AJCN. First published ahead of print October 27, 2010 as doi: 10.3945/ajcn.2010.29771.
A low–glycemic index diet combined with exercise reduces insulin
resistance, postprandial hyperinsulinemia, and glucose-dependent
insulinotropic polypeptide responses in obese prediabetic humans1–4
Thomas PJ Solomon, Jacob M Haus, Karen R Kelly, Marc D Cook, Julianne Filion, Michael Rocco, Sangeeta R Kashyap,
Richard M Watanabe, Hope Barkoukis, and John P Kirwan
ABSTRACT
Background: The optimal lifestyle intervention that reverses dia-
betes risk factors is not known.
Objective: We examined the effect of a low–glycemic index (GI)
diet and exercise intervention on glucose metabolism and insulin
secretion in obese, prediabetic individuals.
Design: Twenty-two participants [mean 6 SEM age: 66 6 1 y;
body mass index (in kg/m2): 34.4 6 0.8] underwent a 12-wk
exercise-training intervention (1 h/d for 5 d/wk at ’85% of max-
imum heart rate) while randomly assigned to receive either a low-GI
diet (LoGIX; 40 6 0.3 units) or a high-GI diet (HiGIX; 80 6 0.6
units). Body composition (measured by using dual-energy X-ray
absorptiometry and computed tomography), insulin sensitivity
(measured with a hyperinsulinemic euglycemic clamp with
[6,6-2H2]-glucose), and oral glucose–induced insulin and incretin
hormone secretion were examined.
Results: Both groups lost equal amounts of body weight (28.8 6
0.9%) and adiposity and showed similar improvements in peripheral
tissue (+76.2 6 14.9%) and hepatic insulin sensitivity (+27.1 6
7.1%) (all P , 0.05). However, oral glucose–induced insulin secre-
tion was reduced only in the LoGIX group (6.59 6 0.86 nmol in the
prestudy compared with 4.70 6 0.67 nmol in the poststudy, P ,
0.05), which was a change related to the suppressed postprandial
response of glucose-dependent insulinotropic polypeptide. When
corrected for changes in b cell glucose exposure, changes in insulin
secretion were attenuated in the LoGIX group but became signifi-
cantly elevated in the HiGIX group.
Conclusions: Although lifestyle-induced weight loss improves in-
sulin resistance in prediabetic individuals, postprandial hyperinsu-
linemia is reduced only when a low-GI diet is consumed. In contrast,
a high-GI diet impairs pancreatic b cell and intestinal K cell function
despite significant weight loss. These findings highlight the impor-
tant role of the gut in mediating the effects of a low-GI diet on type
2 diabetes risk reduction. Am J Clin Nutr doi: 10.3945/ajcn.
2010.29771.
INTRODUCTION
The reversal of progressive pancreatic b cell dysfunction and
oral glucose intolerance is a primary goal for prediabetic in-
dividuals (1). However, solely treating glucose tolerance and
peripheral and hepatic insulin resistance (IR) in overweight and
obese individuals may delay, but is unlikely to prevent, the fu-
ture onset of type 2 diabetes (T2D). Indeed, evidence suggests
Am J Clin Nutr doi: 10.3945/ajcn.2010.29771. Printed in USA. ! 2010 American Society for Nutrition
Copyright (C) 2010 by the American Society for Nutrition
that preserving b cell function in these at-risk populations is
a critical factor in the prevention of T2D onset (2). Therefore,
therapeutic management of such individuals should consider all
processes involved in maintaining glucose homeostasis.
Although the recent Diabetes Prevention Program Outcomes
Study underlined the large effect that intensive lifestyle in-
tervention can have on the prevention of diabetes onset in
overweight individuals (3), the mechanisms by which lifestyle
intervention prevents the development of glucose intolerance are
not fully understood. Exercise training interventions can suc-
cessfully improve glucose tolerance (4, 5), and several groups
have shown that exercise can reverse peripheral tissue and hepatic
IR (6–9). In addition, it has been shown that exercise training can
alter insulin secretion and improve b cell function in obese
humans (10–13). Caloric restriction has also been shown to im-
prove these components of glucose tolerance (8, 14). However,
certain nutrients (high-fat feeding) and elevated glycemic con-
centrations can induce IR and impair b cell function (15–17),
whereas a high-carbohydrate and high-fiber diet can improve
peripheral insulin sensitivity (18). Thus, dietary composition may
play a critical role in determining the ultimate success of such
interventions.
The concept of a dietary glycemic index (GI) has received
much attention: the consumption of high-GI diets may increase
1
From the Department of Pathobiology, Lerner Research Institute (TPJS,
JMH, KRK, MDC, JF, and JPK), and the Departments of Cardiovascular
Medicine (MC), Endocrinology, Diabetes, and Metabolism (SRK), and Gas-
troenterology/Hepatology (JPK), Cleveland Clinic, Cleveland, OH; the De-
partments of Physiology (JMH and JPK) and Nutrition (KRK and JPK), Case
Western Reserve University, Cleveland, OH; and the Department of Preven-
tive Medicine, Physiology, and Biophysics, University of Southern Califor-
nia, Los Angeles, CA (RMW).
2
Supported by the National Institutes of Health (NIH) (grants RO1
AG12834; to JPK) and the NIH National Center for Research Resources
(Cleveland, OH) (Clinical and Translational Science Award
1UL1RR024989).
3
Current address for TPJS: Centre of Inflammation and Metabolism, Rig-
shospitalet, Section 7641, Blegdamsvej 9, 2100 København Ø, Denmark.
E-mail: thomas.solomon@inflammation-metabolism.dk.
