Effects of PGX, a novel functional fibre, on acute and delayed

Transcription

British Journal of Nutrition, page 1 of 4
q The Authors 2011
doi:10.1017/S0007114511005447
Effects of added PGXw, a novel functional fibre, on the glycaemic index
of starchy foods
Jennie C. Brand-Miller1*, Fiona S. Atkinson1, Roland J. Gahler2, Veronica Kacinik3, Michael R. Lyon3,4
and Simon Wood3,5
1
Boden Institute of Obesity, Nutrition and Exercise, School of Molecular Bioscience, University of Sydney, Sydney, NSW 2006,
Australia
2
Factors Group R&D, Calgary, AB, Canada
3
University of British Columbia, Food, Nutrition and Health Program, Vancouver, BC, Canada
4
Canadian Centre for Functional Medicine, Coquitlam, BC, Canada
5
InovoBiologic, Inc., Calgary, AB, Canada
British Journal of Nutrition
(Received 18 July 2011 – Revised 5 September 2011 – Accepted 6 September 2011)
Abstract
The development of lower-glycaemic index (GI) foods requires simple, palatable and healthy strategies. The objective of the present study
was to determine the most effective dose of a novel viscous fibre supplement (PGXw) to be added to starchy foods to reduce their GI.
Healthy subjects (n 10) consumed glucose sugar (50 g in water £ 3) and six starchy foods with a range of GI values (52 –72) along
with 0 (inert fibre), 2·5 or 5 g granular PGXw dissolved in 250 ml water. GI testing according to ISO Standard 26 642-2010 was used to
determine the reduction in GI. PGXw significantly reduced the GI of all six foods (P, 0·001), with an average reduction of 19 % for
the 2·5 g dose and 30 % for the 5 g dose, equivalent to a reducing the GI by 7 and 15 units, respectively. Consuming small quantities of
the novel functional fibre PGXw, mixed with water at the start of a meal, is an effective strategy to reduce the GI of common foods.
Key words: Viscous polysaccharides: Dietary fibre: Glycaemic index: PGXw: PolyGlycopleXw
Postprandial hyperglycaemia and compensatory hyperinsulinaemia are factors linked to the development of lifestyle-related
chronic diseases, including obesity(1), type 2 diabetes(2) and
CHD(3). Carbohydrates are the only food constituents that
directly increase blood glucose concentration, yet the proportion of dietary energy consumed as carbohydrate is not
linked either positively or negatively to disease risk(4 – 6). In
contrast, a large body of evidence suggests that dietary fibre
and glycaemic index (GI)/glycaemic load (a measure of the
glycaemic effect of the diet) have independent effects on the
risk of chronic disease(7 – 11). Developing palatable, high-fibre,
low-GI foods is therefore a new challenge for the food industry.
Quality rather than quantity of fibre is a more important
influence on postprandial glycaemia and the GI of foods.
Indeed, among 121 foods of varying composition but equivalent energy content, increasing amounts of fibre predicted a
marginally positive, rather than inverse, relationship to acute
glycaemia and insulinaemia(12). Soluble fibres that develop
viscosity in solution are more likely to be associated with
reduced glycaemia. Indeed, the higher the viscosity, the
greater the improvement in glucose and lipid metabolism(13).
Unfortunately, in practice, both palatability and acceptability
of functional fibres decline with increasing viscosity(14). In
this context, PGXw, a highly viscous polysaccharide complex,
has been developed that demonstrates a delayed onset of
peak viscosity, allowing for a more acceptable and easy-touse functional fibre(15). Jenkins et al.(16,17) have demonstrated
that PGXw reduces glycaemia in a dose-dependent manner
when added to a glucose drink and carbohydrate-containing
foods. Since the effect of viscous fibre may vary according
to the conditions in the lumen of the gastrointestinal tract,
we undertook a series of studies to investigate the effectiveness of two doses of PGXw dissolved in water on lowering
the GI of a range of common starchy foods.
Materials and methods
The viscous polysaccharide used in the present study is sold
as PolyGlycopleXw or PGXw (a-D -glucurono-a-D -manno-b-D manno-b-D-gluco, a-L -gulurono-b-D -mannurono, b-D -glucob-D -mannan; PGXw; InovoBiologic, Inc., Calgary, AB, Canada).
It is manufactured from highly purified polysaccharides
derived from konjac, sodium alginate and xanthan gum by a
proprietary process (EnviroSimplexw), forming a complex
Abbreviation: GI, glycaemic index.
* Corresponding author: Professor J. C. Brand-Miller, email [email protected]
2
J. C. Brand-Miller et al.
McCains), cornflakes (Kellogg’s, Melbourne, VIC, Australia)
and oat porridge (Quaker Quick Oats; Peterborough, Ontario,
Canada). For the control meal (0 dose PGXw), 5 g of a nonviscous dietary fibre (inulin, Oraftiw; Beneo, Tienen, Belgium)
were used in place of PGXw. Subjects consumed the meals
with a washout period of at least 2 d between the tests. On
arrival at the metabolic kitchen, subjects were weighed and
two fasting blood samples were taken. The test meal and
water containing PGXw were consumed simultaneously at
an even pace within 10 – 12 min. Because PGXw develops
viscosity slowly, the solutions were only slightly viscous by
10 – 12 min (,1000 cps; S Wood, unpublished results). Further
blood samples were taken at 15, 30, 45, 60, 90 and 120 min.
with a viscosity higher than any currently known individual
polysaccharide. Although PGXw complex formation takes place
at secondary and tertiary levels, the primary structures of
the natural polysaccharides remain unchanged(15). The final
product is 87 % dietary fibre, of which 82 % is soluble. Previous
studies have indicated that PGXw is well tolerated in human
subjects(18), has a no observed adverse effect level of 50 000
parts per million(19) and has no mutagenic or genotoxic effects(20).
A pool of twelve healthy subjects (seven females), with a mean
age of 26·1 (SD 5·2) years and a BMI of 22·4 (SD 2·0) kg/m2, was
recruited through the Sydney University Glycemic Index
Research Service volunteer roster. Entry criteria included
BMI , 25 kg/m2, fasting blood glucose ,5·5 mmol/l and no
medication or supplements known to alter carbohydrate metabolism. The study was conducted according to the guidelines
laid down in the Declaration of Helsinki, and all procedures
involving human subjects/patients were approved by the
University of Sydney Human Ethics Committee (protocol no.
12 029). Written informed consent was obtained from all subjects.
Blood glucose analysis
Fingerprick blood samples (0·8 ml) from warmed hands were
collected into Eppendorf tubes containing 10 U heparin, centrifuged and the plasma stored on ice until same-day analysis in
duplicate using a glucose hexokinase assay (Roche Diagnostic
Systems, Sydney, NSW, Australia) for an automatic centrifugal
spectrophotometric analyser (Roche/Hitachi 912w; Boehringer
Mannheim Gmbh, Mannheim, Germany) with internal controls.
Study design
Statistical analysis
The study was undertaken according to the ISO Standard
for GI testing(21). After a 10 – 12 h fast, ten subjects (from the
pool of twelve) consumed in random order eighteen test
meals (six different foods with three doses of PGXw) and
three reference meals (50 g glucose in 250 ml water given on
three separate occasions). Of the twelve subjects, six consumed all six food sets, four subjects consumed five sets
and two consumed only three sets. Each dose of PGXw was
dissolved in 2 £ 250 ml water (0, 2·5 or 5 g) and consumed
simultaneously with a 50 g carbohydrate portion of the following six starchy foods: white bread (Tip Top Wonderwhite;
Goodman Fielder, Ryde, NSW, Australia), white rice (Uncle
Ben’s Jasmine Rice; Mars Canada, Bolton, Ontario, Canada),
boiled potato (McCain Purely Potato Cubes; McCains,
Wendouree, VIC, Australia), French fries (McCain Superfries;
GI
Subjects
100
90
80
70
60
50
40
30
20
10
0
For each test, the incremental area under the curve was calculated
according to the trapezoidal method. Any area under the baseline
(fasting value) was ignored. In each study, the results were
analysed using a general linear model (ANOVA) for the incremental area under the curve, with treatment or food and time as
fixed factors and subject as a random factor. PASW Statistics 18
(SPSS, Inc., Chicago, IL, USA) was used for all statistical analyses.
Results are expressed as means with their standard errors.
Results
All test meals were palatable and well tolerated, and no
adverse events were reported. The effect of PGXw at 0, 2·5
and 5 g doses on the GI of the six foods is illustrated in
*
*
*†
*
*†
*†
Bread
*†
*
Rice
Potato
boiled
*
*†
*
*†
French
fries
Cornflakes Instant oats
Fig. 1. Glycaemic index (GI) of starchy foods with 0 ( ), 2·5 ( ) and 5 g ( ) of PGXw fibre. Values are means (n 10), with standard errors represented by vertical
bars (n 10). All dose levels were significantly different from each other, irrespective of food type (P, 0·001; ANOVA). * Mean value was significantly different from
that of the no dose condition (P, 0·001). † Mean value was significantly different from that of the 2·5 g dose condition (P, 0·001). Without PGXw, the mean GI
values were as follows: bread 70 (SEM 3); rice 84 (SEM 4); potatoes (boiled) 70 (SEM 4); French fries 65 (SEM 4); cornflakes 82 (SEM 4); instant oats 76 (SEM 4).
Effects of PGXw on glycaemic index
Fig. 1. There were significant differences among the doses
(P,0·001), and each dose was significantly different from
every other dose (P,0·001). There was no significant food £
dose interaction, indicating that each dose affected each food
in the same way. On average, a dose of 2·5 g reduced the GI
by 14 units (i.e. by 16 –22 % depending on the food) and a
dose of 5 g reduced the GI by 24 units (28– 35 % depending
on the food). Using the logarithm of the GI, each dose of
PGXw had a similar percentage reduction (21 % for the 2·5 g
dose and 33 % for the 5 g dose), irrespective of the food (i.e.
the food £ dose interaction was again not significant). This
model was as good as the previous model using the GI
alone and the percentage reduction.
Discussion
The present study shows that small quantities of PGXw dissolved in water and consumed with common starchy foods
have clinically important dose-related effects on postprandial
glycaemia. The smaller dose (2·5 g) reduced the blood glucose
response to starchy foods by 21 % and the higher dose (5 g)
by 33 %. PGXw reduced the GI of the foods by between 14
and 24 units (depending on the dose), irrespective of the
food type. Notably, high-GI foods such as rice (GI ¼ 84
in the present study) and intermediate-GI, higher-fat foods
such as French fries (GI ¼ 65 in the present study) were
associated with a similar reduction in GI. All meals were
well tolerated, with no reported gastrointestinal discomfort.
Alternative methods of incorporating PGXw are also effective
in the context of single foods and mixed meals. Jenkins et al.(16)
demonstrated that sprinkling the product on the food just
before consumption or direct inclusion during manufacture
was successful in reducing glycaemia. They calculated that
each gram of PGXw had the ability to reduce the GI by approximately 7 units. The term ‘glycaemic reduction index potential’
was used to describe this ability and allow comparisons
among studies and different fibre preparations. In the present
study, PGXw had a glycaemic reduction index potential value
of 5 – 6 units, perhaps because PGXw was consumed in water
with the meal rather than directly incorporated into the food.
The magnitude of the reduction in glycaemia achieved with
PGXw is superior to many other commercially available functional fibre preparations(13). Inulin, for example, is commonly
added to commercial foods as a prebiotic fibre(22) but the 5 g
dose used as the control (0 g PGXw) in the present study had
no apparent effect on lowering GI. Cornflakes, for example,
with 5 g inulin (0 dose of PGXw) generated a GI of 82, a value
very close to the average of 81 in the published literature(23).
Psyllium fibre can be consumed in solution or incorporated
into foods such as breakfast cereal to reduce cholesterol
absorption, but a 5 g dose produces only a modest 14 %
reduction in postprandial glycaemia(24). In contrast, 5 g PGXw
produced a 33 % reduction in the present study. b-Glucans
(5 g) derived from oats consumed as a beverage reduced
glycaemia by , 20 % when consumed with a bread meal(25).
High-viscosity guar gum (approximately 5 g) can achieve a
very high 50 % reduction when intimately mixed with a meal
but it is not effective when viscosity is low(26).
3
The effectiveness of various fibre preparations has been
directly related to their ability to create viscosity(13). Nonetheless, guar gum is so highly viscous in solution that its
applications are limited due to stickiness and difficulties in
incorporating the product into normal food processing operations. In contrast, the present study shows that PGXw reduces
glycaemia very effectively when consumed in water before
significant gelling has taken place. Guar is also notable for
its capacity to produce excessive gastrointestinal discomfort(14). In a double-blind, randomised controlled trial (n 54),
gastrointestinal symptoms after PGXw supplementation were
rated as mild to moderate and generally well tolerated(18).
In previous trials, we have demonstrated that the effectiveness of PGXw is dependent on dose, timing of consumption
and physical form. Consumption within 15 min of the start
of the meal, but not at 45 or 60 min, reduced glycaemia just
as effectively as when taken with the meal. In contrast,
PGXw consumed as capsules did not produce acute lowering
of glycaemia, but had important ‘second meal’ effects, improving glucose tolerance at breakfast time when consumed with
the previous evening meal.
Reducing postprandial glycaemia and dietary glycaemic
load is a recent target in the management and prevention
of obesity and type 2 diabetes(27,28). A reduction in dietary
GI and glycaemic load led to greater weight loss over 12
weeks(29) and improved maintenance of weight loss in a
large European study(30). High-GI meals and diets are of
greater concern in insulin-resistant individuals who must
increase insulin secretion in order to re-establish glucose
homeostasis, increasing the burden on the b-cell and therefore
the risk of type 2 diabetes. In healthy adults, daily consumption of 5 g PGXw for 3 weeks was associated with improved
insulin sensitivity and higher levels of peptide YY, a hormone
that reduces hunger(31). In adolescents, PGXw in solution (5 g)
was shown to reduce energy intake from a pizza meal given
90 min later(32). In diabetic rats, PGXw was found to improve
glycaemic control and protein glycation, most probably due
to the insulin secretagogue effects of increased glucagon-like
peptide 1(33). The ability of PGXw to reduce the glycaemic
response may be a simple, effective ingredient in the designing of lower-GI diets.
In conclusion, granular PGXw consumed in water with
common starchy foods such as potatoes, bread and rice has
biologically important dose-related effects on acute postprandial glycaemia. As little as 5 g reduced blood glucose
responses over 120 min by 33 % and reduced the GI of
foods by 24 units.
Acknowledgements
Financial support of the study and supply of PGXw were
provided by InovoBiologic, Inc. PGXw, PolyGlycopleXw and
ENVIROSIMPLEXw are trademarks of InovoBiologic, Inc. All
other marks are the property of their respective owners. The
authors’ contributions were as follows: J. C. B.-M., S. W. and
F. S. A. were responsible for the design of the study, collection
and analysis of the data and writing of the manuscript; R. J. G.,
M. R. L. and V. K. contributed to the design of the study and
4
J. C. Brand-Miller et al.
writing of the manuscript. Conflict of interest: J. C. B.-M.
received financial remuneration for the preparation of the
manuscript; F. S. A. was employed by the University of
Sydney to undertake the studies; R. J. G. owns the Factors
Group of Companies, which retains an interest in PGXw;
V. K. is an employee of the Canadian Centre for Functional
Medicine; M. R. L. receives consulting fees from the Factors
Group of Companies; S. W. receives consulting fees from
InovoBiologic, Inc.
18.
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www.nature.com/ejcn
ORIGINAL ARTICLE
Effects of PGX, a novel functional fibre, on acute
and delayed postprandial glycaemia
JC Brand-Miller1, FS Atkinson1, RJ Gahler2, V Kacinik3, MR Lyon3,4 and S Wood5
1
Boden Institute of Obesity, Nutrition and Exercise and the School of Molecular Bioscience, University of Sydney, Sydney, NSW, Australia;
Factors Group R & D, Burnaby, BC, Canada; 3University of British Columbia, Food, Nutrition and Health Program, Vancouver, BC,
Canada; 4Canadian Centre for Functional Medicine, Coquitlam, BC, Canada and 5InovoBiologic Inc., Calgary, AB, Canada
2
Background: Viscous fibre in food has established health benefits, but few functional fibre preparations are both effective and
palatable. Our objective was to determine the most effective dose, formulation and timing of consumption of a novel fibre
supplement (PolyGlycopleX (PGX)) in reducing postprandial glycaemia.
