim for fasting glucose normalization first.
Since most patients prefer to minimize the number of
12.
13.
14.
15.
Push plunger slowly all the way down
Release pinched skin and pull needle straight out
Press alcohol swab over injection site and wipe (do not rub area)
Properly dispose of syringe in a coffee can or a sharps container
Key Points
■
■
■
■
■
■
■
■
Always draw short-acting or rapid-acting insulin into the syringe first.
Then add intermediate form(s) (roll the insulin bottle between your hands
to mix the insulin evenly)
Don't shake insulin vials--such action can cause clumping of the insulin
Long-acting insulin glargine cannot be mixed with any other insulin type
Know what different types of insulin look like
Rapid- and short-acting insulins should look clear
Intermediate- and long-acting insulins should look cloudy, but with
no clumps or crystals
Because many patients may have vision problems; be sure there is
no difficulty reading numbers on bottles and syringes
Tell patients diabetes is a progressive disease; potential need for insulin
should never be regarded as punishment or failure. Keep this in mind
when counseling patients beginning insulin therapy
daily injections, beginning with a single 10-unit
evening injection of basal insulin, such as glargine or
neutral protein Hagedorn is a reasonable starting
point. The dose of basal insulin should be adjusted
once a week, based on the mean of 2 consecutive days’
fasting blood glucose (FBG) until the glucose is less
than 120 mg/dL:
• FBG > 180 mg/dL, increase by 8 units
• FBG > 160 mg/dL, increase by 6 units
• FBG > 140 mg/dL, increase by 4 units
• FBG > 120 mg/dL, increase by 2 units
Some clinicians may be concerned that 8 units of basal
insulin might induce hypoglycemia. If this is a concern, a
6-unit increment can be used for FBG > 160 mg/dL and
FBG > 180 mg/dL. If FBG has been attained and the
patient is not at goal A1C, it will be necessary to obtain a
clear picture of the daily map of glucose control with premeal, postprandial, and bedtime glucose measurements.
Although multiple readings each day provide the most
rapid and complete profile, it is simpler to take twice-daily
glucose measurements at different times until a complete
map of glucose excursions is obtained. Further refinement
of glucose control is predicated upon identifying times of
day when glucose control is suboptimal, and providing
(usually) short-acting insulin (lispro, aspart, or the soonto-be-available glulisine) to address these excursions.
In summary, the primary care practitioner can help
patients understand that
• Diabetes is a progressive disease with severe health
consequences when not controlled
• Insulin is not for only severe diabetes and is not a
last-resort alternative for treatment failure
• Multiple therapies, which may include insulin, will
likely be needed during the course of diabetes
• Diabetic complications are not inevitable ■
References
1. American Diabetes Association. Standards of care. Diabetes Care. 2005;28:S4-S36.
2. American Association of Clinical Endocrinologists. Medical guidelines for the management of diabetes mellitus: The AACE System of Intensive Diabetes Self-management. Endocrine Practice. 2002; 8(1):40-82.
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2005
S1 1
University of Medicine and Dentistry of New Jersey Center
for Continuing and Outreach Education
THE J O U R N A L OF
FAMILY
PRACTICE
To obtain AMA/PRA category 1 credit, complete the posttest by circling the letter that corresponds to
the best answer for each question, along with the registration and activity evaluation forms, and send to:
CME Posttest
1. An early epidemiologic study found an association
between hyperinsulinemia and
a. A decreased risk of atherosclerosis
b. An increased risk of major CHD
c. Weight loss
d. Stable insulin levels
2. Recent evidence suggests that _______, rather than
_______, appears to be correlated with elevated
blood pressure.
a. Hyperinsulinemia, insulin resistance
b. Insulin resistance, glucose intolerance
c. Insulin resistance, hyperinsulinemia
d. Glucose intolerance, hyperinsulinemia
3. Insulin therapy has been found to ______ in patients
with type 2 diabetes.
a. Improve glucose uptake
b. Improve glucose disposal rates
c. Improve beta cell function
d. All of the above
4. The use of insulin glargine has been demonstrated
to be associated with ______ weight gain when
compared with neutral protamine Hagedorn (NPH).
a. More
b. Less
c. Equivalent
5. Normally, insulin will prevent platelet adherence to
______.
a. Collagen
b. Fibrin
c. Thrombin
d. Factor IX
6. Endothelial dysfunction can be demonstrated
by measuring impaired endothelium-dependent
vasorelaxation resulting from a loss of nitric oxide
(NO) bioactivity in the vessel wall.
a. True
b. False
7. In a small study conducted in obese individuals,
insulin decreased ______ levels, which demonstrated
insulin’s ________ effects at the molecular level.
a. Glucose; anti-inflammatory
b. Plasminogen active inhibitor (PAI-1);
c.
d.
anti-inflammatory
Plasminogen active inhibitor (PAI-1); inflammatory
Glucose; inflammatory
8. When initiating insulin therapy, a commonly used
method to achieve control is to normalize ______,
which can be achieved with a ______.
a. Postprandial blood glucose levels/prandial insulin
b. Postprandial blood glucose levels/basal insulin
c. Fasting blood glucose levels/prandial insulin
d. Fasting blood glucose levels/basal insulin
9. An initial insulin regimen suitable for individuals
who want to minimize the number of daily injections
would be:
a. Long-acting basal insulin administered once daily
b. Intermediate-acting insulin administered once at
c.
d.
night
Short-acting insulin administered 3 times daily
Both A and B are reasonable therapeutic options
10. When drawing up insulin into a syringe, ______
insulin is always drawn up first.
a. Long-acting
b. Basal
c. Intermediate-acting
d. Short- or rapid-acting
S1 2
JUNE
2005
•
UMDNJ–Center for Continuing and Outreach Education
via mail: PO Box 1709, Newark, NJ 07101-1709
via fax: (973) 972-7128
Retain a copy of your test answers. Your answer sheet will be graded and if a passing score of 70% or
more is achieved, a CME credit letter awarding AMA/PRA Category 1 credit and the test answer key will be
mailed to you within 4 weeks. Individuals who fail to attain a passing score will be notified and offered the
opportunity to complete the activity again.
N A ME ( FIR ST, M. I., L A ST )
DEGREE
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I attest that I have completed the Insulin Therapy in Type 2 Diabetes: More Than Just Improved Glycemic
Control activity as designed and I am claiming __ (up to 1 credit) AMA/PRA category 1 credit
UMDNJ-Center for Continuing and Outreach Education
PO Box 1709, Newark, NJ 07101-1709
Phone: (973) 972-4267 or 1 (800) 227-4852
Credit for this activity is available
until June 30, 2006
CE Activity Code: 06MC07
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Program objectives
Having completed this activity, you are better able to:
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Understand the common controversies of insulin therapy
5
4
3
2
Describe the effects that insulin has on endothelial function
5
4
3
2
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Explain the anti-inflammatory and antiatherogenic effects of insulin
5
4
3
2
1
The information presented increased my awareness/understanding of the subject.
5
4
3
2
1
The information presented will influence how I practice.
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4
3
2
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The information presented will help me improve patient care.
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4
3
2
1
The faculty demonstrated current knowledge of the subject.
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4
3
2
1
The program was educationally sound and scientifically balanced.
5
4
3
2
1
The program avoided commercial bias or influence.
5
4
3
2
1
Overall, the program met my expectations.
5
4
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I would recommend this program to my colleagues.
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1
1
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