4
Address correspondence to JP Kirwan, Department of Pathobiology,
Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue/NE-40,
Cleveland, OH 44195. E-mail: kirwanj@ccf.org.
Received May 14, 2010. Accepted for publication September 19, 2010.
doi: 10.3945/ajcn.2010.29771.
1 of 10
2 of 10 SOLOMON ET AL

diabetes risk (19), whereas the consumption of low-GI diets may

promote weight loss and glycemic control (20, 21). However, the
combination of exercise training with diets that vary only by GI
and have identical macronutrient and fiber intakes has not been
addressed to our knowledge. Indeed, a low-GI diet may com-
plement exercise training because of the partitioning of fuel
metabolism toward fat use (22–24); however, Solomon et al (25)
recently showed that improvements in IR after 7 d of exercise
training were not influenced by dietary GI, a finding that has been
confirmed by a nonexercise GI study (26). It is possible that
a longer-term intervention is required to see the beneficial effects
of a low-GI diet on IR. However, it is possible that dietary GI does
not affect insulin sensitivity per se, and perhaps the benefits
accrue at the level of the pancreatic b cell and insulin secretion.
Such a hypothesis is supported by data that show that prolonged
hyperglycemia, such as that seen after high-GI consumption
may impair b cell responsiveness to acute glycemia (16, 17) and
affect the gastrointestinal incretin axis (27, 28).
In this study, we investigated the effects of consumption of
a low-GI diet or high-GI diet combined with supervised exercise
training for 12 wk on oral glucose tolerance in older, obese
individuals. We examined physiologic changes in whole-body
insulin sensitivity and insulin and glucose-dependent insulinotropic
polypeptide (GIP) hormone secretion, which are components that
are central to glucose clearance in the postprandial period. We
hypothesized that a low-GI diet in combination with exercise would FIGURE 1. Study flowchart. A total of 413 men and women responded to
elicit greater improvements in glucose metabolism than would the study advertisements. After review of our inclusion and exclusion
a high-GI diet in combination with exercise via larger alterations in criteria, 313 individuals were ineligible to partake in the study. After a full
insulin action and secretion and improved GIP secretion. medical screening, a further 78 potential subjects were excluded from further
participation. Twenty-four individuals were randomly assigned to the 12-wk
exercise-training program combined with either a low–glycemic index diet
(LoGIX; n = 12) or a high–glycemic index diet (HiGIX; n = 12). Two
SUBJECTS AND METHODS subjects were excluded from the LoGIX intervention (one subject failed to
comply with the intervention, and the second subject declined to complete the
Participants postintervention testing). No adverse events were associated with our testing
procedures or the intervention. Final statistical analyses were performed in 22
Twenty-two older, obese patients with prediabetes [mean 6 participants (LoGIX, n = 10; HiGIX, n = 12).
SEM age: 66 6 1 y; body mass index (in kg/m2): 34.4 6 2.8]
volunteered to participate in a 12-wk exercise-training in-
tervention while consuming either a low-GI or high-GI diet. The 5 d/wk for 12 wk (treadmill walking and cycle ergometry) at
study was conducted by using a randomized, controlled, parallel- ’85% of the maximum heart rate obtained during an in-
group, repeated-measures design (Figure 1). Medical screenings cremental maximal aerobic-exercise test [maximal oxygen up-
excluded individuals with heart, kidney, liver, thyroid, intestinal, _ 2max) test; full details of the exercise intervention were
take (VO
and pulmonary diseases or individuals taking medications known previously presented (5)]. Every session was supervised by an
to affect the outcome variables of the study. Resting 12-lead exercise physiologist, and all meals, snacks, and beverages for
electrocardiograms and submaximal exercise stress tests excluded the 12-wk intervention were provided to participants on a daily
individuals with any contraindication to increments in physical basis. Diets were carefully formulated by a registered dietitian
activity. All women were postmenopausal and not using hormone and were isocaloric to the individual requirements of subjects
replacement therapy. Participants had also been weight stable for (screening resting metabolic rate multiplied by a sedentary activity
at least the previous 6 mo. Measurements of resting metabolic factor of 1.2). The dietary macronutrient composition (including
rates via indirect calorimetry were used to ascertain individual fiber) was matched between groups; however, the diets were
caloric requirements. The study was approved by the Cleveland designed so that LoGIX subjects received a diet corresponding
Clinic Institutional Review Board, and all subjects provided in- to a GI of 40 arbitrary units (au), whereas HiGIX subjects were
formed written consent in accordance with our guidelines for the provided an 80-au GI diet. Dietary adherence was ensured via
protection of human subjects. daily food-container weigh backs plus a weekly counseling ses-
sion with a research dietitian. Daily menus contained a variety of
different foods to prevent meal repetition on a 3-wk block rotation
Intervention [sample menus were shown in Solomon et al (25)]. Dietary
Volunteers were randomly assigned to a low-GI diet plus analysis was performed with Nutritionist Pro software (Axxya
exercise group (LoGIX group: n = 10; 3 men, 7 women) or Systems, Stafford, TX). In addition, a subgroup of our participants
a high-GI diet plus exercise group (HiGIX group: n = 12; 5 men, (n = 8) underwent 1-d diet tests. This subgroup was provided with
7 women). All volunteers undertook 60 min of aerobic exercise a sample menu for each diet on 2 separate occasions. Venous
 EXERCISE, GLYCEMIC INDEX, AND b CELL FUNCTION
blood samples were obtained at 10-min intervals for 10 h on each
test day beginning fasted at 0800. The plasma glycemic responses
to these tests are presented in Figure 2.