Subjects/methods: Three trials were undertaken, each with 10 subjects (8M and 8F; age 24.4±2.6 years). Granular supplement
was tested at four doses (0, 2.5, 5.0 and 7.5 g) with breakfast (study 1). Granular and capsule forms of the supplement were
given in a single dose (5 g for granules and 4.5 g in capsules) at 60, 45, 30, 15 and 0 before, and þ 15 min after a bread
meal (study 2). Capsules at increasing doses (1.5, 3, 4.5 and 6 g) were consumed with the evening meal to determine effects on
glucose tolerance at breakfast (study 3). Incremental area under the blood glucose curve was determined.
Results: Granular PGX at breakfast time at doses of 2.5, 5 and 7.5 g reduced the incremental area under the curve by up to 50%
in a linear dose–response fashion (Po0.001). The granular form of PGX (5 g), but not the capsules, reduced glycaemia by up to
28% when consumed from 45 to þ 15 min (Po0.001). Capsules containing 3, 4.5 and 6 g PGX consumed with the evening
meal reduced glycaemia at breakfast by up to 28% (Po0.001).
Conclusions: PGX has biologically important, dose-related effects on acute and delayed (second meal) postprandial glycaemia.
European Journal of Clinical Nutrition advance online publication, 6 October 2010; doi:10.1038/ejcn.2010.199
Keywords: Viscous polysaccharide, dietary fibre, postprandial glycaemia, PGX
Introduction
Increasing evidence from long term, prospective observational studies suggests that diets containing larger quantities
of whole grains and dietary fibre are associated with reduced
risk of type 2 diabetes (Schulze et al., 2004, 2005). In
controlled trials, higher intake of cereal fibre produces
improvements in insulin sensitivity (Pereira et al., 2002),
whereas soluble fibre reduces postprandial glycaemia
(Jenkins et al., 1978), as well as serum lipids (Jenkins et al.,
1993; Vuksan et al., 1999). Most health authorities and
diabetes associations now advise an increase in dietary fibre
intake to at least 14 g per 1000 kcal (Canadian Diabetes
Association 2000; American Diabetes Association 2008).
Correspondence: Professor JC Brand-Miller, Boden Institute of Obesity,
Nutrition and Exercise and the School of Molecular Bioscience, University of
Sydney, Sydney, NSW 2006, Australia.
E-mail: [email protected]
Contributors: JCBM, SW and FSA were responsible for design of the study,
collection and analysis of the data and writing of the paper. RJG, MRL and VK
contributed to the design of the study and writing of the paper.
Received 19 April 2010; revised 7 June 2010; accepted 6 August 2010
Despite community awareness of the health benefits of
dietary fibre, intakes have remained at about half the
recommended level over the last decade (Casagrande et al.,
2007). Thus, supplementation of the diet with purified
dietary fibres that are active in vivo (that is, ‘functional’ fibre
preparations) may be an option to increase fibre intake.
Although both insoluble and soluble fibres can be used this
way, soluble fibres that develop viscosity in solution appear
to provide greater benefits for metabolism. Indeed, the
higher the viscosity, the greater the improvement in glucose
and lipid metabolism (Jenkins et al., 1978). Unfortunately, in
practice both palatability and acceptability of functional
fibres decline with increasing viscosity (Ellis et al., 1981).
Recent advances in food science suggest that optimal
viscosity can be reached by using a combination of different
viscous fibres resulting in an induced viscosity that is greater
than the viscosity of the individual components (Wood et al.,
1994). This may allow smaller doses to be used that may
increase acceptability while maintaining efficacy (Vuksan
et al., 2000).
Recently, PolyGlycopleX (PGX), a highly viscous polysaccharide complex has been developed that demonstrates a
Effects of PGX on postprandial glycaemia
JC Brand-Miller et al
2
delayed onset of peak viscosity, allowing for a more palatable
and easy-to-use functional fibre. As the effect of viscous fibre
may vary according to the conditions in the lumen of the
gastrointestinal tract, we undertook a series of studies to
investigate the effectiveness of two alternate forms of the
product (granules or capsules), the timing of the dose with
respect to that of a carbohydrate-containing meal, and the
presence or absence of a ‘second meal’ effect (that is, the
ability to reduce postprandial glycaemia the following
morning after an evening dose of the supplement).
Fibre supplement
PGX (a-D-glucurono-a–manno-b-D-manno-b-D-gluco), (a-Lgulurono-b-D mannurono), b-D-gluco-b-D-mannan; (PGX);
Inovobiologic Inc., Calgary, Canada) is a novel functional
fibre complex manufactured by a proprietary process
(EnviroSimplex) from three dietary fibres to form a highly
viscous polysaccharide with high water holding and gelforming properties. A proprietary process causes strong
interactions to be formed between these to produce a
resultant polysaccharide complex (Abdelhameed et al.,
2010), with a level of viscosity that is higher than any
currently known individual polysaccharide. The final
product is a novel soluble, highly viscous polysaccharide
(functional fibre) that has been shown to be well tolerated by
rodents (Matulka et al., 2009) and humans (Carabin et al.,
2009). A case study in relating pre-clinical, clinical and
postmarketing surveillance data reviewed over 54 million
serving of PGX over a 4-year period and found PGX to be
well tolerated when used to supplement the diet (unpublished findings). Genotoxicity studies of PGX have shown no
mutagenic effects using bacterial reverse mutation and
mouse micronucleus assays (Marone et al., 2009). PGX is
87.4% dietary fibre, of which 81.8% is soluble. It is available
in two physical forms: a granular product that is dissolved in
water or sprinkled on food before consumption, and as a
soft-gelatin capsule that is swallowed whole.
Study design
Three single-blind, randomized controlled trials were undertaken in three groups of 10 healthy subjects selected from a pool
of 16 (8M and 8F; age 24.4±2.6 years (range: 20.3–29.2 years);
body mass index 21.7±2.3 kg/m2 (range: 18.2–24.8 kg/m2)).
Subjects were recruited through the Sydney University
Glycemic Index Research Service volunteer roster. Entry
criteria included body mass index o 25 kg/m2 and fasting
blood glucose o5.5 mmol/l. Subjects taking medications
or dietary supplements were excluded. The study was
conducted at the University of Sydney and was approved
by the Human Research Ethics Committee of the University
of Sydney. Informed written consent was obtained from all
subjects before the start of the study. Subjects received
a small financial reward for their participation.
European Journal of Clinical Nutrition
Treatments were randomized within each series with 6, 7
and 16 treatments in study 1, 2 and 3, respectively. Each
subject undertook up to two tests per week with at least 2 days
between tests. On each test day, subjects arrived at the
metabolic kitchen in the morning after a 10–12 h overnight
fast. After being weighed and having two fasting blood samples
obtained by finger-prick, the subject consumed the test meal
within 10 min, and further blood samples were obtained at 15,
30, 45, 60, 90 and 120 min after the start of eating.
Study 1. The aim was to investigate the dose–response
relationship using four doses of PGX granules taken with a
white bread meal (Tip Top, George Weston Foods, Sydney,
NSW, Australia) containing 50 g available carbohydrate
(defined as total carbohydrate minus dietary fibre). There
were six treatments consisting of three placebo tests (0 g) and
one each with 2.5, 5 and 7.5 g supplement. The active
granules were dissolved in 2 250 ml glasses of water.
Study 2. The aim was to determine whether the timing of a
single dose of PGX (5 g) was critical, and whether the ability
to lower postprandial glycaemia (effectiveness) varied with
the form of the supplement (capsules or granules). Of the 16
treatments, four were placebo, six were capsules and six were
granules, given at times 60, 45, 30, 15, 0 and þ 15 min
relative to the start of eating. The meal consisted of a 50 g
available carbohydrate portion of white bread. The granular
supplement was dissolved in 2 250 ml water and consumed
within 5 min, whereas capsules were consumed with the
same volume of water (0 time).
Study 3. The aim was to investigate whether increasing
amounts of the capsule form of PGX had a ‘second meal’
effect, that is, a beneficial effect on glucose tolerance at
breakfast following supplementation at the previous evening
meal. Subjects underwent a total of seven sessions in which
the same meal (teriyaki chicken stir-fry with vegetables and
Jasmine rice, with a cereal snack bar for dessert) containing
120 g available carbohydrate and 3000 kJ (approximately 717
Cal) (female meal) and 3300 kJ (approximately 789 Cal)
(male meal) was consumed in the evening together with 1.5,
3, 4.5 or 6 g of PGX (2, 4, 6 and 8 capsules, respectively, given
in random order) or 4, 6 or 8 placebo capsules (that is, a total
of three placebo tests) and 2 250 ml water. The evening
meal was consumed within 20 min and the capsules were
taken at the start of the meal. On the following morning
after a 12-h fast, subjects consumed a standard breakfast of
white bread containing 50 g available carbohydrate.
Blood glucose analysis
Finger-prick blood samples (0.8 ml) from warmed hands were
collected into Eppendorf tubes containing 10 U heparin,
centrifuged and the plasma stored on ice until same-day
analysis in duplicate using a glucose hexokinase assay (Roche
3
Diagnostic Systems, Sydney, NSW, Australia) and an automatic centrifugal spectrophotometric analyser (Roche/
Hitachi 912, Boehringer Mannheim Gmbh, Germany) with
internal controls.
Statistical analysis
For each test, the incremental area under the curve (iAUC)
was calculated according to the trapezoidal method. Any
area under the baseline (fasting value) was ignored. In each
study, the results were analyzed using a general linear
model (analysis of variance) for iAUC with treatment or
food and time as fixed factors and subject as a random
factor. PASW Statistics 18 (SPSS Inc., Chicago, IL, USA) was
used for all statistical analyses. Results are expressed as
means±s.e.m.
consumed at the start of the meal (0 time, 28% reduction,
145±5 vs 103±11 mM/120 min, Po0.001), followed by 30
and 15 min. There was no significant effect of capsules,
irrespective of timing (Figure 2b).
Study 3 determined whether there was a ‘second meal’
effect at breakfast following supplementation with capsule
form in the previous evening meal. Doses of 3, 4.5 and 6 g
(but not 1.5 g) reduced blood glucose iAUC relative to
placebo (171±4 (0 g), 150±8 (3 g), 130±8 (4.5 g) and
123±8 (6 g) mM/120 min, respectively), with the greatest
reduction seen with the largest number of capsules (Figure 3).
There was a significant dose–response effect at the second
meal, indicating that each extra active capsule reduced the
incremental AUC by B6 units or B3–4%.
Adverse events
Although no formal assessment was made, all test meals were
well tolerated and no adverse events were reported.
Study 1 investigated the dose–response effect of 0, 2. 5, 5 and
7.5 g of the granular form of PGX dissolved in water and
taken with the meal. The highest dose reduced the iAUC by
50% from 151±5 to 76±9 mM/120 min (Po0.005). Treating
dose as a continuous variable with values 0, 1, 2 and 3, there
was a significant linear reduction of postprandial glycaemia
(iAUC 151±5, 113±9, 88±9 and 76±9 mM/120 min,
Po0.001, Figure 1) with each additional gram of supplement
reducing iAUC by B11 units or 7%. In pairwise comparisons,
adjacent doses were not significantly different, but all other
comparisons were significant at P ¼ 0.005.
Study 2 determined whether the timing of a single dose
(5 g) relative to the meal influenced postprandial glycaemia,
and whether the physical form of the supplement (capsules
or granules) was important. The granular form, but not the
capsules, significantly reduced glycaemia relative to placebo
(Po0.001) when consumed at 45, 30, 15, 0 or þ 15 min,
but not –60 min, relative to the meal (Figure 2a). The most
effective reduction in iAUC occurred when the granules were
[Plasma Glucose] (mmol/L)
8.0
Discussion
This series of studies shows that PGX has clinically
important, dose-related effects on acute and delayed postprandial glycaemia. The highest dose of the granular form
(7.5 g) dissolved in water and consumed with a carbohydrate
meal at breakfast time, reduced the blood glucose response
in healthy individuals by 50%. Effectiveness of PGX granules
was also related to timing: consumption within 15 min of
the start of the meal, but not 45 or 60 min, reduced
glycaemia just as effectively as when taken with the meal
(0 time). In contrast, PGX (4.5 g) consumed as capsules did
not produce acute lowering of glycaemia, yet had important
‘second meal’ effects, improving glucose tolerance at
breakfast time when consumed with the previous evening
meal. These findings indicate that the effectiveness of
PGX is dependent on dose, timing of consumption and
physical form.
0.0 g granules
2.5 g granules
5.0 g granules
7.5 g granules
7.5
7.0
6.5
6.0
5.5
180
iAUC Glucose (mmol/L.min)
Results
a
160
140
b
120
100
b,c
c
80
60
40
20
0
5.0
0
15
30
45 60 75
Time (min)
90
105 120
0.0
2.5
5.0
7.5
Granules Dosage (g)
Figure 1 Acute dose–response effects. Incremental postprandial blood glucose responses and corresponding incremental area under the curve
(iAUC) of 10 healthy subjects after four meals containing 50 g available carbohydrate as white bread supplemented with 0, 2.5, 5 or 7.5 g of PGX
granules dissolved in 500 ml of water. Columns with different letters are significantly different (Po0.01). P-values are for analysis of variance with
pairwise comparisons.
4
a
Granules
Placebo (Av)
-60 min
-45 min
-30 min
-15 min
0 min
+15 min
7.5
7.0
6.5
8.0
6.0
5.5
5.0
0
30
45
60
75
Time (min)
90
105
a
a,b
Placebo -60
(Av)
120
b
b
-45
-30
b
-15
b
b
0
+15
Time of granules consumption (min)
Capsules
8.0
Placebo (Av)
-60 min
-45 min
-30 min
-15 min
0 min
+15 min
7.5
7.0
6.5
6.0
5.5
5.0
0
15
30
45
60
75
90
105
b
15
180
160
140
120
100
80
60
40
20
0
180
160
140
120
100
80
60
40
20
0
120
Placebo -60
(Av)
Time (min)
-45
-30
-15
0
+15
Time of capsules consumption (min)
Figure 2 Timing of consumption. Incremental postprandial blood glucose responses and corresponding incremental area under the curve
(iAUC) of 10 healthy subjects after a meal containing 50 g available carbohydrate as white bread supplemented at 60, 45, 30, 15, 0 and
þ 15 min with PGX granules (5 g) dissolved in 500 ml of water (a) and as PGX capsules consumed with 500 ml water (b). Bars with different
letters are significantly different (Po0.001). P-values are for analysis of variance with pairwise comparisons.
0 capsules
2 capsules
4 capsules
6 capsules
8 capsules
7.5
7.0
6.5
6.0
5.5
200
iAUC Glucose (m mol/L.min)
[Plasma Glucose] (m mol/L)
8.0
180
160
140
a
a,b
b
b
b
120
100
80
60
40
20
0
5.0
0
15
30
45 60 75
Time (min)
90
105 120
0
2
4
6
8
Dosage (g) as capsules
Figure 3 Delayed ‘second meal’ effects. Incremental postprandial blood glucose responses and corresponding incremental area under the
curve (iAUC) of 10 healthy subjects after a standard breakfast containing 50 g available carbohydrate as white bread. On the evening before the
breakfast, 0, 1.5, 3, 4.5 and 6 g PGX in the form of capsules were consumed with the evening meal. Bars with different letters are significantly
different (Po0.01). P-values are for analysis of variance with pairwise comparisons.
The magnitude of the reduction in glycaemia achieved
with PGX appears to be comparable with or superior to
other commercially available functional fibre preparations
(Jenkins et al., 1978). High viscosity guar gum (B5 g) also
reduces glycaemia by up to 50% when intimately mixed with
a meal, but it is not effective when viscosity is low (Leclere
5
et al., 1994). In contrast, pysllium fibre (5 g) produced only a
14% reduction in postprandial glycaemia when consumed
with a breakfast meal (Pastors et al., 1991). b-glucans (5 g)
derived from oats, but not barley, reduced glycaemia
by o20% when consumed with a bread meal (Biorklund
et al., 2005).
The beneficial effects of functional fibre preparations are
highly dependent on the food matrix. PGX has also been
found to be just as effective when sprinkled on food as
dissolved in water (unpublished data). This ability provides
a significant advantage in terms of palatability because it
delays the onset of viscosity. Nonetheless, PGX was not
effective when consumed encased in gelatin capsules, even
when a 15, 30, 45 or 60-min time gap was permitted between
consumption of the capsules and the start of the meal to
allow development of viscosity in vivo.
The effectiveness of various fibre preparations has been
directly related to their ability to create viscosity (Jenkins
et al., 1978). Nonetheless, extreme viscosity is not desirable.
Guar gum is so highly viscous that its applications are
limited because of the difficulties in incorporating the
product into normal food processing operations. To be
effective, guar gum must be mixed with a blender to prevent
clumps, and allowed to reach its full viscosity before
incorporation, often resulting in an undesirable food texture
or mouth-feel. In contrast, the present studies show that
PGX reduces glycaemia very effectively when consumed in
water before significant gelling has taken place. Guar is also
noted for its capacity to produce excessive gastrointestinal
discomfort (Ellis et al., 1981). In a double blind, randomized
controlled trial (n ¼ 54), gastrointestinal symptoms after
PGX supplementation were rated as mild to moderate, and
generally well tolerated (Carabin et al., 2009).