Inpatient control period
Pre- and postintervention assessments of body composition,
aerobic fitness, insulin sensitivity and secretion, and substrate
metabolism were performed during a 3-d inpatient stay in the
Clinical Research Unit at the Cleveland Clinic. During this time,
participants received a weight-maintenance isocaloric diet (55%
carbohydrate, 30% fat, and 15% protein). The postintervention
inpatient stay included the final 2 d of the GI dietary provision
and exercise prescription so that day 3 of this stay occurred the
day after the final exercise session. Metabolic measures were
performed on this third day ’16 h after the last exercise bout.
Body composition
Height and body weight were measured by standard techniques
(5). Whole-body adiposity [fat mass (FM) and fat-free mass
(FFM)] was measured by dual-energy X-ray absorptiometry
(model iDXA; Lunar, Madison, WI) as previously described (25).
Computerized tomography scanning was used to quantify sub-
cutaneous and visceral abdominal adiposity with a SOMOTOM
FIGURE 2. Mean (6SEM) study-diet glycemic responses. A subgroup of
individuals (n = 8) were selected to undergo two 1-d diet tests in which they
consumed meals (solid black arrows) representative of our low–glycemic
index diet (LoGIX) and high–glycemic index diet (HiGIX) study groups
in a counterbalanced crossover design. A: Plasma glucose concentrations
were measured every 10 min for 10 h. B: The incremental area under the
glucose-response curve (iAUC) was calculated over the 10-h diet test. *The
HiGIX (black bar) meals elicited a greater glycemic response than did
the LoGIX (gray bar), P , 0.05 (paired t test).
3 of 10
Sensation 16 Scanner (Siemens Medical Solutions, Malvern, PA),
as previously described (5).
Aerobic fitness
An incremental, graded treadmill exercise test (modified Borg)
was used to determine VO _ 2max (Jaeger Oxycon Pro; Viasys,
Yorba Linda, CA). The test was deemed satisfactory if !3 of the
following criteria were attained: plateau in oxygen consumption
with increasing workloads, volitional fatigue, a heart rate "10
beats/min of the age-predicted maximum, or a respiratory ex-
change ratio .1.10. The maximal heart rate recorded during this
test was used to prescribe the correct exercise intensity during
_ 2max tests were also performed at weeks 4 and 8
training (5). VO
to maintain the appropriate exercise intensity corresponding to
changes in the aerobic fitness of participants. To control for the
acute effects of exercise, preintervention VO _ 2max tests were
conducted .48 h before metabolic measures.
Insulin sensitivity
After an overnight fast, at 0800, a 2-h primed (3.28 mg/kg)
continuous (0.036 mg # kg21 # min21) infusion of [6,6-2H2]-
glucose was begun (Cambridge Isotope Laboratories, Andover,
MA). At 1000 (t = 0 min), a 40 mU # m22 # min21 hyper-
insulinemic euglycemic (90 mg/dL) clamp proceeded as pre-
viously described (25). Fluctuations in arterialized venous plasma
glucose concentrations were titrated via a variable-rate hot glu-
cose (20% dextrose plus [6,6-2H2]-glucose) infusion; adjustments
were made every 5 min on the basis of the algorithm of
DeFronzo et al (29). Rates of glucose appearance (Ra) and disap-
pearance (Rd) were calculated during basal (t = 230 to 0 min) and
insulin-stimulated (t = 90–120 min) conditions by using Steele’s
single-pool model of glucose kinetics (25). Hepatic glucose pro-
duction (Ra HGP) was calculated as the difference between the total
glucose Ra and the exogenous glucose-infusion rate. A measure of
IR was calculated as the reciprocal of glucose Rd divided by the
steady-state plasma insulin concentration during hyperinsulinemia.
Oral glucose–induced insulin and incretin hormone
secretion
A 75-g oral-glucose-tolerance test (OGTT) was performed at
0800 after an overnight fast, and blood samples were drawn from
an antecubital vein at baseline and every 30 min for 3 h. Pre-
hepatic insulin secretion was calculated by deconvolution analysis
of peripheral blood C-peptide concentrations after oral glucose
ingestion by using a 2-compartment model of C-peptide kinetics
(30). The b cell insulin secretory response to glucose was esti-
mated as the insulin secretion rate divided by the plasma glucose
response to the OGTT (ISR/G) (31). In addition, to control for the
reductions in pancreatic exposure to glucose because of increases
in insulin sensitivity, the b cell insulin secretory response to
glucose was divided by the glucose clamp-derived measure of IR
(ISR/G 4 IR, an index of b cell function) (31).
Biochemical analyses
Plasma glucose concentrations were measured with a YSI
2300 STAT Plus analyzer (Yellow Springs Instruments, Yellow
Springs, OH), plasma insulin concentrations were measured
4 of 10 SOLOMON ET AL

via radioimmunoassay (Millipore, Billerica, MA), and C-peptide TABLE 1

concentrations were measured by using enzyme-linked immuno- Study diets1
sorbent assay (Millipore). Plasma triglycerides and cholesterol were Study diet LoGIX HiGIX
analyzed by using enzymatic methods with an automated platform
GI (au) 39.8 6 0.3 80.0 6 0.6*
(Roche Modular Diagnostics, Indianapolis, IN). Glycated he-
GL (au) 98.5 6 6.2 205.5 6 9.3*
moglobin (Hb A1c) was measured via nonporous ion exchange EI (kcal/d) 1760 6 109 1791 6 83
high-performance liquid chromatography (G7 HPLC Analyzer; Carbohydrate (g/d) 247 6 16 258 6 12
Tosoh Bioscience, San Francisco, CA). Samples for incretin Percentage of energy 54.7 6 0.1 55.6 6 0.2
hormone analysis were collected in EDTA evacuated tubes that Fat (g/d) 56.7 6 3.4 57.3 6 2.9
contained aprotinin and dipeptidyl peptidase IV inhibitor. Total Percentage of energy 28.3 6 0.1 27.8 6 0.2
GIP concentrations were analyzed by enzyme-linked immuno- Protein (g/d) 76.8 6 4.8 76.7 6 3.5
sorbent assay (Millipore). For glucose kinetics analyses, plasma Percentage of energy 17.0 6 0.1 16.6 6 0.1
Fiber (g/d) 28.5 6 1.6 26.1 6 1.4
glucose underwent derivatization to synthesize a pentacetate-
Compliance (%) 98 6 1 96 6 1
glucose derivative, and glucose enrichment was measured via
1
gas chromatography–mass spectrometry (Hewlett-Packard, Palo All values are means 6 SEMs (n = 22). LoGIX, low–glycemic index
Alto, CA) (25). diet; HiGIX, high–glycemic index diet; GI, glycemic index; au, arbitrary
units; GL, glycemic load; EI, energy intake. *Significant group differences,
P , 0.05 (paired t test).
Statistics
Between-group (LoGIX compared with HiGIX) comparisons Blood biochemistry
were analyzed by using 2-factor (group · time) repeated-measures The lifestyle intervention reduced fasting plasma glucose, tri-
analysis of variance (ANOVA), and Bonferroni post hoc tests glyceride, and cholesterol concentrations equally in the LoGIX and
were applied to significant group · time interactions. Baseline HiGIX groups (Table 2; P , 0.05). No prestudy group differences
values for each variable were compared between groups by using in these blood biochemistry measures were observed (P . 0.05).
unpaired t tests. In the event of a significant t statistic, baseline Fasting plasma insulin and C-peptide concentrations were also
values were used as a covariate in the 2-factor repeated-measures reduced in both groups (Table 2; both P , 0.05). No changes in
ANOVA. Bivariate correlation analyses were used to identify Hb A1c were identified after the study (Table 2; P . 0.05)
relations between variables. Significance was accepted at P ,
0.05. Additional ANCOVA analyses were performed by using sex
as a covariate and revealed no sex effects on any of the outcome Insulin sensitivity
variables in this intervention. Analyses were carried out with
During hyperinsulinemia, steady-state euglycemia was ach-
StatView for Windows 5.0.1 (SAS Institute, Cary, NC), and all
ieved [88.7 6 0.6 mg/dL prestudy (CV = 4.2 6 0.5%) and
data are expressed as means 6 SEMs.
88.7 6 0.4 mg/dL poststudy (CV = 3.4 6 0.4%)]. Basal glucose Ra
HGP was significantly reduced after the intervention (Table 3,
RESULTS Figure 3A; 231.1 6 6.7%; P , 0.05), whereas insulin sup-
pression of Ra HGP (Table 3, Figure 3B; +27.1 6 7.1%;
Diet and exercise P , 0.05) and insulin-stimulated glucose Rd increased (Table 3,
Dietary analyses for the LoGIX and HiGIX groups are shown Figure 3C; +76.2 6 14.9%; P , 0.05). These changes were
in Table 1. Group diets were carefully matched with respect to similar between groups (Figure 2; LoGIX compared with Hi-
macronutrient composition, including fiber, with GI units of GIX; 2-factor ANOVA interaction, P = NS), and no prestudy
39.8 6 0.3 and 80.0 6 0.6 au, respectively. The significant differences were evident (P . 0.05).
difference in GIs between our study diets was confirmed by the
study diet tests (Figure 1; P , 0.05). Dietary compliance was
high (97 6 1%), and there was a 95 6 1% attendance at exercise Oral glucose–induced metabolic responses
sessions. During the intervention, exercise was performed for The glucose (Figure 4A), insulin (Figure 4B), C-peptide
56 6 5 min/d at 83.4 6 0.6% of the maximum heart rate, and (Figure 4C), and GIP (Figure 4D) responses to oral glucose
_ 2max in each
after the study, there was an equal increment in VO ingestion, before and after the intervention, are shown in Figure
group (Table 2). In addition, there were significant improve- 4. The area under the glucose response curve improved in the
ments in resting blood pressures (Table 2; P , 0.05). LoGIX group only; however, these data did not reach signifi-
cance (main effect of time, P = 0.10; interaction, P = 0.16;
LoGIX: 1.38 6 0.07 compared with 1.30 6 0.04 mol # L/min for
Body composition pre- and poststudy, respectively; HiGIX: 1.32 6 0.06 compared
Similar weight loss was achieved after both interventions (Table with 1.31 6 0.06 mol # L/min for pre- and poststudy, respec-
2; 28.8 6 0.9%; P , 0.05). This improvement was driven by tively). Insulin, C-peptide, and GIP responses to the OGTT were
decreases in whole-body fat mass and deep subcutaneous and significantly attenuated after the intervention in the LoGIX
visceral abdominal adipose tissue (Table 2; P , 0.05). Fat-free group only (P , 0.05; Figure 4) and showed no changes in the
mass showed a significant decrease; however, this change was HiGIX group. The area under the GIP response curve (0–180
clinically insignificant (21.4 6 0.6%). No prestudy group dif- min) and the early phase GIP response (D0–30 min) were re-
ferences in body composition were observed (P . 0.05). duced in the LoGIX group (both P , 0.05).