In the third study in this series, we showed that PGX in
capsule form had dose-related ‘second meal’ effects. This
phenomenon describes the ability of a food or supplement to
improve glucose tolerance at the following meal, for
example, from dinner in the evening to breakfast the next
day or from breakfast to lunch or lunch to dinner on the
same day. In the case of PGX, 6 g consumed as capsules in the
evening reduced glycaemia at breakfast by almost 30%. This
is a useful attribute because it implies that not all meals must
be consumed with the supplement in order to see benefits on
postprandial glycaemia. Many fibres, both soluble and
insoluble, as well as low glycaemic index foods, have been
shown to produce second meal effects (Brighenti et al.,
2006). The effect of wheat fibre is thought to be directly
related to an acute improvement (within 24 h) in wholebody insulin sensitivity caused by the absorption of the
products of fermentation of the fibre in the large bowel into
the portal bloodstream (Weickert et al., 2005). In the case of
low glycaemic index foods, the mechanism may be related to
prolonged carbohydrate absorption and suppression of free
fatty acid release (Jenkins et al., 1990). It is, therefore,
possible that the second meal effects of PGX could be even
greater in the granular form.
In the past, the ability of fibre preparations to improve
lipid metabolism was the focus of most research (Brown
et al., 1999). But increasingly, reductions in postprandial
glycaemia (glycemic ‘spikes’) have been encouraged as part
of the management and prevention of impaired glucose
tolerance (pre-diabetes) and type 2 diabetes (Ceriello, 2004;
Dickinson and Brand-Miller, 2005). In the STOP-NIDDM
trial, treatment with the a-glucosidase inhibitor, acarbose, a
compound that specifically reduces postprandial hyperglycaemia, reduced the risk of type 2 diabetes (Chiasson et al.,
2002), weight gain over time (Chiasson et al., 2002, 2003),
and cardiovascular disease (Chiasson et al., 2003). The
repeated challenge to b-cell function induced by low-fibre,
high-carbohydrate meals is of concern in insulin-resistant
individuals who must increase insulin secretion to
re-establish glucose homeostasis. In this phenotype, adherence to a conventional low fat diet produces both higher
postprandial glycaemic and insulinaemic excursions and
greater demands on b-cell function, which could eventually
promote b-cell dysfunction and type 2 diabetes. PGX’s ability
to reduce postprandial glycaemia also suggests a potential
role in the treatment and prevention of obesity. Low
glycaemic index carbohydrates have been associated with
lower fat mass accretion in animal models (Pawlak et al.,
2004; Isken et al., 2009) and greater fat loss in some weight
loss trials (McMillan-Price et al., 2006; Ebbeling et al., 2007).
In adolescents, PGX in solution (5 g) was shown to reduce
energy intake from a pizza meal given 90 minutes later more
effectively than less viscous fibres, such as glucomannan and
cellulose (Vuksan et al., 2009).
In conclusion, PGX in granular form has biologically
important, dose-related effects on acute postprandial glycaemia. As little as 7.5 g of the granules reduces blood glucose
responses over 120 min by 50%. Precise timing was not
critical and consumption within 15 min either side of the
start of the meal was effective. PGX in capsule form did
not reduce acute glycaemia with the meal it was taken with
but had a biologically important effect when consumed with
the evening meal whereby it improved glucose tolerance at
breakfast (that is, a ‘second meal effect’). Further research is
needed to evaluate the long-term health benefits of this
promising viscous polysaccharide.
Conflict of interest
JCBM received financial remuneration for the preparation of
the paper. FSA was employed by the University of Sydney
to undertake the studies. RJG owns the Factors Group of
Companies, which retains an interest in PGX. VK is
an employee of the Canadian Centre for Functional
Medicine. MRL receives consulting fees from the Factors
Group of Companies. SW receives consulting fees from
InovoBiologic Inc.
PGX and Envirosimplex are trademarks of InovoBiologic Inc.
All other marks are the property of their respective owners.
6
Acknowledgements
InovoBiologic Inc., Calgary, AB, Canada supported the study
and supplied PGX.
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This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this
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Curr Obes Rep
DOI 10.1007/s13679-012-0016-9
OBESITY TREATMENT (AM SHARMA, SECTION EDITOR)
Is There a Place for Dietary Fiber Supplements
in Weight Management?
Michael R. Lyon & Veronica Kacinik
# The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract Inadequate dietary fiber intake is common in modern diets, especially in children. Epidemiological and experimental evidence point to a significant association between a
lack of fiber intake and ischemic heart disease, stroke atherosclerosis, type 2 diabetes, overweight and obesity, insulin
resistance, hypertension, dyslipidemia, as well as gastrointestinal disorders such as diverticulosis, irritable bowel disease,
colon cancer, and cholelithiasis. The physiological effects of
fiber relate to the physical properties of volume, viscosity, and
water-holding capacity that the fiber imparts to food leading
to important influences over the energy density of food.
Beyond these physical properties, fiber directly impacts a
complex array of microbiological, biochemical, and neurohormonal effects directly through modification of the kinetics
of digestion and through its metabolism into constituents such
as short chain fatty acids, which are both energy substrates
and important enteroendocrine ligands. Of particular interest
to clinicians is the important role dietary fiber plays in glucoregulation, appetite, and satiety. Supplementation of the diet
with highly functional fibers may prove to play an important
role in long-term obesity management.
Introduction
The “eat less and exercise more” paradigm has proven to be
of little value in the clinical management of the obese
patient. Likewise, treatments that rely upon complex or
rigorous dietary plans tend to result in poor long-term benefits with patients typically drifting back to their old habits
once the novelty of the diet has worn off. Clinicians are
increasingly assisting obese patients in the establishment of
more achievable long goals, including the avoidance of
further weight gain as a realistic end point in some patients.
Rather than complex dietary regimens, most patients respond more favorably to incorporating eating strategies that
help them achieve and maintain a sense of satiety while
reducing their caloric intake. Significantly increasing the
consumption of dietary fiber to reduce the caloric density
of food and reduce the glycemic impact of the food is
generally considered to play an important, if not essential,
part of long-term weight management [1].
What Is Dietary Fiber?
Keywords Dietary fiber . Obesity . Appetite regulation .
Glycemic index . GLP-1 . PYY . CCK . Oxyntomodulin .
L-cells . Free fatty acid receptors . Bile acid receptors
M. R. Lyon : V. Kacinik
Canadian Center for Functional Medicine,
1550 United Boulevard,
Coquitlam, BC, Canada V3K 6Y2
M. R. Lyon (*)
Food, Nutrition and Health Program,
University of British Columbia,
1550 United Boulevard,
Coquitlam, BC, Canada V3K 6Y2
e-mail: [email protected]
Dietary fiber is a non-starch polysaccharide in (mostly) plant
food that is poorly digested by humans. Based on a recent US
government consensus report, fiber can exist as dietary fiber
(naturally occurring in food), or functional fiber (added during
the processing or preparation of food or consumed separately
as a supplement) [2]. Fiber can be insoluble or soluble in
water. Insoluble fibers include cellulose, hemicellulose, and
lignins, whereas soluble fibers include various gums, pectins,
β-glucans, oligosaccharides, resistant dextrans, and resistant
starches. Chitin and chitosan are indigestible aminopolysaccharides that are found in or are derived from the
exoskeletons of arthropods such as crabs and lobster, as well
Curr Obes Rep
as the cell walls of most fungi, and could functionally be
regarded as fiber, although they are not recognized as fiber
by most regulatory authorities. The distinction between soluble and insoluble fibers is due to the chemical properties of the
fiber, resulting in its tendency to absorb water. Various physicochemical properties of fiber (viscosity, water-holding capacity, cation exchange capacity, adsorption of organic
materials, and fermentability) are now thought to be fundamental to its beneficial physiologic effects. The Institute of
Medicine has proposed a new definition of dietary fiber that
encompasses both its physical characteristics and its physiologic effects in humans [3]. A fiber’s viscosity, its waterholding capacity, and its fermentability are the chief determinates of fiber’s physiologic effects.
The regulatory classification of fiber varies considerably
in different countries. The Codex Alimentarius Commission of the World Health Organization has defined dietary
fiber upon analytic methods rather than its physical or
physiologic characteristics [4].
Sources
The typical Western diet is generally lacking in sufficient
dietary fiber, being composed principally of refined grains
and other highly digestible sources of starch, sugar, various
fats, and animal products. Children in particular are commonly fiber deficient, with daily intakes often under 5 g and
with little soluble fiber. Likewise, many adults in Western
society consume 5 to 10 g of fiber daily, as opposed to the
35 to 50 g that is considered desirable for optimal health [5].
Moreover, because most fiber in the Western diet is derived
from cereal grains, the intake of viscous soluble fiber is
typically inadequate.
A diet focusing on a large intake of vegetables and fruits as
well as unrefined whole grains and legumes should be the
foundation of a healthy lifestyle. With this “whole-foods”
based diet, it is certain that dietary fiber intake will substantially increase [6]. Unfortunately, only a minority of the population, particularly children, are likely to adopt a largely
whole-foods diet anytime in the near future. Because of this,
efforts are underway to establish effective means to fortify the
Western diet with dietary fiber through the use of functional
fibers (various fibers as food additives or ingredients as well
as the use of readily accepted fiber supplements).
Health Effects
There is compelling epidemiologic and experimental data
associating numerous disorders, at least in part, to a lack of
dietary fiber. Ischemic heart disease, stroke atherosclerosis,
type 2 diabetes, overweight and obesity, insulin resistance,
hypertension, dyslipidemia, as well as gastrointestinal disorders such as diverticulosis, irritable bowel disease, colon
cancer, and cholelithiasis are just a few of the many conditions that seem to be influenced by the adequacy of dietary
fiber intake [7, 8].
Numerous studies have demonstrated that certain fibers
decrease the glycemic response to food, promote satiety,
lower serum cholesterol, promote bowel regularity, positively influence colonic microflora, provide nutritional substrates for colonic mucosal cells, improve mucosal barrier
function, as well as aid in the sequestration and elimination
of toxic and carcinogenic dietary and environmental compounds. These and other effects constantly interplay to
increase or decrease the development of a wide range of
health conditions.
Viscous dietary fibers have been correlated with moderation in blood glucose and cholesterol concentrations, prolonged gastric emptying, and slower transit time through the
small intestine [9]. Among viscous fibers, fermentability is
mostly associated with large bowel function. Rapidly fermented fiber sources provide substrates for short-chain fatty
acid (SCFA) production by microflora in the large bowel,
whereas slowly or incompletely fermented fiber sources
improve bowel health by promoting laxation, reducing
colonic transit time, and increasing stool weight [10].
Mechanisms of Action of Dietary Fiber
Dietary fiber exerts its effects through an interaction between
the physical properties it imparts to foods accompanied by a
complex array of microbiological, biochemical, and neurohormonal influences. Dietary fiber can have a strong influence
on the palatability of food, and may require longer periods of
mastication before swallowing, thus influencing ingestive
behavior. In the stomach, fiber affects the volume and viscosity of food, which has a highly significant effect on satiety
[11]. This “volumetric” effect on food promotes a sense of
fullness and a delay in gastric emptying, which tends to
naturally result in a decrease in caloric intake. Various fibers
differ dramatically in their ability to impart volume and viscosity to foods, and it has been shown that simple distention of
the gastric antrum by soluble, viscous fibers leads to a sensation of satiety that tends to promote cessation of eating during
meal time [12]. Viscous fiber has also been shown to slow
gastric emptying, thus resulting in a prolongation of the mechanical distention of the stomach [13]. As well, viscous fiber
consumption results in a delayed postprandial rise of ghrelin,
the principle peripheral orexigen that promotes meal initiation. This delay in the pre-meal elevation of ghrelin is thought
to result from slowed absorption of glucose and amino acids
and a resultant increase in the delivery of these nutrients to the
jejunum and ileum [14].
Curr Obes Rep
Viscosity of Fiber
Water-Holding Capacity and Energy Density
Viscosity as related to dietary fiber refers to the ability of
some polysaccharides to thicken or form gels when mixed
with fluids resulting from physical entanglements and hydrophilic interactions among the polysaccharide constituents within the fluid or solution [15]. Gums, pectins, and
β-glucans make up the majority of viscous dietary fibers.
Apples, legumes, and oats are common dietary sources of
viscous fibers. The viscosity that a fiber imparts to the
gastric and small intestinal contents is directly correlated
with the ability of the fiber to reduce postprandial glycemic
response, promote satiety, decrease serum cholesterol, and
decrease serum uric acid [16, 17••]. The viscosity of fiber is
also thought to play an important role in the augmentation of
gut mucosal protection through the stimulation of enteral
mucus production and goblet cell hypertrophy and replication [18]. Additionally, those viscous fibers that are largely
fermented by colonic microflora exert a wide array of physiologic effects through the production of SCFAs (the principle energy substrates of colonocytes), the promotion of
beneficial colonic microbial populations, and the augmentation of important gut-derived peptide hormones.
The viscosity of fiber is best measured by methods that
quantify a hydrated fiber’s internal friction and its ability
to resist flow. Viscosity is usually expressed in units of
millipascal seconds or centipoise [19]. Other factors, such
as shear stress (e.g., mastication, peristalsis), acid pH,
dilution, and chemical components of food determine the
real viscosity that a fiber will impart to food rather than
just its in vitro viscosity.
The concept of the glycemic index (GI) came about
through the work of Jenkins et al. [20] as they examined the impact of viscous fiber ingestion on glucose
tolerance. It is now generally accepted that the GI of a
carbohydrate-containing food is directly correlated to
the viscosity of that food after ingestion. Viscous fibers
increase small intestinal transit time, thus decreasing
the speed of macronutrient digestion and absorption
[14]. Along with changes in absorptive rate, prolonging
the exposure of the enteral mucosa to macronutrients
augments the liberation of anorexigenic peptides. Fat
and protein in the proximal small bowel stimulate the
release of cholecystokinin (CCK), which promotes
acute postprandial satiety. As well, the elevated delivery of carbohydrates to the distal small intestine, stimulate the release of the anorexigenic peptides glucagonlike peptide 1 (GLP-1) and peptide YY (PYY) in a
manner perhaps akin to that which occurs (on a greater
scale) from the malabsorption accompanying gastric
bypass surgery [21, 22•]. These mechanisms tend to
promote satiety between meals and result in a delay
in the onset of hunger.
The ability of a fiber to absorb and hold on to water as it
transits the gut is key factor that contributes to its functional effects. Soluble fibers have the capacity to create a
stable gel that results in stomach volume being occupied
and a sense of satiety created without the addition of
significant calories. This concept has been referred to as
“caloric displacement,” meaning that the consumption of
low-calorie-density food or supplemental fiber can result
in the achievement of satiety with a caloric intake that is
less than if the food consumed was higher in caloric or
energy density.
A food’s energy density consists of the net quantity of
calories in a particular weight of food (usually expressed
as kcal/g). Several strategies have been employed involving the addition of substantial amounts of low-energydensity foods to a meal plan. For instance, consuming a
high-fiber, low-energy-density soup as a “preload” before
the rest of a meal significantly reduces the ad libitum
food intake for that meal while increasing feelings of
satiety [23]. Similarly, consuming a large, low-energydensity salad at the onset or during a meal reduces the
total ad libitum consumption of food for that meal [24••].
Recently, it has been demonstrated that a variety of highfiber vegetables can be added to acceptable foods resulting in a significant decrease in the calorie density of the
food without a negative impact upon the palatability of
the food, even with children [25••]. Consuming functional fiber supplements prior to or with meals can also
reduce the caloric density of meals and promote satiety.
As an example, our research group recently studied the
effect of adding a highly viscous functional fiber supplement (PGX®) to each meal with food, or in liquid meal
replacements in women on a low-calorie diet. In this
double-blind placebo-controlled trial, each 5-g dose of
the highly viscous fiber was estimated to hold approximately 1 L of water in its passage through the stomach
and small intestine, essentially adding 3 L or over 6 lb of
non-caloric food mass to the daily food intake. In this
study we were able to show that the viscous fiber supplement significantly reduced hunger feelings and promoted satiety during a period of significant caloric
reduction (Fig. 1) [26••].
Those who work in the field of obesity management
generally accept the necessity of teaching patients practical strategies that promote the consumption of lowcalorie-density, highly volumetric foods in the dietary
management of overweight and obesity [27••, 28, 29].
Functional fiber supplements may play a significant role
in assisting patients in the achievement of consistent
reductions in the energy density of their diets, especially
during periods of significant caloric reduction.
Curr Obes Rep
Fig. 1 Comparison of pre-dinner mean hunger and prospective consumption scores of day 3 of the 1000-calorie diet supplement with 5 g
of PGX or placebo at each meal. Values are mean±SE (n035). Asterisk
(*) indicates significantly lower scores with PGX than the placebo
supplement (P<0.05). VAS—visual analogue scale
Prebiotic Effects of Fiber
It is increasingly recognized that certain forms of fiber are
fermentable, providing important metabolic substrates in the
metabolism of gut flora. By definition, humans lack the
enzymes specific to digest fiber. In the case of insoluble
fiber, most gut microbes cannot utilize this as an energy
source, and so it is typically excreted without any molecular
alteration other than by forming a surface for the adsorption
of water, organic matter, and cations. Soluble fibers vary in
their fermentability and in the specific microbes that can
utilize them as substrates. The term “prebiotic” was coined
by Gibson and Roberfroid [30, 31] in 1995, and was defined
as an indigestible carbohydrate that is fermentable in the
lower gastrointestinal tract that selectively promotes the
growth of desirable (prebiotic) microflora and is associated
with a positive health outcome. Although there may be
exceptions, prebiotics tend to reduce populations of potentially pathogenic flora while promoting desirable commensals such as Bifidobacteria.
Recent evidence suggested that this effect might play an
important role in both the reduction in adiposity as well as a
decline in the contribution of adipocytes to inflammation. It
has been demonstrated in animal models that prebiotic supplementation might reduce the development of large adipocytes (those that predominate in the visceral compartment),
which are highly involved in the overactivation of a wide
variety of inflammatory processes associated with overeating,
obesity, diabetes, cardiovascular disease, and pain [32, 33].
Pathways of inflammation associated with atopic disease
may also be intimately associated with gut flora. Both probiotics and prebiotics are believed to hold significant promise in the prevention and treatment of allergies and atopic
disorders, such as eczema [34–37], and they may have the
potential to play a significant role in the management of
inflammation as it relates to metabolic syndrome and other
obesity-related comorbidities such as nonalcoholic steatohepatosis [38, 39].
Lack of sufficient intake of prebiotics early in life may
have lasting ill effects on glucoregulation, which may result
in a substantial predilection toward obesity, diabetes, and
cardiovascular disease later in life [40]. Unfortunately, there
is little effort being made to increase fermentable soluble
fiber intake in infants and children. This may have serious
consequences and may be one of the many reasons for the
current obesity epidemic. The food industry has just begun
to respond to this with the introduction of prebiotic-fortified
infant formulas. Because breast milk contains significant
quantities of prebiotic oligosaccharides, adding analogous
agents to infant formulas would help these formulas to more
closely mimic breast milk. This strategy results in a gut flora
predominated by Bifidobacteria, rather than potential pathogens such as Clostridia and Enterobacter that tend to predominate in formula-fed infants [41]. There is now a
growing body of evidence that alterations in gut flora (eg,
a relative absence of Bifidobacteria) are significantly associated with obesity [42]. In this regard, prebiotic fiber supplementation may play a clinically important role in the
promotion of a more desirable gut microbiological milieu.
Neuroendocrine Effects of Fiber
One of the most intriguing and rapidly unfolding discoveries
is related to the role played by dietary fiber in the modulation of important neuroendocrine physiology, which may be
related fundamentally to the etiology of obesity and related
conditions. Of particular interest is the impact of fiber on the
density and activity of a specialized enteroendocrine cell
known as the L cell [43]. The L cell is located throughout
the terminal ileum and colon, and it is responsible for the
secretion of the peptide hormones GLP-1, PYY, and oxyntomodulin [44]. After a meal, oxyntomodulin and PYY are
released synchronously and they both act as potent anorexigens. The rapid rise of these peptides signals a change in
energy status to the brain and it also acts locally to enhance
digestive and metabolic processes. GLP-1 is an incretin
hormone that also plays a pivotal role in glucoregulation
through the stimulation of accurately timed insulin secretion
and suppression of inappropriate glucagon secretion from
the pancreas. It has been established that diminished GLP-1
production plays a central role in the etiology of diabetes, a
discovery that has led to the development of an important
class of diabetes drugs, the incretin analogues. Augmentation of PYY and GLP-1 are thought to play a central role in
the regulation of the “ileal brake.” The ileal brake is a
Curr Obes Rep
feedback mechanism that results in inhibition of proximal
gastrointestinal motility and secretion when nutrients and
nutrient metabolites arrive in sufficient quantities to the
luminal surface of the ileum. Animal and human studies
show that activation of the ileal brake by local perfusion
of the ileum with nutrients increases feelings of satiety and
reduces ad libitum food intake while slowing gastric and
proximal intestinal transit [45].
It has been recently shown that (bariatric) gastric bypass
surgery frequently results in rapid amelioration of diabetes
that often precedes significant weight loss [46]. Current
evidence points to a rapid and sustained increase in circulating GLP-1 and PYY after this procedure that has profound effects on appetite and glucoregulation. It is now
thought that the malabsorption of macronutrients and rapid
gastrointestinal transit after gastric bypass results in an increased delivery of carbohydrates and their fermentation
products (SCFAs) as well as bile acids, both of which
activate L cells via free fatty acid (FFA) receptors and bile
acid receptors [47–51].
It is most interesting that fermentable soluble fiber has the
potential to generate a significant supply of SCFAs that might
mimic, on a lesser scale, the mechanism of gastric bypass
surgery through stimulation of FFA receptors with a resultant
increase in GLP-1 and PYY and augmenting the ileal brake
[52–54]. Viscous soluble fiber also effectively sequesters bile
acids, reducing their usual absorption through the jejunum
and delivering them to the same L cells where they stimulate
bile acid receptors. Thus, viscous soluble fiber that is also
fermentable may exert an appetite-reducing and glucoregulating effect through L-cell activation via both FFA receptors and
bile acid receptors as well as by suppression of the orexigenic
(appetite-stimulating) hormone ghrelin and augmentation of
CCK secretion [55–57].
Sequestration of bile acids by viscous soluble fiber is also
known to be a principle mechanism by which viscous fiber
lowers serum cholesterol, because sequestration of bile
acids decreases the enterohepatic recycling of bile acids, a
major cholesterol reservoir for the human [58].
Effect of Fiber on Postprandial Glycemia
Dietary recommendations for weight management usually include advice regarding the quantity of carbohydrates or the
percentage of daily calories from carbohydrate-containing
foods. A more meaningful recommendation might be based
upon the GI (the quantitative effect of a food on postprandial
glycemia) and the glycemic load (GL; the mathematical product
of the GI and carbohydrate content). The GI of carbohydratecontaining foods has long been known to be directly related to
the quantity and form of dietary fiber in the food [59]. Recently,
it has been verified that the GI and GL are more important
determinants of glycemic and insulinemic response than that of
carbohydrate intake alone [60, 61]. This may have profound
implications in the management of obesity and related conditions. In diabetes, continuous glucose monitoring has
confirmed that GI and GL predict glycemic variability independent from total carbohydrate intake [62].
Low GI-based diets have been shown to promote satiety
and reduce postprandial insulinemia [63]. However, the
evidence in favor of low GI/GL is inconsistent with many
weight loss studies showing only a trend in favor of this
approach [64]. Long-term adherence to a low GI diet may be
part of the problem in some studies. Regular use of viscous
fiber supplements may help obese subjects to consistently
achieve a lower GL while eating a diet that they can reasonably maintain.
Maintenance of weight after weight loss interventions is
an elusive goal that has recently become the focus of several
important studies. The Diogenes (Diet, Obesity, and Genes)
study was designed to assess the efficacy of moderated fat
diets that vary in protein content and GI in the prevention of
weight regain and obesity-related risk factors after weight
loss [65••]. In this trial, the group maintained on the low GI
diet with moderately higher protein (25% of calories from
protein) had the highest compliance, the lowest dropout rate,
and was the only group that did not regain weight by the end
of the 26-week weight maintenance intervention period.
Data from the same study concluded that the low GI diets
also had a more substantial effect on the reduction of inflammation (as evidenced by C-reactive protein) than the
other diet interventions [66]. This finding is in keeping with
other studies pointing to a substantial benefit of dietary fiber
in the reduction of CRP, oxidative stress, and proinflammatory cytokines [67–69].
The consistent addition of functional fiber supplements
to the diet may present a practical means to achieve
meaningful reductions in the GI/GL. Recently, our research group was involved in several studies looking at
the effects of adding a novel, highly viscous functional
fiber supplement (PGX®) to various foods on GI, serum
cholesterol [71], hunger, and satiety in healthy humans
[26••, 71••, 72, 73••, 74, 75]. The novelty of this fiber
relates to its viscosity, which is higher than other fibers
thus studied and the fact that its viscosity slowly evolves
once hydrated. This allows consumption before palatability is significantly affected. This viscous fiber is fermentable and prebiotic [76] and it is tasteless, and disperses
readily when added to food or mixed with beverages. Its
viscosity develops several minutes after initial hydration,
making it easy to consume the small amounts needed to create
a highly viscous and volumetric gastric milieu, leading to its
resultant physiologic effects.
In several studies, we have shown that the GI of food
can be substantially reduced with a small preload or
Curr Obes Rep
intra-meal load of this highly viscous fiber [71••, 72,
73••, 75]. It has also been shown to promote satiety
and reduce subsequent food consumption [25••]. In a
human clinical trial, this novel viscous fiber has been
associated with an increase in the appetite-reducing
hormone PYY [77]. In studies of Zucker diabetic fatty
rats, the effects of diets supplemented with this highly
viscous fiber were compared with other dietary fibers.
Only the diet supplemented with the highly viscous
fiber substantially decreased postprandial blood glucose and insulin secretion, decreased hepatic fatty infiltration, and preserved pancreatic β-cell mass [78].
These effects were accompanied by an increase in the
production of the glucoregulatory incretin hormone
GLP-1 [79].
Recommended Intake of Fiber for Weight Management
The dietary fiber intake for typical Americans is usually
less than desirable, with typical intakes averaging only 14
to 15 g/day and children consuming less than 5 g/day [4].
The American Dietetic Association currently recommends
that healthy adults should consume 20 to 35 g of fiber per
day and children should consume at least 5 g/day plus 1 g
for every year of their age [80]. They point out that
insoluble, nonfermentable, and low-viscosity fiber is principally consumed to promote laxation and other aspects of
colon health, whereas viscous soluble fibers are necessary
to reduce serum cholesterol, blunt postprandial glycemic
response, and promote satiety. A fiber-rich meal, particularly a meal high in viscous, soluble fiber, is processed
more slowly, promoting earlier satiety, and is frequently
less calorically dense and lower in fat and added sugars.
All of these characteristics are typical of a dietary profile
optimized to treat and prevent obesity. In one study, consisting of 252 middle-aged women it was observed that
over a 20-month period participants lost an average of
4.4 lb in association with an 8-g increase in dietary fiber
per 1000 kcal [81]. Likewise, in a prospective cohort
study of nearly 30,000 men, a dose–response relationship
was found between fiber intake and weight gain over a
period of 8 years. They reported that for every 40-g/d
increase in whole-grain intake, weight gain decreased by
1.1 lb. Moreover, the addition of supplemental bran
seemed to play an important role in the reduction of
weight gain by 0.8 lb per 20 g/d intake [82]. Pal et al.
[83••] at Curtin University in Australia demonstrated the
utility of high-dose psyllium given as a premeal supplement (12 g before each of 3 meals) as an adjunct to a
short-term, calorie-reduced weight loss program. Other
studies have demonstrated conflicting results from supplemental fiber in short-term weight management [71, 85].
Conclusions
Most clinicians in the field of obesity medicine agree that
dietary intervention for long-term weight management
should include practical eating strategies that promote and
maintain satiety to improve compliance and to minimize
discomfort in patients working to reduce energy intake. In
this regard, many clinicians now recommend volumetric,
low-calorie-density, low GL diets supplemented with moderate amounts of protein. Increasing the intake of fiber by
consuming more high-fiber foods should play a central role
in this regard. These changes alone may not be sufficient to
bring about long-term weight reduction [85]. Supplementation of the diet with functional fiber supplements may significantly augment high-fiber eating strategies by further
promoting satiety and reducing cardiometabolic risk factors.
Long-term clinical trials looking at the optimal form, quantity, and frequency of dietary fiber supplements are greatly
needed to clarify their potential in the long-term management of obesity.
Disclosure Conflicts of interest: M.R. Lyon: has been a consultant for
Factors Group Inc.; V. Kacinik: is employed by the Canadian Center for
Functional Medicine; and has received grant support, honoraria, and
travel/accommodations expenses covered or reimbursed from Factors
Group Inc.
Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution,
and reproduction in any medium, provided the original author(s) and
the source are credited.
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63. Krog-Mikkelsen I, Sloth B, Dimitrov D, Tetens I, Björck I, Flint A,
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Effects of a 3-month supplementation with a novel soluble highly
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71. •• Brand-Miller JC, Atkinson FS, Gahler RJ, Kacinik V, Lyon MR,
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72. Jenkins AL, Kacinik V, Lyon M, Wolever TM. Effect of adding the
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73. •• Jenkins AL, Kacinik V, Lyon M, Wolever TM. Reduction of
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RA, et al. Effects of the soluble fiber complex PolyGlycopleX on
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79. Grover GJ, Koetzner L, Wicks J, Gahler RJ, Lyon MR, Reimer
RA, et al. Effects of the soluble fiber complex PolyGlycopleX®
(PGX®) on glycemic control, insulin secretion, and GLP-1 levels
in Zucker diabetic rats. Life Sci. 2011;88(9–10):392–9. Epub 2010
Nov 30.
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the usefulness of psyllium supplementation in short-term weight loss.
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Citation: Nutrition and Diabetes (2011) 1, e22; doi:10.1038/nutd.2011.18
& 2011 Macmillan Publishers Limited All rights reserved 2044-4052/11
www.nature.com/nutd
ORIGINAL ARTICLE
Effect of PGX, a novel functional fibre supplement, on
subjective ratings of appetite in overweight and obese
women consuming a 3-day structured, low-calorie diet
V Kacinik1, M Lyon1,2, M Purnama1, RA Reimer3, R Gahler4, TJ Green2 and S Wood2,5
1
Canadian Centre for Functional Medicine, Coquitlam, British Columbia, Canada; 2Faculty of Land and Food Systems and
Food, Nutrition and Health Program, University of British Columbia, Vancouver, British Columbia, Canada; 3Faculty of
Kinesiology and Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada;
4
Factors Group Research & Development, Burnaby, British Columbia, Canada and 5InovoBiologic, Calgary, Alberta, Canada
Introduction: Dietary factors that help control perceived hunger might improve adherence to calorie-reduced diets.
Objectives: The objective of the study was to investigate the effect of supplementing a three-day, low-calorie diet with
PolyGlycopleX (PGX), a highly viscous fibre, on subjective ratings of appetite compared with a placebo.
Methods: In a double-blind crossover design with a 3-week washout, 45 women (aged 38±9 years, body mass index
29.9±2.8 kg m2) were randomised to consume a 1000-kcal per day diet for 3 days, supplemented with 5 g of PGX or placebo
at each of breakfast, lunch and dinner. Subjective appetite was assessed using 100 mm visual analogue scales that were
completed daily before, between and after consumption of meals.
Results: Thirty-five women completed the study. Consumption of PGX compared with placebo led to significantly lower mean
area under the curve for hunger on day 3 (440.4 versus 375.4; P ¼ 0.048), prospective consumption on day 3 (471.0 versus
401.8; P ¼ 0.017) and the overall 3-day average (468.6 versus 420.2; P ¼ 0.026). More specifically, on day 3 PGX significantly
reduced total appetite, hunger, desire to eat and prospective consumption for 2.5 and 4.5 h after lunch and before dinner times,
with hunger also being reduced 2.5 h after dinner (Po0.05).
Conclusion: The results show that adding 5 g of PGX to meals during consumption of a low-calorie diet reduces subjective
ratings of prospective consumption and increases the feelings of satiety, especially during afternoon and evening. This highly
viscous polysaccharide may be a useful adjunct to weight-loss interventions involving significant caloric reductions.