 EXERCISE, GLYCEMIC INDEX, AND b CELL FUNCTION 5 of 10
TABLE 2
Subject characteristics1
LoGIX HiGIX P (2-factor ANOVA)

Subject characteristics Prestudy Poststudy Prestudy Poststudy Time Trial Time · trial

n (M, F) 10 (3 M, 7 F) 10 (3 M, 7 F) 12 (5 M, 7 F) 12 (5 M, 7 F) — — —
Age (y) 67 6 2 67 6 2 64 6 1 64 6 1 — — —
Weight (kg) 97.4 6 3.8 89.6 6 3.4 94.7 6 4.4 85.7 6 4.1 ,0.0001 0.46 0.52
BMI (kg/m2) 34.9 6 1.1 32.1 6 1.3 34.1 6 1.1 30.9 6 1.2 ,0.0001 0.40 0.43
FM (kg) 46.8 6 2.0 40.0 6 2.2 42.0 6 2.2 36.1 6 2.9 ,0.0001 0.33 0.49
FFM (kg) 49.9 6 2.9 49.7 6 2.8 55.2 6 3.6 53.9 6 3.5 0.02 0.08 0.08
TAAT (cm2) 620.4 6 31.3 535.3 6 33.2 553.4 6 44.9 432.0 6 48.9 ,0.0001 0.25 0.12
Super SAT (cm2) 264.0 6 23.7 262.4 6 27.6 218.9 6 20.2 202.0 6 27.1 0.26 0.27 0.35
Deep SAT (cm2) 249.5 6 27.4 194.2 6 16.8 217.0 6 22.5 156.9 6 18.2 ,0.0001 0.50 0.83
VAT (cm2) 106.9 6 12.7 78.7 6 12.1 117.5 6 26.3 73.0 6 18.5 ,0.0001 0.17 0.27
_ 2max (L/min)
VO 2.03 6 0.15 2.32 6 0.22 2.19 6 0.14 2.45 6 0.18 ,0.0001 0.52 0.81
_ 2max (mL # kg21 # min21)
VO 20.4 6 1.1 25.6 6 2.1 23.2 6 1.9 28.8 6 1.8 ,0.0001 0.67 0.78
SBP (mm Hg) 127 6 3 118 6 2 133 6 5 119 6 4 0.0002 0.42 0.30
DBP (mm Hg) 76 6 3 73 6 2 79 6 3 71 6 3 0.02 0.27 0.26
Hb A1c (%) 5.66 6 0.14 5.44 6 0.16 5.48 6 0.15 5.53 6 0.13 0.57 0.44 0.27
FPG (mg/dL) 101.1 6 2.3 97.6 6 1.5 96.7 6 2.0 90.8 6 1.7 0.02 0.71 0.92
FPI (lU/mL) 24.6 6 4.8 14.2 6 2.4 20.9 6 6.4 9.2 6 1.2 ,0.0001 0.06 0.04
FC-pep (ng/mL) 3.18 6 0.58 2.53 6 0.34 2.11 6 0.27 1.88 6 0.16 0.0008 0.09 0.13
TG (mg/dL) 164.2 6 26.1 110.9 6 12.2 129.8 6 18.9 89.0 6 14.2 0.0004 0.49 0.58
Cholesterol (mg/dL) 214.6 6 11.3 183.5 6 9.6 207.3 6 8.3 181.2 6 9.2 ,0.0001 0.35 0.60
HDL cholesterol (mg/dL) 53.3 6 3.5 50.3 6 3.9 49.8 6 4.1 47.0 6 3.6 0.06 0.46 0.93
VLDL cholesterol (mg/dL) 32.8 6 5.3 22.1 6 2.4 25.9 6 3.8 17.8 6 2.8 0.0004 0.80 0.62
LDL cholesterol (mg/dL) 128.5 6 9.1 111.1 6 9.7 131.6 6 6.7 116.4 6 7.8 0.001 0.53 0.80
1
All values are means 6 SEMs (n = 22). LoGIX, low–glycemic index diet; HiGIX, high–glycemic index diet; FM, fat mass; FFM, fat-free mass; TAAT,
_ 2max, maximal oxygen uptake during
total abdominal adipose tissue; Super, superficial; SAT, subcutaneous adipose tissue; VAT, visceral adipose tissue; VO
exhaustive aerobic exercise; SBP, systolic blood pressure; DBP, diastolic blood pressure; Hb A1c, glycated hemoglobin; FPG, fasting plasma glucose; FPI,
fasting plasma insulin; FC-pep, fasting C-peptide; TG, triglycerides. After the intervention, both groups showed significant improvements in body compo-
sition, aerobic fitness, fasting glycemia, and lipemia (P , 0.05, 2-factor ANOVA). No between-group prestudy differences were observed (all P . 0.05,
unpaired t test).