Nutrition and Diabetes (2011) 1, e22; doi:10.1038/nutd.2011.18; published online 12 December 2011
Keywords: viscous; soluble; fibre; appetite; PGX; PolyGlycopleX
Introduction
Obesity increases the risk of type 2 diabetes, cardiovascular
disease and other chronic diseases.1,2 Weight reduction is
associated with significant improvements in blood pressure,
serum cholesterol levels and glycaemic control.3 Achieving
negative energy balance is an important factor in determining the magnitude and rate of weight loss.4 Calorie-restricted
diets, ideally combined with exercise and behaviour modification, are considered to be the initial treatment strategy
for overweight and obese individuals. Low-calorie diets at a
level of 1000–1200 kcal per day for most overweight women
and 1200–1600 kcal per day for most overweight men are
Correspondence: V Kacinik, Canadian Centre for Functional Medicine,
1550 United Boulevard, Coquitlam, British Columbia, Canada V3K6Y2.
E-mail: [email protected]
Received 6 October 2011; accepted 24 October 2011
often recommended for weight loss.5 With low-calorie diets,
maintaining satiety is critical, as perceived hunger has been
shown to be a significant predictor of failure to lose weight.6
After weight loss is achieved, appetite often increases leading
to refractory weight gain.7 Identifying factors that suppress
appetite is important for successful weight loss and maintenance.
Increased fibre intake has been associated with reduced
energy intake and increased satiety, and may be an
important factor in obesity management.8 A meta-analysis
of 22 studies concluded that consumption of 14 g of fibre per
day resulted in a 10% decrease in energy intake and a 1.9-kg
weight loss over 3.8 months.9 Viscous soluble fibres, in
particular, appear to increase satiety10–14 and promote
adherence to calorie-reduced diets.15,16 Accordingly, consuming substantial quantities of viscous dietary fibre may
provide significant therapeutic benefits under conditions of
reduced energy intake. However, as the benefit of these fibres
Novel fibre PGX increases satiety
V Kacinik et al
2
is related to viscosity,17 their acceptance is often hampered
by issues of palatability.18
Recently, PolyGlycopleX (PGX), a novel, highly viscous
non-starch polysaccharide complex has been developed for
human consumption. This soluble dietary fibre displays
delayed viscosity for 15–30 min after ingestion, thus, allowing for a more palatable and easy-to-use functional fibre.
In a recent randomised, placebo-controlled trial, PGX was
shown to diminish hunger and reduce ad libitum food
consumption compared with less viscous fibres (cellulose
and glucomannan) given in meal-replacement drinks.19 The
objective of this study was to investigate the effect of supplementing a three-day low-calorie diet with PGX on subjective
ratings of appetite compared with a placebo in overweight
and obese women.
Subjects
Subjects were recruited through local newspaper advertisements. Women with a body mass index between 25 and
34.9 kg m2 and between 20 and 50 years of age were eligible
to participate. Exclusion criteria included: pregnancy or
lactation, smoking, consumption of more than two alcoholic
drinks daily or nine alcoholic drinks weekly, recent participation in a calorie-reduced diet, the presence of chronic
diseases, past history of gastrointestinal surgery, a change in
body weight of more than 3 kg during the last 3 months,
hypersensitivity to the study foods, taking medication or
natural health products, which may affect gastrointestinal
motility hunger or appetite. Furthermore excluded were
those who scored 9 or more on the restraint scale; 27 or
above for uncontrolled eating, or 18 or greater for emotional
eating on the Three-Factor Eating Questionnaire-R18V2,
validated for Canadian and US obese and non-obese
individuals.20 As lower palatability of foods may diminish
the sensation of hunger and desire to eat,21 a Food Preference
Questionnaire was used to ensure that all the participants
expressed acceptance of the foods included in the study.
Those scoring less than 3 for more than 50% of the food
items were excluded from the study. The University of British
Columbia Research Ethics Committee approved the study
and all subjects gave informed consent to participate.
Study supplements
PGX (a-D-glucurono-a-D-manno-b-D-manno-b-D-gluco), (a-Lgulurono-b-D mannurono), b-D-gluco-b-D-mannan (Inovobiologic, Calgary, Alberta, Canada) is a novel functional
fibre complex22,23 manufactured by a proprietary process
from three fibres (konjac (glucomannan), sodium alginate
and xanthan gum) to form a highly viscous polysaccharide (higher viscosity than any currently known individual
polysaccharide or fibre blend) with high water-holding and
gel-forming properties. PGX has been shown to be safe and
Nutrition and Diabetes
well tolerated in rodents24 and in humans.25 Genotoxicity
studies of PGX have shown no mutagenic effects using
bacterial reverse mutation and mouse micronucleus assays.26
PGX is 87.4% dietary fibre, of which 81.8% is soluble. It can
be sprinkled on food before consumption or taken with soup
or beverage before meals. Rice flour was used as a placebo
and has been used in other clinical trials for its white colour,
neutral taste and hypoallergenicity.27,28 PGX and rice flour
both consist of approximately similar carbohydrate content
with carbohydrate in PGX being dietary fibre and in rice
flour being starch. Boiling or other forms of moist heat
processing is required for rice flour to be effectively digested.
Without cooking, only about 1% of the starch in raw rice
flour is digested.29 Therefore, the carbohydrate in uncooked
rice flour is essentially dietary fibre resulting in rice flour’s
caloric value that closely approximates PGX. Both study
supplements were packaged with clear plastic scoops in
white plastic containers containing 100 g and were indistinguishable from each other.
Study design/protocol
The study was a prospective, randomised, double-blind,
placebo-controlled crossover trial. The study had two
experimental phases with a 3-week washout. Test periods
were on the same days of the week (Tuesday–Thursday) and
were conducted during the follicular phase (days 4–10) of the
women’s menstrual cycle to minimise hormonal influences
on eating/feeding behaviour and appetite.30 On Monday of
the test week, subjects attended the clinic where their
bodyweight was measured, study food was provided and
they were randomised to either the test or placebo supplement. During the test period, subjects consumed the breakfasts, lunches and dinners provided immediately after the
food was sprinkled with 5 g of supplement or placebo.
Participants completed visual analogue scales (VAS) questionnaires at specified times (see below). To avoid a second
meal effect and to minimise differences in glycogen stores,
the night before consumption of the 3-day low-calorie diet,
all subjects consumed the same evening meal. In addition,
participants were instructed not to consume alcohol or
engage in vigorous physical activity 48 h before consuming
the low-calorie diet. On Friday, subjects returned to the clinic
to have their compliance assessed, documents reviewed and
to have any adverse effects recorded. To assess compliance,
subjects kept a log of daily food and study product consumed
and returned the product containers for weighing.
Low-calorie diet
A three-day structured low-calorie diet of 1000 kcal per day
was provided with the intention that caloric restriction
would accentuate feelings of hunger. The low-calorie diet
was designed to provide participants with 65% of energy
as carbohydrate, 10% protein, and 15% fat (Appendix 1).
Commercially available frozen dinner entrees (President’s
V Kacinik et al
3
Choice Blue Menu, Loblaw, Ontario, Canada) were provided
to participants to standardise caloric intake and macronutrient composition.
Subjective appetite measures
Rating subjective appetite using VAS is a valid and reliable
measure of appetite under both experimental and free-living
conditions, especially when using a within-subject design, as
used in the current study.31,32 VAS ratings were made on a
100-mm scale with words anchored at either end in the
following order: first, ‘How strong is your desire to eat?’ (Very
strongFVery weak); second, ‘How hungry do you feel?’ (Not
hungry at allFVery hungry); third, ‘How full do you feel?’
(Very fullFNot at all full); and fourth, ‘How much food do
you think you could eat?’ (A large amount–Nothing at all),
which assesses prospective consumption. The palatability of
the meals was also evaluated after meals by a fifth question
asking ‘How would you rate the overall palatability of the
food? (UnpalatableFVery palatable). The times of rating
were the same every day for both phases; however, to work
with participants at various schedules, different start times in
the morning were available. VAS were completed before
(e.g., 0755 h) and after breakfast (e.g., 0830 h), in between
the morning meals (e.g., 1030 h), before (e.g., 1225 h) and
after (e.g.,1300 h) lunch, in between meals in the afternoon
(e.g., 1500 h, 1700 h), before (e.g., 1725 h) and after (e.g.,
1800 h) dinner and in the evening (e.g., 2000 h). Participants
were provided with programmable alert wrist watches
(CADEX Medication reminder watch, e-pill, LLC., Wellesley,
MA, USA) to remind them when to eat and when to
complete the questionnaires. Participants were allowed
20 min to consume the food, supplement and 500 ml of
water, and were allowed to consume an additional 500 ml of
water between meals. Participants were instructed not to
consume water 30 min before completing premeal VAS. All
food and water consumed during Phase 1 was recorded and
the same amount was provided for Phase 2.
Statistical analyses
Changes in weight over each test period were tested for
differences between treatment groups using the Wilcoxon
rank sum test. For compliance, the P-values of differences
between the two treatment groups within a single period
were calculated from two-sample t-tests; the statistical test
for the summary across both periods of data used a linear
mixed model approach, which took into consideration that
the same participants appeared once on each of the two
treatments (due to the crossover design). For VAS score
analyses, the area under the curve was analysed on the log
scale to meet the distributional assumptions required for the
statistical methods. The treatment effect was estimated from
a linear mixed-effects model to take into consideration the
crossover design of the study; the model was adjusted for
phase, treatment, randomised sequence and a within-patient
comparison was made to assess the treatment effect. With
the different study days expected to give differences in
results, the analysis was carried out by days 1, 2, 3 and on the
mean of days 1–3. To analyse VAS scores by time point, a
similar linear mixed model was used incorporating terms in
the model for treatment, phase, randomised group and time
point, and then contrasts used to compare the treatment
groups at the different time points. Statistical testing of the
adverse event rates by treatment (either overall rates,
treatment-related rates or rates for specific types of adverse
events) was performed using generalised estimating equations logistic regression models. To evaluate whether
there was a carryover effect in the second period by the
randomised sequences, a standard statistical approach by
Jones et al.33 was used to assess. For all statistical tests, the
significance level was set at 0.05. All analyses were performed
using SAS (Version 9.1.3, SAS Institute, Cary, NC, USA).
Results
In total, 51 individuals were recruited for the study of which
45 were randomised (Table 1). After Phase 1, five discontinued from the study. The reasons for withdrawal were
adverse events (n ¼ 2), dislike of the frozen meals offered
(n ¼ 1) and personal reasons unrelated to the study (n ¼ 2).
Overall, 40 participants completed the entire study; however, only 35 participants were included in the per-protocol
analyses as 2 participants deviated from the protocol and
3 reported feeling sick, which might affect subjective
appetite ratings. Compliance was high for both groups, with
107% and 97% for the rice flour and PGX groups,
respectively. There was no carryover effect in the second
period by the randomised sequences.
Weight loss was similar between groups over the two
phases (PGX 1.3 kg versus placebo 1.4 kg; P ¼ 0.376). From
the intent-to-treat analysis (n ¼ 40), the PGX treatment
resulted in a significantly lower mean area under the curve
Table 1
Subject characteristics
Value (range)
Age (years)
Weight (kg)
Body mass index (kg m2)
Waist circumference (cm)
38.6±9.1
79.8±9.3
29.9±2.8
87.0±7.4
Three-factor eating questionnairea
Cognitive
Uncontrolled eating
Emotional eating
7.3±3.1 (4.0–25.0)
21.2±4.6 (5.0–27.0)
14.3±3.8 (7.0–24.0)
(20–50)
(59.4–107.8)
(25.0–34.8)
(73.3–106.0)
Values are mean±s.d.; n ¼ 45. aThe Three-Factor Eating Questionnaire
evaluates some aspects of eating behaviours such as cognitive restraint
(i.e., the voluntary control of eating), the tendency to lose control of food
intake when faced with external cues, mood changes or disruptive events
(i.e., disinhibition) and susceptibility to feelings of hunger. In this study, the
Three-Factor Eating-R18V2 questionnaire was used as a means to exclude
those who have potentially disordered eating motivation and to assess
motivation of the participants eligible for the study.20
V Kacinik et al
4
Discussion
This study demonstrates that adding 5 g of PGX to meals at
the start of a low-calorie diet helps manage appetite by
increasing satiety and decreasing prospective consumption
(the amount one thinks one could eat). This effect was not
statistically significant until day 3; however it resulted in
reductions above 10% compared with the control, a
50
Placebo
PGX
45
Mean VAS score (mm)
on day 3 for prospective consumption (P ¼ 0.018) and a
trend towards significance for hunger (P ¼ 0.059). After
elimination of the protocol deviators (n ¼ 35), a similar
pattern was seen with the differences between groups
stronger with a mean percent change of prospective
consumption at 14.7 (P ¼ 0.017) and hunger at 14.8 on
day 3 (P ¼ 0.048, Table 2). There were no statistical
differences in mean area under the curve for any of the
scores for day 1 or 2, or the mean days 1–3, except for
prospective consumption (P ¼ 0.026). The majority of differences in subjective ratings between the placebo and PGX
groups at various time points were detected on day 3. PGX
supplementation significantly reduced total appetite, desire
to eat, hunger, prospective consumption, and it was
associated with increased fullness at 2.5 h after lunch
(Figure 1); reduced total appetite, desire to eat, hunger and
prospective consumption at 4.5 h after lunch (Figure 2) and
reduced total appetite, hunger and prospective consumption
before dinner (Figure 3). Hunger was also reduced at 2.5 h
after dinner (Po0.05). For palatability, there was a statistically significant difference in mean palatability VAS scores by
treatment for each day (Po0.05), with PGX-supplemented
meals scoring above 50 mm, but 5–10 mm below mean rice
flour scores (data not shown).
Adverse events reported by both treatment groups are
summarised in Table 3. There was no statistical difference
between the two treatment groups in terms of the adverse
events experience of the participants. Furthermore, the
overall or treatment-related adverse events were similar for
the two treatments.
40
*
35
*
30
*
25
20
2.5 hrs post
breakfast
2.5 hrs post
lunch
Hunger
2.5 hrs post
dinner
2.5 hrs post
breakfast
2.5 hrs post
lunch
2.5 hrs post
dinner
Prospective Consumption
Figure 1 Comparison of 2.5 h post breakfast, lunch and dinner mean
hunger and prospective consumption scores of day 3 of the 1000-kcal calorie
diet supplement with either 5 g of PGX or placebo at each meal. Values shown
are mean±s.e. (n ¼ 35). *Significantly lower scores with PGX than with the
placebo supplement (Po0.05).
Table 2 Daily and 3-day average comparison of subjective appetite measurements calculated as mean area under the curve in response to placebo or PGX for the
per-protocol subject group
Score
Day
Placebo
PGX
% Change
P-value
Prospective consumption
1
2
3
Average days 1–3
457.2±29.4
477.9±33.1
471±32.5
468.6±28.9
432.5±27.8
427.1±29.6
401.8±27.7
420.2±25.9
5.4
10.6
14.7
10.3
0.358
0.079
0.017
0.026
Desire
1
2
3
Average days 1–3
432.5±29.4
456.3 ±34.2
427.7±35
438.6±29.7
428.8±29.1
416.9±31.3
387.9±31.7
410.8±27.8
0.9
8.6
9.3
6.3
0.894
0.273
0.280
0.303
Fullness
1
2
3
Average days 1–3
598.3±40.3
584.5±50.7
614.1±47.2
598.8±43.8
591.6±39.9
574.5±49.8
632.3±48.6
599±43.9
1.1
1.7
3
0
0.832
0.785
0.592
0.996
Hunger
1
2
3
Average days 1–3
431.5±28.6
434.9±33.6
440.4±32.9
435.6±28.4
418.3±27.7
407.6±31.5
375.4±28
400±26.1
3.1
6.3
14.8
8.2
0.651
0.429
0.048
0.162
Total appetite
1
2
3
Average days 1–3
469.8±27.3
475.9±31.8
464.5±31.9
470±27.9
458.7±26.7
449.4±30.0
414.3±28.4
440.4±26.2
2.4
5.6
10.8
6.3
0.675
0.390
0.106
0.215
Abbreviation: PGX, PolyGlycopleX. Note: P-value is from a linear mixed-model fit on log scale of area under curve and adjusting for potential sequence and period
effects in addition to treatment (significance level Po0.05). Values shown are mean±s.e.; n ¼ 35.
V Kacinik et al
5
80
Placebo
PGX
Mean VAS score (mm)
75
70
*
*
65
60
55
50
4.5 hrs post lunch
Hunger
4.5 hrs post lunch
Figure 2 Comparison of the 4.5 h post lunch mean hunger and prospective
consumption scores of day 3 of the 1000-kcal calorie diet supplement with
either 5 g of PGX or placebo at each meal. Values shown are mean±s.e.
(n ¼ 35). *Significantly lower scores with PGX than with the placebo
supplement (Po0.05).
90
Placebo
PGX
Mean VAS scores (mm)
85
80
*
75
*
70
65
60
55
Pre Dinner
Hunger
Pre Dinner
Figure 3 Comparison of predinner mean hunger and prospective
consumption scores of day 3 of the 1000-kcal calorie diet supplement with
either 5 g of PGX or placebo at each meal. Values shown are mean±s.e.
(n ¼ 35). *Significantly lower scores with PGX than with the placebo
supplement (Po0.05).
magnitude which is considered to be of practical relevance.32
With respect to time of day, PGX was found to exert its
strongest effects in the afternoon and in the evening, reducing
total appetite, hunger, desire to eat and prospective consumption. These results might be particularly helpful in managing
obesity, given reports that food intake tends to be less in the
morning and greater in the afternoon and highly evening in
obese versus normal weight individuals.34 One explanation for
the effect seen with PGX on day 3 could be the increased fibre
load. This particular test day had 7 g more dietary fibre and 9–
10 g less protein than on day 1 or 2, resulting in a possible
synergistic effect and interaction between the PGX and the
dietary fibre content of the meals. Another possibility may be
the cumulative effects of PGX over time with the potential for
upregulation of gut-satiety hormone gene expression (such as
proglucagon) via fermentation and production of short-chain
fatty acids in the large bowel.35
Soluble fibres that are fermentable by gut microbiota and
produce significant quantities of short-chain fatty acids may
contribute to appetite regulation by stimulating the release
of gut-satiety hormones such as peptide YY (PYY) and
glucagon like peptide-1.36 In a study using Zucker diabetic
rats, PGX consumption was associated with a significant
increase in glucagon like peptide-1 levels.37 In a 3-week
human tolerance trial, supplementation of regular diets with
10 g of PGX per day was associated with higher fasting PYY
levels than placebo control.38 It has been reported that obese
individuals have lower fasting and postprandial circulating
PYY levels than lean individuals,39,40 which may result in
impaired satiety and may contribute to the development of
obesity and may hinder weight loss efforts. To produce an
equivalent stimulation of PYY sufficient to promote satiety,
obese individuals need to consume a much greater caloric
load than their lean counterparts.39 An alternative to a
greater caloric load could be a volumetric, lower energy
dense load from supplementing a meal with PGX to
augment PYY levels and stimulate satiety. Further investigation of a low-calorie diet supplemented with PGX on
gut-satiety hormones is thus warranted.
Under conditions of fixed energy intake, such as a lowcalorie diet, viscous soluble fibres may also alter the viscosity
of gastrointestinal content resulting in multiple effects on
satiety. A magnetic resonance imaging study by Marciani
et al.41 showed that a high-viscosity nutrient meal had the
strongest additive effect in gastric distension and delayed
gastric emptying compared with low-viscosity non-nutrient,
low-viscosity nutrient and high-viscosity non-nutrient
meals. Viscous soluble fibres also delay the absorption of
nutrients by thickening the unstirred layer at the gut
mucosal surface. This results in the transport of larger
amounts of nutrients to the ileum and/or distributes
nutrient absorption over a larger intestinal luminal surface
area, leading to a more pronounced inhibitory feedback from
the distal gut and activation of the ileal brake.42 Other
mediators of the ileal brake include the gut-satiety hormones
PYY and glucagon like peptide-1 and vagal nerve stimulation.43 The ileal brake is a distal to proximal negative
feedback mechanism that inhibits gastric emptying, proximal gastrointestinal motility and secretion to control the
transit of a meal through the gastrointestinal tract, which
consequently optimises nutrient digestion and absorption.44
As a highly viscous soluble fibre, PGX may cause a delay in
gastric emptying and/or prolong the transport of nutrients
down the gastrointestinal tract as demonstrated by previous
research on its effects on the glycaemic index (GI). The GI is
a property of carbohydrate-containing food that describes
the rise of blood glucose occurring after a meal. High GI
V Kacinik et al
6
Table 3
Summary of the adverse events (AEs) by treatment allocation
Variable
Number of participants
Participants reporting adverse events
Total adverse events
Participants reporting treatment-related events
Total treatment-related Events
Placebo
PGX
38
13 (34.2%)
25
8 (21.1%)
19
42
12 (28.6%)
28
11 (26.2%)
24
Total adverse events (by severity)
Unknown severity
Mild
Moderate
Severe
0
5
13
7
0
2
21
5
Total treatment-related events (by severity)
Unknown Severity
Mild
Moderate
Severe
0
4
9
6
0
2
18
4
Participants reporting AEs by type of AE
Constipation
Diarrhea
Bloating
Flatulence
Headache
Cramping
Sick/unwell
Other
3
0
4
0
4
3
4
3
(7.9%)
(0.0%)
(10.5%)
(0.0%)
(10.5%)
(7.9%)
(10.5%)
(7.9%)
1
3
8
2
1
3
1
7
(2.4%)
(7.1%)
(19%)
(4.8%)
(2.4%)
(7.1%)
(2.4%)
(16.7%)
P-value
0.7
0.34
0.15
NA
0.07
NA
0.17
0.59
0.08
0.06
Abbreviation: PGX, PolyGlycopleX. Parentheses denote the percentage from the total number of participants. Some P-values were not possible to compute due to no
events being reported under one of the treatment groups. These are noted as ‘NA’ in the table.
foods are classified as being rapidly digested and absorbed
into the bloodstream, resulting in a sharp rise and in a steep
decline of blood glucose after consumption, whereas low GI
foods are broken down more slowly by a slower rate of
digestion and absorption and releasing glucose more gradually into the bloodstream.45 When 2.5–5 g of PGX was
sprinkled on high and moderate GI foods, it was consistently
shown to be highly effective in significantly reducing their
glycaemic index.45,46 Influencing the digestive rate of foods
and their blood glucose response may have an important
effect on the perception of satiety. Arumugam et al.47
examined the effects of high-GI versus low-GI meals on
subjective satiety in overweight and obese women. They
found that the appetite score was 35% higher at 4 h after the
high-glycaemic versus low glycaemic breakfast, and that at 3,
4 and 5 h after lunch, the appetite score was 30–44% higher
in the high glycaemic condition.47 Many other short-term
studies (o1 day) have also reported a significant relationship
between the glycaemic response and satiety using foods with
varying glycaemic indices.48–51 In the present study, the
frozen meals were chosen to represent the average Western
diet with convenient, processed higher GI foods and as such
the effect of PGX supplementation on the study foods’
glycaemic indices might be related to the 28%, 14%, 12%
reduction of total appetite score at 2.5, 4.5, 5 h, respectively,
after consuming the lunch on day 3. If however the study
foods had a low GI, PGX may not have exerted as significant
an effect on satiety.
This study was designed to alleviate some potentially
confounding variables in appetite research. The timing of the
test phases was scheduled according to participants’ menstrual
cycle, given that previous research has linked changes in
gastrointestinal function, appetite and energy intake to the
follicular and luteal phases of menstruation.30 The energy
intake, macronutrient composition, water consumption and
eating schedule for all the meals over the three-diet days were
controlled, demonstrating the effect of PGX on homeostatic
hunger (physiological). Although the effect of PGX on
ad libitum food intake cannot be concluded, prior research
has shown that subjective ratings of appetite appear to be good
indicators of motivation to eat and are predictors of actual food
intake.31,52,53 However, it should also be mentioned that
appetite ratings have not always been found to correlate with
ad libitum food intake,10 as many factors influence food intake,
including sensory hedonics, external factors, cognitive issues,
body weight, genes and so on.54–56
To minimise the effect of palatability on appetite ratings,
women who rated the palatability of the meals low were
excluded. However, a significant difference in palatability
between meals supplemented with PGX and rice flour was
observed on all of the three-diet days. Previous research with
PGX has not found any significant differences in palatability
scores in comparisons with controls.19,45 Study participants
were advised to sprinkle PGX granules as they ate; however,
the hot microwaved meals for lunch and dinner more than
likely accelerated viscosity development, thereby affecting
texture and palatability. This difference may be related more
to texture than to any gastrointestinal discomforts experienced with PGX, as there was no statistical difference in
adverse events reported between PGX and rice flour.
Although palatability affects appetite,57,58 this did not
translate into significant differences in subjective appetite
V Kacinik et al
7
scores for days 1 and 2, suggesting that the difference
observed on day 3 may have not been due to the palatability
of the PGX-supplemented meal. When designing placebocontrolled trials with PGX, it is difficult to find a comparable
inert substance and completely avoid any potentially
confounding effect. Uncooked rice flour was found to closely
approximate PGX in terms of flavour and texture, and it was
thus judged to be a suitable placebo. However, the presence
of resistant starches may have produced an increase in
fermentation in the control group and dampened the
difference in results between the two interventions.
As an initial investigation, this study was performed over 3
days because of the number of VAS questionnaires dispensed
and strict adherence required for the food and meal
schedule. It was conducted under free-living conditions so
as to mimic people following a structured low-calorie diet in
their regular lives. However, this inherently introduced some
variability in the participants’ environment, occupational
and non-occupational activities, which could have resulted
in diurnal variations in appetite.59 Furthermore, the diet
during the two test phases was self-administered and even
though compliance of the study supplements was high, the
possibility of noncompliance with the prescribed diets could
not be completely avoided.
In summary, this study indicates that the supplementation
of highly viscous PGX to meals could be a useful weight
management aid during a low-calorie diet to help lessen
feelings of hunger and to moderate food portions. Weight
relapse after consuming a low-calorie diet is a common
outcome of obesity interventions. Therefore, long-term studies
investigating the effects of PGX on subjective appetite and the
maintenance of reduced body weight would be warranted. In
addition, it would be useful to examine the effects of PGX on
biomarkers such as glucagon like peptide-1, PYY and ghrelin to
better understand some of the physiological influences of PGX
on satiety. By virtue of its multiple physiological effects on the
mechanisms of satiety, PGX may be an effective weightmanagement aid for low-calorie diets.
Conflict of interest
VK and MP are employees of the Canadian Centre for
Functional Medicine where the study took place. ML is a
consultant to the parent company of the sponsor. TG, RAR
and SW receive consulting fees from InovoBiologic. RG is the
owner of the Factors Group of Nutritional Companies and
retains an interest in PGX. PGX, PolyGlycopleX are trademarks of InovoBiologic. All other marks are the property of
their respective owners.
Acknowledgements
We wish to thank the efforts of Ms Tracey Wood and
Ms Suzana Damjanovic, whose support and organisational
expertise were invaluable during the completion of this
study, and Dr Natalie Kacinik for editorial assistance in
the completion of this manuscript. We would also like to
acknowledge support of the study and supply of PGX by
InovoBiologic.
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This work is licensed under the Creative
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V Kacinik et al
9
Appendix 1
The nutritional composition of the three-day low calorie diet
Quantity
Day 1
Breakfast
Blue Menu granola cereal
Milk 2%
Tea or Coffee brewed
Lunch
Blue Menu Chicken Bangkok
Juice, Orange
Dinner
Blue Menu Chinese Sweet & Sour Chicken
Marble cheese stick
Day 2
Breakfast
Maple Brown Sugar Oatmeal
Milk 2%
Lunch
Blue Menu Ginger Glazed Chicken
Blue Menu Multigrain Pretzels
Dinner
Blue Menu Thai Sweet Chili Lemon Grass
Chicken
Marble cheese stick
Day 3
Breakfast
Blue Menu Oatmeal Bagel
Blue Menu Old-Fashioned Peanut Butter
Banana, fresh, medium
Lunch
Blue Menu Roasted Vegetable Lasagna
Banana, fresh, medium
Carrots, baby, fresh
Dinner
Blue Menu Indian Butter Chicken
Orange, medium
Calories
Carbohydrate (g)
Fibre (g)
Protein (g)
Fat(g)
1004
244
165
77
2
340
230
110
420
350
70
156
38
30
7
0.7
58
32
26
60
60
0
7
55
8
3
5
0
20
19
2
27
22
5
16
5
2
3
0
3
3
0
8
2
6
157
41
33
7
0.7
57
32
25
59
59
7
1 pkg
1002
249
170
77
2
333
220
113
420
350
54
9
4
5
0
22
19
3
23
18
15
2
2
0
0
2
2
0.3
11
5
1 piece
70
0
5
6
1005
246
160
33
2
53
346
240
53
53
413
370
43
166
45
30
1
0.7
13
58
33
13
12
63
52
11
45
9
7
1
0
1
14
12
1
1
22
21
1
20
5
2
3
0
0.2
6
6
0.2
0
9
9
0
0.5 cup
150 ml
1 cup
1 pkg
1 cup
1 pkg
1
1 pkg
150 ml
1 cup
1 pkg
30 g
1
1 tsp
1 cup
1/2
1 pkg
1/2
1 cup
1 pkg
0.5
3
2
2
3
2
1
1
14
5
0.3
1.5
3
1.5
2.5
2
2
Abbreviations: pkg, package; tsp, teaspoon.
The Journal of Nutrition. First published ahead of print August 22, 2012 as doi: 10.3945/jn.112.163204.
The Journal of Nutrition
Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions
Sitagliptin Reduces Hyperglycemia and
Increases Satiety Hormone Secretion More
Effectively When Used with a Novel
Polysaccharide in Obese Zucker Rats1–3
Raylene A. Reimer,4,5* Gary J. Grover,6,7 Lee Koetzner,6 Roland J. Gahler,8 Prateek Juneja,9,10
Michael R. Lyon,9,10 and Simon Wood8,10
Abstract
The novel polysaccharide (NPS) PolyGlycopleX (PGX) has been shown to reduce glycemia. Pharmacological treatment
with sitagliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor, also reduces glycemia by increasing glucagon-like peptide-1
(GLP-1). Our objective was to determine if using NPS in combination with sitagliptin reduces hyperglycemia in Zucker
diabetic fatty (ZDF) rats more so than either treatment alone. Male ZDF rats were randomized to: 1) cellulose/vehicle
[control (C)]; 2) NPS (5% wt:wt)/vehicle (NPS); 3) cellulose/sitagliptin [10 mg/(kg d) (S)]; or 4) NPS (5%) + S [10 mg/(kg d)
(NPS+S)]. Glucose tolerance, adiposity, satiety hormones, and mechanisms related to DPP4 activity and hepatic and
pancreatic histology were examined. A clinically relevant reduction in hyperglycemia occurred in the rats treated with
NPS+S (P = 0.001) compared with NPS and S alone. Blood glucose, measured weekly in fed and feed-deprived rats and
during an oral glucose tolerance test, was lower in the NPS+S group compared with all other groups (all P = 0.001). At
wk 6, glycated hemoglobin was lower in the NPS+S group than in the C and S (P = 0.001) and NPS (P = 0.06) groups. PGX
(P = 0.001) and S (P = 0.014) contributed to increased lean mass. Active GLP-1 was increased by S (P = 0.001) and GIP was
increased by NPS (P = 0.001). Plasma DPP4 activity was lower in the NPS+S and S groups than in the NPS and C groups
(P = 0.007). Insulin secretion and b-cell mass was increased with NPS (P < 0.05). NPS alone reduced LDL cholesterol and
hepatic steatosis (P < 0.01). Independently, NPS and S improve several metabolic outcomes in ZDF rats, but combined,
their ability to markedly reduce glycemia suggests they may be a promising dietary/pharmacological co-therapy for type
2 diabetes management.
J. Nutr. doi: 10.3945/jn.112.163204.
Introduction
The health and economic toll of obesity continues to rise,
seemingly unabated, worldwide (1). There are currently an
estimated 1.5 billion overweight and obese individuals globally
(2). The NIH has recommended that combined lifestyle and
1
Supported by InovoBiologic Inc., Calgary, Canada.
Author disclosures: R. A. Reimer receives consulting fees from InovoBiologic
Inc. and received financial support for the preparation of this manuscript. G. J.
Grover and L. Koetzner received funding from InovoBiologic Inc to perform this
study and have no financial interest in PGX. R. J. Gahler is the owner of the
Factors Group of Nutritional Companies, which retains an interest in PGX. M. R.
Lyon receives consulting fees from the Factors Group of Companies and has no
financial interest in PGX. P. Juneja was an employee of Canadian Centre of
Functional Medicine. S. Wood receives consulting fees from InovoBiologic Inc
and has no financial interest in PGX.
3
Supplemental Table 1 and Figure 1 are available from the ‘‘Online Supporting
Material’’ link in the online posting of the article and from the same link in the
online table of contents at http://jn.nutrition.org.
* To whom correspondence should be addressed. E-mail: [email protected].
2
pharmacological therapy be used for all obese individuals or
overweight individuals with at least one co-morbidity (3). There
are currently a limited number of dietary and pharmacological
co-therapies that have been sufficiently evaluated to move this
recommendation forward.
Sitagliptin (S)10 is an oral antidiabetic medication that blocks
dipeptidyl peptidase 4 (DPP4), the enzyme responsible for the
rapid degradation of active glucagon-like peptide-1 (GLP-1) (4).