Oral glucose–induced insulin secretion
Basal ISR was significantly decreased in both groups after the
intervention, with larger changes seen in the LoGIX group (Table
3). Oral glucose–induced ISR was decreased only in the LoGIX
group after the lifestyle intervention (Figure 5A) despite the finding
that IR (Figure 5B) was attenuated to a similar extent in both
LoGIX and HiGIX groups (main effect of time, P , 0.05; LoGIX
compared with HiGIX; P = NS). When corrected for changes in
IR, oral glucose–induced ISR became elevated in the HiGIX
group, whereas there were no intervention-induced effects in the
LoGIX group (Figure 5C). Correction of ISR for changes in IR was
appropriate as indicated by the strong relation between the 2

TABLE 3
Glucose metabolism, insulin secretion, and b cell function1
P (2-factor
LoGIX HiGIX ANOVA)
Glucose metabolism and
insulin kinetics Prestudy Poststudy Prestudy Poststudy Time Trial Time · trial
21 21
Basal Ra, (mg # kg # min ) 2.43 6 0.57 1.52 6 0.07 2.60 6 0.27 1.43 6 0.12 0.005 0.51 0.69
Insulin Ra (percentage suppression) 52.7 6 5.9 76.6 6 7.2 33.6 6 9.0 63.5 6 11.4 0.002 0.22 0.68
Insulin Rd (mg # kg21 # min21) 2.22 6 0.26 4.12 6 0.40 3.12 6 0.40 4.60 6 0.59 ,0.0001 0.31 0.42
Insulin Rd (mg # kg21 FFM # min21) 4.41 6 0.56 7.48 6 0.80 5.48 6 0.75 7.75 6 0.96 ,0.0001 0.31 0.39
Basal ISR (nmol/min) 2.86 6 0.49 1.87 6 0.31 1.80 6 0.23 1.45 6 0.15* 0.0004 0.02 0.05
OGTT ISRauc (nmol) 6.59 6 0.86 4.70 6 0.67 4.40 6 0.55 4.25 6 0.66 0.01 0.02 0.02
ISR/G (au) 8.28 6 0.91 6.41 6 0.89 6.01 6 0.72 5.65 6 0.64* 0.02 0.07 0.09
ISR/G 4 IR (au) 31.5 6 4.1 32.6 6 4.3 26.8 6 3.0 37.3 6 3.3* 0.01 0.03 0.04
1
All values are means 6 SEMs (n = 22). LoGIX, low–glycemic index diet; HiGIX, high–glycemic index diet; Basal Ra, rate of appearance of plasma
glucose during fasting conditions; Insulin Ra, insulin-stimulated rate of appearance of plasma glucose; Rd, insulin-stimulated rate of disappearance of plasma
glucose; FFM, fat-free mass; Basal ISR, insulin secretion rate during fasting conditions; OGTT ISRauc, total area under the insulin secretion rate curve after
ingestion of 75 g glucose (oral-glucose-tolerance test ); ISR/G, insulin secretory response to OGTT divided by the plasma glucose response; ISR/G 4 IR,
insulin secretory response to OGTT corrected for changes in insulin resistance; au, arbitrary units. After the study, both groups showed significant improve-
ments in insulin sensitivity, whereas only the LoGIX group showed improvement in insulin secretion. *Group differences between poststudy values, P , 0.05.
With the exception of basal ISR (P = 0.05), no between-group prestudy differences were observed (all P . 0.05, unpaired t test).
6 of 10 SOLOMON ET AL
FIGURE 3. Mean (6SEM) insulin sensitivity (n = 22). After 12 wk of
aerobic exercise combined with either a low–glycemic index diet (LoGIX;
gray bars) or a high–glycemic index diet (HiGIX; black bars), changes in
glucose kinetics were measured during 40 mU # m22 # min21 hyperinsulinemic
euglycemic clamps. Values represent poststudy minus prestudy changes (D) in
glucose kinetics. Basal rates of glucose appearance (Ra) decreased significantly
(A) [basal Ra of hepatic glucose production (Basal Ra HGP); main effect of
time, P , 0.05 (2-factor ANOVA)], whereas insulin-suppression of HGP
(Insulin-Suppressed Ra HGP) increased after the intervention (B) (P ,
0.05). Rates of glucose disappearance during hyperinsulinemia (Insulin-
Stimulated Rd) increased significantly (C) (P , 0.05). No significant
differences between LoGIX and HiGIX groups were observed (P = NS).
variables (r = 0.59, P = 0.002). Prestudy baseline variables showed
a trend toward ISR being higher in the LoGIX group; however, of
these variables, only the basal ISR reached significance (P , 0.05).
Correlation analyses
Intervention-induced changes in the ISR were not related to
changes in body weight (r = 0.16, P = 0.47) or fat mass (r = 0.09,
P = 0.69); however, the early phase insulin response (ISR: 0–30
min) was correlated with the oral glucose–induced GIP response
(0–30 min; r = 0.44, P = 0.03).
DISCUSSION
The key finding in this study is that, when older, obese,
prediabetic individuals underwent a 12-wk diet and exercise-
based lifestyle intervention, reductions in compensatory hyper-
insulinemia were only seen when individuals consumed a low-GI
diet. It was also observed that a high-GI diet increased the b cell
insulin secretory response to glucose when correcting the changes
in oral glucose–induced insulin secretion for changes in the un-
derlying IR, which was indicative of b cell dysfunction. These, to
our knowledge, novel findings were shown to be independent of
the ’9% decrease in body weight and fat mass but were related to
changes in the gastrointestinal incretin peptide, GIP, the post-
prandial response of which was decreased only in subjects who
consumed a low-GI diet.
It was previously shown that weight loss via caloric restriction
and/or exercise reduced IR in obese men and women (6–8, 14).
Such improvements in peripheral tissue glucose disposal or
suppression of hepatic glucose production, as seen in this study,
reduce hyperglycemia. This alone reduces glucose exposure of
the pancreatic b cells and thus reduces insulin secretion; however,
this does not reflect an alteration in b cell function per se. In this
study, reductions in hyperinsulinemia and postprandial insulin
secretion were only seen in the LoGIX group. Because changes
in b cell glucose exposure (DIR) were identical in both dietary
groups, it was surprising that the HiGIX group showed no
change in postprandial ISR. These observations suggest that it is
appropriate to control for b cell glucose exposure (eg, ISR/G 4
IR) when assessing insulin secretion. As such, no intervention-
induced changes in b cell function per se were evident in the
LoGIX group, whereas there was an elevation in this index in
the HiGIX group. These data indicate that when a low-GI diet is
combined with exercise training in hyperinsulinemic in-
dividuals, the reduction in insulin secretion is driven by reduced
b cell glucose exposure, but that there is an inappropriate in-
crease in the b cell response to glucose, and compensatory hy-
perinsulinemia is not corrected, when a high-GI diet is
consumed, which indicates evidence of b cell dysfunction.