10
Abbreviations used: AST, alanine aminotransferase; C, control; DPP4, dipeptidyl
peptidase 4; GIP, glucose-dependent insulinotropic polypeptide; GIPr, glucosedependent insulinotropic polypeptide receptor; GLP-1, glucagon-like peptide 1;
HbA1c, glycated hemoglobin; InsAUC15:GluAUC20, ratio of insulin AUC:glucose
AUC from 0 to 15 min of the oral glucose tolerance test; InsAUC30:GluAUC30, ratio
of insulin AUC:glucose AUC from 0 to 30 min of the oral glucose tolerance test;
InsAUC120:GluAUC120, ratio of insulin AUC:glucose AUC from 0 to 120 min of the
oral glucose tolerance test; NPS, novel polysaccharide; OGTT, oral glucose
tolerance test; PGX, PolyGlycopleX; PYY, peptide tyrosine tyrosine; S, sitagliptin;
WAT, white adipose tissue; ZDF, Zucker diabetic fatty.
ã 2012 American Society for Nutrition.
Manuscript received April 17, 2012. Initial review completed June 3, 2012. Revision accepted July 19, 2012.
doi: 10.3945/jn.112.163204.
Copyright (C) 2012 by the American Society for Nutrition
1 of 9
Downloaded from jn.nutrition.org at UNIVERSITY OF CALGARY on August 22, 2012
4
Faculty of Kinesiology, and 5Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Calgary, Calgary,
AB, Canada; 6Department of Pharmacology, Product Safety Labs, Dayton, NJ; 7Department of Physiology and Biophysics, Robert Wood
Johnson Medical School, Piscataway, NJ; 8Factors Group of Nutritional Companies Inc. R and D, Burnaby, BC, Canada; 9Canadian
Centre for Functional Medicine, Coquitlam, BC, Canada; and 10University of British Columbia, Food, Nutrition and Health Program,
Vancouver, BC, Canada
collected. S was administered prior to the baseline blood draw. A 1-g/kg
dose of glucose was given via oral gavage and subsequent blood samples
collected via tail nick at 10, 20, 30, 60, and 120 min. Blood glucose
concentrations were immediately determined with a glucometer. A
second and separate oral glucose tolerance test (OGTT) was performed
for satiety hormone analysis on the final day of the study. Following
overnight feed deprivation and morning S administration, a baseline
blood sample was collected. Glucose (2 g/kg) was given via gavage and
subsequent blood samples taken at 15, 30, 60, and 90 min via tail nick.
Blood was collected with the addition of diprotinin-A (0.034 g/L blood;
MP Biomedicals), Sigma protease inhibitor (1 g/L blood; Sigma Aldrich),
and Roche Pefabloc (1 g/L of blood; Roche). Plasma was stored at –80°C
until later analysis. To assess the increment in insulin secretion triggered
by an increment in plasma glucose (termed the insulinogenic index), we
calculated insulin response for the early and total secretory phases as
follows: the ratio of insulin AUC:glucose AUC from 0 to 15 min of the
OGTT (InsAUC15 : GluAUC20) (correlates with early-phase insulin
release during the OGTT) and the ratio of insulin AUC : glucose AUC
from 0 to 120 min of the OGTT (InsAUC120 : GluAUC120) (correlates
with second-phase and total insulin release during the OGTT). In a
human validation study (23), InsAUC30 : GluAUC30 was highly correlated with first-phase insulin secretion. In rodents, however, peak insulin
secretion occurs between 10 and 20 min (24) and insulin secretion at
15 min was therefore used for calculations. The composite insulin
sensitivity index (CISI), which takes into account glucose excursion and
AUC, was also calculated as previously described (17). Higher scores
represent improved insulin sensitivity.
Methods
Tissue collection and necropsy. At the termination of the study,
following overnight feed deprivation and regular S treatment in the
morning, rats were overanesthetized with isoflurane and a blood sample
was collected via cardiac puncture. A section of the distal ileum, one
kidney, and one liver lobe were snap-frozen for later DPP4 mRNA
analysis. The pancreas and one liver lobe were fixed in 10% neutral
buffered formalin for later processing. One liver lobe was snap-frozen
for determination of lipid content with Sudan Black staining. The
pancreas was transferred to 70% ethanol after 24 h. Tissues were
processed and embedded in paraffin. The liver was sectioned (5 mm) and
stained with hematoxylin and eosin or immunohistochemically stained
with a mouse antibody against rat insulin (1:300, Cell Signaling
Technology) according to previous work (26). The histopathology
scoring was: 0, within normal limits; 1, minimal; 2, mild; 3, moderate; 4,
marked; and 5, severe.
Rats and treatments. Ethical approval for the experimental protocol
was granted by the Eurofins Institutional Animal Use and Care
Committee and all procedures conformed to the Guide for Care and
Use of Laboratory Animals. Forty-four male ZDF/Crl-Leprfa/fa rats
(ZDF) were obtained from Charles River at 9 wk of age and individually
housed in a temperature- (18–22°C) and humidity-controlled (44–68%)
room with a 12-h-light/-dark cycle. Water and feed were provided ad
libitum. Male ZDF rats were selected as representing a good model of
obesity with comorbid type 2 diabetes and reduced insulin sensitivity
(20,21). Following 4 d of acclimation, rats were randomly assigned
to 1 of 4 groups: 1) control [cellulose fiber/vehicle (C)]; 2) NPS [5%
wt : wt/vehicle (NPS)]; 3) cellulose/S [10 mg/(kg d) via oral gavage (S)];
or 4) NPS (5%) + S [10 mg/(kg d) (NPS+S)]. There were n = 11 rats/
group. The NPS was PGX (InovoBiologic). NPS was shipped to Research
Diets for incorporation into a high-fat rodent diet (D12451) at 5%
wt : wt (Supplemental Table 1). Cellulose was selected as the insoluble
reference fiber that is considered to be inert (22). S phosphate
monohydrate (JANUVIA, Merck and Co) was obtained by prescription
at a pharmacy in Dayton, NJ and prepared in water and given daily by
gavage (10 mg/kg) in the morning.
Continuous study measures. Body weight was measured once each
week. Food intake, accounting for spillage, was measured 3 times/wk.
Blood glucose was measured weekly using a Bayer Ascensia Elite
Glucometer (Bayer Health Care). The blood was collected via tail nick
following S administration: one sample when food was present for the
previous 24 h and one sample was collected on another day when food
was not available overnight (16 h feed deprived).
Oral glucose tolerance tests. Three days before the end of the study
and following 16 h of feed deprivation, a baseline blood sample was
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Reimer et al.
Lipid determination, plasma DPP4 activity, and clinical chemistry.
At the termination of the study, a blood sample was collected via retroorbital bleed under isoflurane anesthesia. Serum was analyzed for lipid
concentrations (total, LDL, HDL cholesterol, and TG) using an analyzer
(Polymer Technology Systems CardioChek). DPP4 activity in plasma
was measured according to Kirino et al. (25). A clinical chemistry
panel was analyzed in plasma, including blood urea nitrogen, glucose,
electrolytes, creatinine, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase (AST), and bilirubin (direct + indirect).
Biochemical analysis. A Rat Gut Hormone Multiplex kit (Millipore)
was used to measure insulin, active GLP-1, active amylin, active ghrelin,
leptin, total PYY, and total GIP according to our previous work (27,28).
Glycated hemoglobin (HbA1c) was measured in blood using a clinical
analyzer (Bayer DCA 2000).
Statistical analysis. All data are presented as mean 6 SEM. A 2-way
ANOVA was used to determine the main effects of diet (NPS vs.
cellulose) and drug (S vs. vehicle) and their interaction. When a
significant interaction effect was identified, a 1-way ANOVA with
TukeyÕs multiple comparison post hoc test was used to identify
differences between groups. For parameters where repeated measurements were taken over time (i.e., body weight, glucose, HbA1c, and
satiety hormones), a 2-way repeated-measure ANOVA was performed
with between-subject factor (treatment of 4 levels) and within-subject
factor (time). Noninterval data (e.g., histology scores) were analyzed by
In addition to exerting potent insulinotropic activity, GLP-1 also
reduces food intake, suppresses glucagon secretion, slows gastric
emptying, and stimulates b-cell regeneration (5). DPP4 inhibitors are orally active and can inhibit >90% of plasma DPP4
activity over a 24-h period (6). Inhibition of DPP4 improves
insulin sensitivity and results in reduced blood glucose concentrations (7,8). S specifically has been approved by the FDA,
Health Canada, and the European Commission as a single
therapy for the treatment of diabetes and it can be effectively
combined with metformin or glitazone (9,10).
Dietary fibers have numerous health benefits, including
lowering plasma cholesterol levels, reducing hyperglycemia,
enhancing the secretion of satiety hormones, and improving
bowel function (11). Some dietary fibers enhance the secretion of
GLP-1 and another anorexigenic gut hormone, peptide YY
(PYY) (12–16). We have previously shown that the highly
viscous functional fiber, PolyGlycopleX (PGX) (a-D-glucuronoa-D-manno-b-D-manno-b-D-gluco a-L-gulurono-b-D mannurono,
b-D-gluco-b-D-mannan; InovoBiologic) novel polysaccharide
(NPS) reduces hyperglycemia and increases GLP-1 secretion
in obese Zucker diabetic fatty (ZDF) rats (17). We have also
demonstrated that NPS increases the anorexigenic hormone PYY
in healthy humans (18) and it decreases hunger and promotes
satiety in obese humans undergoing a low-energy diet regime (19).
Whether or not combining the glycemia-lowering actions of NPS
with the known GLP-1–protective and hypoglycemic actions of
sitagliptin improves glucose tolerance in rats is not known.
Our objective was to determine the effects of the combined
treatment of NPS with S on glucose tolerance in obese ZDF rats.
Secondary outcomes were measured to gain insight into the
mechanisms of NPS and S actions and included body composition, satiety hormone secretion, pancreatic islet and liver
histology, and DPP4 activity.
Kruskal Wallis test and DunnÕs multiple comparison test. Significance
was set at P < 0.05.
Results
Glycemic response. Both time (P = 0.001) and treatment (P =
0.001) and their interaction (P = 0.001) affected blood glucose
concentrations measured weekly in feed-deprived rats (Fig. 1A).
Rats treated with NPS+S had lower blood glucose than all other
groups at 6 wk (P < 0.01) [lower than C and S at 3, 4, and 5 wk
(P < 0.02) and lower than C at every week after baseline (P <
0.003)]. Given that NPS is highly viscous and affects intestinal
glucose absorption when present in the lumen, we also measured
blood glucose concentrations in fed rats once each week. Both
time (P = 0.001) and treatment (P = 0.001) and their interaction
(P = 0.001) affected blood glucose concentrations in the fed state
(Fig. 1B). At 4, 5, and 6 wk, the NPS+S rats had lower blood
glucose than all other groups (P < 0.002). From 2 wk onwards,
rats treated with NPS+S had lower blood glucose than the C and
S rats (P = 0.01). Similarly, there was an effect of time (P = 0.001)
and treatment (P = 0.001) and their interaction (P = 0.001) for
repeated HbA1c measurements (Fig. 1C). At 3 wk, the NPS+S
rats had lower HbA1c than C rats (P = 0.01) and at 6 wk, the
NPS+S group was lower than C and S groups (P = 0.001) and
showed a trend to be lower than the NPS group (P = 0.06).
Interactive effects on glucose and satiety hormones
during OGTT. There was an effect of time (P < 0.01) for all
satiety hormones at the final OGTT except ghrelin (Fig. 2).
Treatment influenced insulin secretion (P = 0.038) such that the
NPS group was higher than the C group (P = 0.049) (Fig. 2A).
Treatment (P = 0.001) and its interaction with time (P = 0.001)
Surrogate indexes of first-phase and total insulin secretion and insulin sensitivity. Given that the b-cell responds
to increments in plasma glucose concentration with an increment in plasma insulin secretion (29), we calculated the
insulin response for both the early (0–15 min) and total secretory
phases (0–120 min). Both the InsAUC15 : GluAUC20 and
InsAUC120 : GluAUC120 ratios were increased by NPS (P =
0.001) but not S (P = 0.3) or their interaction (P = 0.9) (Table 2).
The CISI scores did not significantly differ among the groups
(Table 2).
Changes in DPP4 activity. DPP4 activity in the plasma was
affected by NPS (P = 0.001), S (P = 0.001), and their interaction
(P = 0.007) (Fig. 3). C had higher plasma DPP4 activity than all
other groups (P = 0.001). In the liver, DPP4 activity was reduced
TABLE 1 Energy intake and body composition of obese ZDF rats treated with NPS, S, both,
or neither for 6 wk1
Two-way ANOVA P values
Treatment
Food intake, g/d
Final body weight, g
Total weight change, g
Fat mass, g
Lean mass, g
Percent fat, %
Bone mineral density, g/cm3
C
NPS
S
NPS+S
Diet
Drug
Diet 3 drug
26 6 0.5
405 6 17.4
106 6 13.8
218 6 13.3
113 6 3.5
53.5 6 1.14
0.167 6 0.001
20 6 0.6
431 6 9.60
128 6 7.10
228 6 9.1
130 6 3.84
52.7 6 1.28
0.168 6 0.002
23 6 0.7
411 6 16.1
111 6 12.5
213 6 9.81
123 6 5.40
51.8 6 0.92
0.169 6 0.003
18 6 0.5
441 6 5.32
139 6 4.21
224 6 7.83
142 6 4.02
50.8 6 1.39
0.169 6 0.003
0.001
0.027
0.011
0.29
0.001
0.48
0.83
0.001
0.52
0.36
0.67
0.014
0.15
0.54
0.23
0.88
0.78
0.97
0.92
0.94
0.70
1
Values are means 6 SEM, n = 8–11. C, control; NPS, novel polysaccharide; NPS+S; novel polysaccharide and sitagliptin; S, sitagliptin;
ZDF, Zucker diabetic fatty.
Novel polysaccharide and sitagliptin co-therapy
3 of 9
NPS and S effects on food intake and body weight. Both
NPS (P = 0.001) and S (P = 0.001) contributed to changes in food
intake (Table 1). Rats fed NPS had 20% lower food intake than
those fed cellulose and rats given S had 11% lower food intake
than vehicle. Body weight increased with time (P = 0.001)
(Supplemental Fig. 1). Diet affected final body weight (P =
0.027) and weight gain (P = 0.011), with rats fed NPS having
greater overall weight gain and higher final body weight (Table
1). Lean mass was influenced by NPS (P = 0.001) and S (P =
0.014), with greater lean mass in rats treated with NPS
compared with those treated with cellulose and in rats treated
with S compared with vehicle. Fat mass (expressed as grams or
percentage of body fat) and bone mineral density did not
significantly differ between groups.
affected GIP during the OGTT (Fig. 2B). At 15, 30, and 60 min,
the NPS group had higher GIP than all other groups (P < 0.04).
At 15 min, the S (P = 0.046) and NPS+S (P = 0.04) rats had
higher active GLP-1 compared with C rats (Fig. 2C). At 30 min,
the S group had higher GLP-1 than the C (P = 0.003) and NPS (P
= 0.04) groups. Leptin was affected by time (P = 0.01) but not
the treatments (P = 0.14) (Fig. 2D). NPS increased 0, 15, and 30
min amylin concentrations during the OGTT compared with C
(P < 0.038) (Fig. 2E). The NPS+S rats also had higher amylin at
15, 30, and 60 min compared with the C and S groups (P < 0.05).
Blood glucose was also measured following an oral glucose load
3 d before the end of the study (Fig. 2F). Time (P = 0.001),
treatment (P = 0.001), and their interaction (P = 0.001) affected
glucose, with a marked reduction occurring in the NPS+S group
compared with all other groups throughout the 120-min OGTT.
There was an effect of time (P = 0.001) for PYY and no
significant differences in ghrelin (data not shown).
The AUC during the OGTT was calculated for all satiety
hormones and glucose. The AUC for insulin increased with NPS
compared with cellulose (P = 0.009) (Table 2). Both diet (P =
0.003) and drug (P = 0.001) and their interaction affected the
GIP AUC, with the NPS group having higher AUC than all other
groups (P < 0.002). Active GLP-1 increased with S compared
with vehicle (P = 0.001). Amylin, co-secreted with insulin, was
affected by NPS (P = 0.001) and S (P = 0.039) such that NPS and
S independently increased the AUC. The glucose AUC was
reduced with NPS (P = 0.009) and S (P = 0.003). Despite a 50%
reduction in glucose AUC in NPS+S compared with C and an
;32% reduction in AUC compared with NPS and S alone, the
interaction between NPS and S was not significant (P = 0.7),
although probably physiologically relevant.