These findings are clinically significant with regards to the
pharmacologic management of individuals at risk of developing
T2D. Current evidence indicates that the treatment of hyper-
glycemia in prediabetic individuals must target insulin action
and secretion to prevent the onset of T2D (ie, treating IR alone
will merely delay the onset of diabetes) (2). In the context of our
current findings, it is clear that, although diet and exercise-induced
weight loss will reverse peripheral and hepatic IR, only a diet
that elicits lower postprandial glycemic responses will reduce
compensatory hyperinsulinemia, whereas a high-GI diet appears
to exacerbate b cell dysfunction. These data suggest that a high-
GI diet, when combined with exercise, may delay the onset of
T2D in at-risk individuals, but only a low-GI treatment method
will prevent diabetes onset.
To the best of our knowledge, this is the first investigation to
prescribe and provide isocaloric macronutrient-matched meals
with low or high GI values during a long-term lifestyle in-
tervention in older, obese men and women at risk of developing
diabetes. To our knowledge, this is also the first dietary in-
tervention to use identical recipes and meal patterns in each of the
2 interventions by substituting only low-GI compared with high-
GI foods. The glucose responses during our study diets (Figure 2)
confirmed the GI differences between the LoGIX (GI = 40) and
HiGIX (GI = 80) groups. A comprehensive evaluation of the
effects of GI on oral glucose tolerance has not previously been
published. The mechanistic advantage of the OGTT is the ability
to study incretin-dependent insulin secretion. Although we
showed no group differences in IR (or body composition) for the
2 diets, the beneficial reduction in insulin secretion in the LoGIX
 EXERCISE, GLYCEMIC INDEX, AND b CELL FUNCTION 7 of 10

FIGURE 4. Mean (6SEM) oral glucose–induced metabolic responses (n = 22). After the 12-wk intervention, changes in the glucose [A(i) and A(ii) (low–
glycemic index diet [LoGIX] and high–glycemic index diet [HiGIX], respectively)], insulin [B(i) and B(ii)], C-peptide [C(i) and C(ii)], and glucose-dependent
insulinotropic polypeptide (GIP) [D(i) and D(ii)] secretory responses to oral glucose were assessed. Each panel represents the metabolic response after glucose
ingestion (oral-glucose-tolerance test) at t = 0 min. Solid lines represent prestudy values; dotted lines represent poststudy values. Glucose, insulin, C-peptide,
and GIP responses to oral glucose ingestion were attenuated in the LoGIX group only after the intervention. *Significant prestudy compared with poststudy
differences, P , 0.05 (2-factor ANOVA). The black bar is positioned above prestudy and poststudy time points that were significantly different. #Significant
differences between groups (LoGIX compared with HiGIX) with regard to the pre- to postintervention changes at specific time points, P , 0.05.

group was related to reduced postprandial GIP responses. This
opens up a novel paradigm whereby the LoGIX-induced
reductions in insulin secretion appear not to be due to changes in
b cell function when accounting for b cell glucose exposure but
instead are related to an incretin-mediated effect on the b cell.
The incretin axis may be critical for appropriate b cell function
(32) as GIP (and glucagon-like peptide 1) secretion is reduced in
T2D (33), pancreatic b cells are insensitive to incretin action in
insulin resistant and T2D patients (34, 35), whereas b cell GIP
insensitivity has been reported in human aging (36). Thus, the
8 of 10 SOLOMON ET AL
FIGURE 5. Mean (6SEM) oral glucose–induced insulin secretion (n =
22). After 12 wk of aerobic exercise combined with either a low–glycemic
index diet (LoGIX; gray bars) or a high–glycemic index diet (HiGIX; black
bars), changes in oral glucose–induced insulin secretion were assessed via
peripheral blood C-peptide deconvolution. Values represent poststudy minus
prestudy changes (D). A: The oral glucose–induced insulin secretion rate
area under the curve (ISR AUC) was significantly reduced only in the LoGIX
group (#LoGIX compared with HiGIX: P , 0.05, 2-factor ANOVA). B:
Insulin resistance (IR; defined as the reciprocal of the glucose rate of
disappearance divided by the steady state plasma insulin concentration)
was equally reduced in both groups (LoGIX compared with HiGIX, P =
NS). C: Oral glucose–induced insulin secretion corrected for changes in
insulin resistance [the insulin secretory response to an oral-glucose-
tolerance test corrected for changes in IR (ISR/G 4 IR)] was unchanged
in the LoGIX group but increased in the HiGIX group (#LoGIX compared
with HiGIX, P , 0.05). *Significant prestudy compared with poststudy
differences, P , 0.05. a.u., arbitrary units,
absence of an intervention effect on the incretin axis in the
HiGIX group may partly explain the ensuing b cell dysfunction.
Kashyap et al (37) recently showed that the Roux-en-Y gastric
bypass alters the incretin axis in line with beneficial changes in
insulin secretion; the current study builds on these observations
and adds some mechanistic insight into the effect of a non-
surgical lifestyle intervention on the incretin axis. Chronic hy-
perglycemia impairs b cell function in humans (16) and isolated
pancreatic islets (17). Our high-GI diets elicited significantly
higher day-long plasma glycemia (Figure 1); therefore, it is
possible that 12 wk of a high-GI diet exposed intestinal incretin-
secreting cells and pancreatic b cells to higher glucose con-
centrations. Glucotoxicity is a phenomenon related to b cell
dysfunction (38); thus, one may speculate that a similar stressor
acts on the incretin-releasing K cells (GIP) of the intestinal tract,
causing impaired function that prevents the exercise and diet-
induced reduction in incretin secretion. To support this hy-
pothesis, hyperglycemia has been shown to down-regulate GIP
receptor expression (27, 39), alter the postprandial incretin re-
sponse (28), and to increase GIP glycation (40). However, the
precise mechanisms for the role of incretin peptides and in-
testinal K cell function in hyperglycemia-related disease require
further investigation.