Discussion
FIGURE 1 HbA1c (C) and blood glucose concentrations in feeddeprived (A) and fed (B) obese ZDF rats treated with NPS, S, both, or
neither for 6 wk. Values are mean 6 SEM, n = 8–11. Labeled means at
a time without a common letter differ, P , 0.05. C, control; HbA1c,
glycated hemoglobin; NPS, novel polysaccharide; NPS+S; novel
polysaccharide and sitagliptin; S, sitagliptin; ZDF, Zucker diabetic fatty.
by S compared with vehicle (P = 0.001) and there was no further
decrease in combination with NPS.
Pancreatic immunohistochemistry. Pancreatic b-cell mass
(Fig. 4) was altered by diet (P = 0.001). The insulinimmunoreactive area was greater with NPS (50 6 1.9%)
compared with cellulose (39 6 2.1%). Pancreatic islet fibrosis,
scored on a scale of 0 (pathology absent) to 5 (severe pathology),
was reduced (P = 0.001) with NPS (1.4 6 0.1) compared with
cellulose (2.1 6 0.1). The interaction between NPS and S was
significant for islet hypertrophy (P = 0.003), wherein NPS alone
had greater islet hypertrophy (3.9 6 0.2 score) compared with
NPS+S (3.1 6 0.3 score) (P = 0.055). Islet degeneration was
lower (P = 0.001) with NPS (0.96 6 0.09 score) compared with
cellulose (1.54 6 0.11 score). Deposits of hemosiderin or
mononuclear cell infiltrate did not differ between groups.
4 of 9
Reimer et al.
As the rates of obesity and type 2 diabetes continue to rise
worldwide, there is growing pressure to identify effective
treatments to manage these diseases (30). For a number of
decades, increased intake of viscous dietary fiber has been recommended for the management of type 2 diabetes due to its
ability to slow glucose absorption from the small intestine
(31,32). More recently, the pharmacological agent S, which
prevents the degradation of GLP-1 by inhibiting DPP4, has been
shown to reduce peak glucose concentrations during an OGTT
and lower HbA1c (33). Our objective was to determine if
combining a dietary treatment with effective glucose-lowering
action with a pharmacological agent, S, would further improve
glucose control over either treatment alone. Although we confirm that independent administration of NPS or S is effective
at lowering food intake (both), increasing lean mass (both),
reducing LDL cholesterol and hepatic steatosis (NPS), and
increasing active GLP-1 (S), the combined actions of NPS and S
on reducing glycemia more so than either treatment alone are
significant and clinically relevant.
The chief finding of this study is the marked and significant
reduction in blood glucose in ZDF rats with the combined
treatment of NPS+S. We measured glucose control in 4 distinct
ways, including weekly measures of blood glucose in the fed and
fasted states, HbA1c, and an OGTT. All measures of glucose
response showed the combined therapy to be highly effective in
reducing glycemia. The interaction between NPS and S during
weekly blood glucose measurements showed the combined
therapy to be more effective than either treatment alone at
reducing glucose, particularly fed blood glucose concentrations
in the final 3 wk of the study and during an acute OGTT. The
therapeutic potential of these findings is highlighted in work
showing that the degree of hyperglycemia is directly associated
with the incidence of microvascular and macrovascular complications (34). Reductions in fed blood glucose concentrations
may be particularly relevant given the recent demonstration by
Cavalot et al. (35) that cardiovascular events and all-cause
mortality are predicted by postprandial blood glucose. The
physical properties of NPS may make it especially effective at
lowering postprandial glucose concentrations.
In ZDF rats, glucose intolerance usually develops by the age
of 8 wk, followed by overt hyperglycemia by age 10–12 wk (36).
Changes in serum lipids and hepatic biomarkers. Total
cholesterol was affected by diet (P = 0.001) such that rats
consuming NPS had lower cholesterol than those consuming
cellulose (Table 3). LDL concentrations were influenced by NPS
(P = 0.001) and S (P = 0.01), wherein both NPS and S
independently reduced LDL cholesterol. Concentrations of
serum TG were above the detection limit of the assay for all
groups except NPS+S, even following dilution, and are therefore
not reliable. In the liver, hepatic steatosis was evaluated with
Sudan Black staining (Table 3). There was an effect of diet for
steatosis (P = 0.013), wherein rats fed NPS had lower scores than
those fed cellulose. Microvesicular vacuolation scores were
influenced by NPS (P = 0.033) and S (P = 0.036), with lower
pathology scores independently seen for NPS and S. Serum
aspartate aminotransferase concentrations were lower with NPS
compared with cellulose (P = 0.001). The interaction between
NPS and S (P = 0.048) affected serum AST concentrations, with
C rats having higher AST than NPS (P = 0.017) but not S or
NPS+S.
If human criteria for postprandial hyperglycemia are used
(>11.1 mmol/L), all of our rats would be considered diabetic at
baseline (0 wk in Fig. 1B). Rats in the C and S groups remained
diabetic throughout the study. The NPS rats had lower postprandial glycemia after 1 and 2 wk of treatment but remained diabetic
from 3 to 6 wk inclusive. Rats in the NPS+S group, however, had
normoglycemia for all intervention weeks except for the very last
week. This may reflect diminished treatment effectiveness at
this late time point or possibly a greater stress response to the
increased number of tests performed in the final week. If we
consider the human diabetes criteria for fasting hyperglycemia
(>7.1 mmol/L), all of the rats were normoglycemic at baseline.
All groups would be classified as diabetic thereafter except for
the NPS+S group that had fasting glucose levels <7.1 mmol/L.
These results suggest that NPS+S was able to attenuate diabetes in
the ZDF rat.
NPS is a novel functional fiber that is highly viscous and
has high water-holding and gel-forming properties (37). Other
viscous soluble fibers have been shown to improve postprandial
glycemia and insulin response via a slowing of gastric emptying
TABLE 2 Plasma AUC for glucose and satiety hormones of obese ZDF rats treated with NPS,
S, both, or neither for 6 wk1
Insulin, pmol/L 3 90 min
GIP, pmol/L 3 90 min
GLP-1, pmol/L 3 90 min
PYY, pmol/L 3 90 min
Ghrelin, pmol/L 3 90 min
Leptin, pmol/L 3 90 min
Amylin, pmol/L 3 90 min
Glucose, mmol/L 390 min
InsAUC15:GluAUC20, pmol/mmol
InsAUC120:GluAUC120, pmol/mmol
CISI, score
C
NPS
S
NPS+S
Diet
Drug
Diet 3 drug
66.5 6 12.7
2.9 6 0.4a
3.0 6 0.2
2.2 6 0.2
1.8 6 0.7
158 6 13.9
2.9 6 0.4
723 6 81.6
154 6 28.4
127 6 24.8
0.64 6 0.13
184 6 26.5
4.6 6 0.1b
3.6 6 0.3
1.9 6 0.2
2.3 6 0.5
142 6 13.3
6.5 6 0.7
525 6 57.2
675 6 123
652 6 129
0.43 6 0.06
136 6 34.3
2.5 6 0.2a
5.1 6 0.6
2.3 6 0.3
1.7 6 0.3
149 6 9.53
4.9 6 0.6
500 6 59.2
330 6 109
294 6 99.9
0.55 6 0.15
178 6 31.4
2.7 6 0.2a
4.6 6 0.5
2.2 6 0.2
2.2 6 0.4
123 6 8.12
8.0 6 1.0
345 6 59.1
782 6 180
875 6 175
0.79 6 0.13
0.009
0.003
0.92
0.29
0.28
0.07
0.001
0.009
0.001
0.001
0.95
0.28
0.001
0.001
0.300
0.80
0.23
0.039
0.003
0.30
0.15
0.28
0.20
0.012
0.20
0.64
0.96
0.63
0.71
0.73
0.80
0.84
0.07
Values are means 6 SEM, n = 9–10. Labeled means without a common letter differ, P , 0.05. C, control; CISI, composite insulin
sensitivity index; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide 1; InsAUC15:GluAUC20, ratio of insulin
AUC:glucose AUC from 0 to 15 min of the oral glucose tolerance test; InsAUC120:GluAUC120, ratio of insulin AUC:glucose AUC from 0 to
120 min of the oral glucose tolerance test; NPS, novel polysaccharide; NPS+S; novel polysaccharide and sitagliptin; PYY, peptide tyrosine
tyrosine; S, sitagliptin; ZDF, Zucker diabetic fatty.
1
5 of 9
FIGURE 2 Plasma insulin (A), GIP (B), GLP-1 (C), leptin (D), amylin (E), and blood glucose (F) of obese ZDF rats during an OGTT. Values are
mean 6 SEM, n = 8–11. Labeled means at a time without a common letter differ, P , 0.05. C, control; GIP, glucose-dependent insulinotropic
polypeptide; GLP-1, glucagon-like peptide 1; NPS, novel polysaccharide; NPS+S; novel polysaccharide and sitagliptin; OGTT, oral glucose
tolerance test; S, sitagliptin; ZDF, Zucker diabetic fatty.
and macronutrient absorption (32). It is likely, however, that
other actions of NPS alone and in combination with S contributed to the improved glucose control in this study. Both NPS and
S contributed to increased lean mass. Skeletal muscle is a major
site for glucose disposal in the body (38). The reasons for the
increase in lean mass with both NPS and S are likely distinct.
The increase in lean mass with NPS or S was achieved in the
context of reduced food intake and without significant changes
to fat mass. Although we are not aware of any studies that lend
insight into the effects of S on lean mass, the increase in overall
body weight and lean mass in NPS-treated rats could be related
to the increased GIP in these rats. Several lines of evidence
suggest that GIP is a key link between overnutrition and obesity,
including the finding that dietary fat stimulates GIP secretion
and elevated GIP is observed in obesity (5). The recent work by
Ugleholdt et al. (39) using GIP receptor (GIPr) expression
targeted to white adipose tissue (WAT) or pancreatic b-cells is
interesting in this regard. Mice with WAT-targeted GIPr
expression had significantly greater weight gain in response to
a high-fat diet, which was due to an increase in lean mass rather
than fat mass (39). Whether or not the elevated circulating GIP
levels observed in our NPS-treated rats are linked to increased
lean mass via the GIPr in WAT is not known.
There are several other possible explanations for the seemingly disparate relationship between food intake and body
weight gain. It is also possible that alterations in energy expenditure and/or physical activity related to NPS consumption
FIGURE 4 Photomicrographs of pancreas of obese ZDF rats treated with NPS, S, both, or neither for 6 wk. The bars are 200 mm. The brownstained tissue is positive for insulin-containing cells within the pancreas. Photographs were selected as representative of the respective
treatments. C, control; NPS, novel polysaccharide; NPS+S; novel polysaccharide and sitagliptin; S, sitagliptin; ZDF, Zucker diabetic fatty.
6 of 9
Reimer et al.
FIGURE 3 Plasma and liver DPP4 activity in obese ZDF rats treated
with NPS, S, both, or neither for 6 wk. Values are mean 6 SEM, n =
8–11. Labeled means without a common letter differ, P , 0.05. C,
control; DPP4, dipeptidyl peptidase 4; NPS, novel polysaccharide;
NPS+S; novel polysaccharide and sitagliptin; S, sitagliptin; ZDF, Zucker
diabetic fatty.
could explain the increase in body weight, but this remains to be
measured. Perhaps more likely is that by improving the diabetic
state of the rats treated with NPS+S, there was reduced energy
loss via the urine due to glucosuria. This is suggested by Sturis
et al. (40), who also showed reduced food intake but increased
body weight in ZDF rats after 42 d of treatment with the GLP-1
analogue, liraglutide. Similar to our NPS+S-treated rats, the
liraglutide-treated rats had lower body weight during the first
10 d of treatment, but with increasing duration, body weight
increased despite reduced food intake. Untreated control rats
would lose energy via the urine, whereas treatment with liraglutide
or NPS+S could potentially reduce this loss.
As expected, active GLP-1 was increased by S (41). This
increase in active GLP-1 is the result of the DPP4 inhibitory
actions of the drug (42). DPP4 is expressed on the surface of
various types of cells, including the kidney, liver, small intestine,
and in a soluble form in plasma (25). Whether or not DPP4
activity is correlated with the severity of diabetes is controversial, but Kirino et al. (25) showed that rats fed a high-fat or a
high-sucrose diet had higher DPP4 activity in plasma compared
with rats fed a control diet. In our study, both NPS and S reduced
plasma DPP4 activity, although the effect of S was greater in
magnitude than that of NPS. The 38% reduction in plasma
DPP4 activity with NPS is nearly identical to the 37% decrease
in DPP4 activity observed with the soluble, but low-viscosity
fiber oligofructose (27), which leads us to speculate that fermentation end-products of dietary fibers, SCFA, may contribute
to the inhibitory effects of soluble fibers to DPP4 activity. While
the major action of S is known to be the inhibition of DPP4
activity, recent work by Sangle et al. (43) suggests that S may
also exert direct effects on intestinal L cells and act as a GLP-1
secretagogue. In a previous study, we showed that NPS treatment
also acted as a GLP-1 secretagogue in the absence of increased
GLP-1–immunoreactive L-cell density (17).
Insulin secretion was increased with NPS but not S, a finding
reflected in the increased b-cell mass seen with NPS but not S.
The long-term presence of type 2 diabetes is characterized by a
40–60% reduction in b-cell mass (44). Early in the development
of insulin resistance, b-cell compensation, involving the expansion of b-cell mass and insulin biosynthesis, allows blood
glucose levels to remain in the normal range (45). In type 2
diabetes, the classical characteristic of hyperglycemia likely
reflects an impaired ability for b-cell compensation (45). In our
study, NPS was associated with increased b-cell mass, which
may explain in part the improved glucose tolerance in these rats.
Indeed, the surrogate indexes of first-phase and total insulin
secretion (InsAUC:GluAUC at 0–15 and 0–120 min) were
significantly higher with NPS, implicating an improved b-cell
function and insulin secretion. Bi et al. (29) showed that
InsAUC30:GluAUC30 and InsUC120:GluAUC120 were both re-
TABLE 3 Serum lipid concentrations and hepatic histology in obese ZDF rats treated with
NPS, S, both, or neither for 6 wk1
C
Total cholesterol, mmol/L
LDL cholesterol, mmol/L
HDL cholesterol, mmol/L
Sudan Black staining score
Macrovesicular vacuolation score
Microvesicular vacuolation score
Aspartate aminotransferase, IU/L
AST, IU/L
5.8 6 0.4
4.5 6 0.3
2.0 6 0.1
3.1 6 0.3
0.88 6 0.13
3.1 6 0.3
102 6 16.2
83.8 6 4.1a
NPS
4.3 6
2.9 6
2.5 6
2.5 6
0.82 6
2.5 6
60.3 6
52.4 6
0.2
0.3
0.1
0.2
0.12
0.2
4.92
2.33b
S
5.8
3.3
2.0
2.8
0.89
2.6
79.4
60.4
6 0.4
6 0.3
6 0.1
6 0.4
6 0.20
6 0.4
6 5.09
6 5.81ab
NPS+S
Diet
Drug
Diet 3 drug
3.8 6 0.2
2.1 6 0.1
2.2 6 0.1
1.8 6 0.2
0.91 6 0.09
1.8 6 0.2
53.4 6 2.08
57.1 6 3.64ab
0.001
0.001
0.18
0.013
0.90
0.033
0.001
0.016
0.37
0.010
0.54
0.08
0.71
0.036
0.06
0.18
0.39
0.52
0.51
0.52
0.78
0.79
0.31
0.048
Values are means 6 SEM, n = 8–11. Labeled means without a common letter differ, P , 0.05. AST, alanine aminotransferase; C, control;
NPS, novel polysaccharide; NPS+S; novel polysaccharide and sitagliptin; S, sitagliptin; ZDF, Zucker diabetic fatty.
1
Administered separately, dietary interventions and pharmacological treatments can improve metabolic disease and reduce
associated health risks. However, as the rates of obesity and type
2 diabetes rise worldwide, there is a growing need to identify
effective therapies that maximize the potential benefits, which
could be achieved if significant interaction effects occur between
the dietary and pharmacological treatment. Our findings suggest
that the combined actions of NPS and S markedly reduce glycemia
consistently across both acute and long-term measures of glucose
response. This novel treatment may be a promising dietary/
pharmacological co-therapy for type 2 diabetes management.
Acknowledgments
The authors thank Kristine Lee (University of Calgary), Joan
Wicks (Alizee), and Jamie Boulet, Leia Rispoli, Harry Maselli,
and Jessica Beyenhof (Product Safety Labs) for their technical
assistance with this work. PGX and PolyGlycopleX are registered trademarks of InovoBiologic Inc, Canada. All other trademarks belong to their respective owners. All authors designed
research; G.J.G., L.K., R.A.R., and P.J. conducted research;
R.A.R., G.J.G., and L.K. analyzed data; R.A.R. wrote the paper;
and R.A.R. and S.W. had primary responsibility for final content.
All authors read and approved the final manuscript.
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Effects of PGX, a novel functional fibre, on acute and delayed

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