Previous data have shown marked attenuation of peripheral
tissue and hepatic IR and improved oral glucose tolerance after
exercise training or weight loss via exercise and/or caloric re-
striction (4–9). Furthermore, a reversal of hyperinsulinemia has
been shown in overweight and obese men and women (11–13),
whereas improvements in b cell function have been identified in
T2D patients (10, 41). Experiments in our laboratory have
shown that the reduction in compensatory hyperinsulinemia
in obese nondiabetic individuals after 12 wk of lifestyle-induced
weight loss is driven by reduced b cell glucose exposure rather
than an intrinsic alteration in b cell function (41). Previous work
by Solomon et al (41) and Kelly et al (42) has also shown that
lifestyle-induced changes in insulin secretion are related to
changes in GIP. The current data further highlight the impor-
tance of incretin-mediated effects on the b cell after weight loss,
which are independent of b cell glucose exposure. While bari-
atric surgery and pharmaceutical intervention has identified the
incretin axis as a key mediator of insulin secretion, these current
findings highlight the value of lifestyle intervention for the
treatment of incretin-axis dysfunction and hyperglycemia-
related disease.
An optimal dietary prescription for individuals at risk of de-
veloping T2D is important in order to maintain glycemic control.
The concept of dietary GI has been well studied. Reports have
indicated that, when compared with a high-GI diet, low-GI di-
etary intake may be advantageous for promoting weight loss (21)
and glycemic control (20) and for reducing IR (43) and risk of
cardiovascular disease (44). However, there have also been equiv-
ocal findings with regard to weight loss (45, 46), disease risk (47,
48), and effects on Hb A1c (49). Previously, Solomon et al (25)
reported that a 7-d LoGIX compared with a HiGIX interven-
tion improved, but had no divergent effects on, IR. Herein,
we showed that extending the duration of the intervention to
12-wk produced a similar result concerning peripheral insulin
sensitivity. Although Kirwan et al (50) previously showed that
dietary switching from a high-GI to a low-GI diet may augment
insulin sensitivity, to our knowledge, only the First Step First
Bite program group has previously examined a combined ex-
ercise and low-GI approach (51). Their findings indicated no
increased benefit of adding low-GI foods to a low-intensity
walking program on metabolic or anthropometric variables,
including Hb A1c. However, in contrast to their diet/exercise
counseling, our current study program offers a more robust and
highly controlled dietary provision and daily exercise super-
vision and adds strong evidence to the hypothesis that a low-GI
diet may be advantageous for reducing diabetes risk.
In conclusion, this study showed that although diet and
exercise-induced improvements in body composition and IR in
obese patients with prediabetes were not influenced by dietary
GI, the consumption of a high-GI diet during such therapy im-
paired pancreatic b cell function and prevented the improvement
in intestinal K cell function. In contrast, a low-GI diet decreased
both hyperglycemia and hyperinsulinemia and thus relieved b
 EXERCISE, GLYCEMIC INDEX, AND b CELL FUNCTION
cell stress, therefore potentially preventing diabetes onset. These
findings support an important role for gut hormones in mediat-
ing the metabolic effects of a low-GI diet in obese, prediabetic
patients.
We thank the research volunteers for their outstanding dedication and effort
and the nursing staff of the Clinical Research Unit and the staff and students
who helped with the implementation of the study and assisted with data col-
lection. We also thank the dietary staff in the Bionutrition Unit of the CTSC
for their assistance with preparing meals for this study.
The authors’ responsibilities were as follows—JPK and HB: conception
and design; TPJS, JMH, KRK, MDC, JF, MR, SRK, HB, and JPK: data ac-
quisition; TPJS, JMH, KRK, SRK, RMW, HB, and JPK: analysis and inter-
pretation of data; TPJS: drafting of the manuscript; JMH, SRK, RMW, HB,
and JPK: critical revision of the manuscript; TPJS: statistical analyses; JPK:
obtained funding; MDC and JF: technical support; HB: dietary support; MR
and SRK: clinical support; and HB and JPK: supervision. None of the authors
had a personal or financial conflict of interest.
REFERENCES
1. Jallut D, Golay A, Munger R, et al. Impaired glucose tolerance and
diabetes in obesity: a 6-year follow-up study of glucose metabolism.
Metabolism 1990;39:1068–75.
2. Defronzo RA. Banting Lecture. From the triumvirate to the ominous
octet: a new paradigm for the treatment of type 2 diabetes mellitus.
Diabetes 2009;58:773–95.
3. Knowler W, Fowler S, Hamman R, et al. 10-year follow-up of diabetes
incidence and weight loss in the Diabetes Prevention Program Outcomes
Study. Lancet 2009;374:1677–86.
4. Rogers MA, Yamamoto C, King DS, Hagberg JM, Ehsani AA, Holloszy
JO. Improvement in glucose tolerance after 1 wk of exercise in patients
with mild NIDDM. Diabetes Care 1988;11:613–8.
5. O’Leary VB, Marchetti CM, Krishnan RK, Stetzer BP, Gonzalez F,
Kirwan JP. Exercise-induced reversal of insulin resistance in obese elderly
is associated with reduced visceral fat. J Appl Physiol 2006;100:1584–9.
6. Haus JM, Solomon TP, Marchetti CM, Edmison JM, Gonzalez F,
Kirwan JP. Free fatty acid-induced hepatic insulin resistance is attenu-
ated following lifestyle intervention in obese individuals with impaired
glucose tolerance. J Clin Endocrinol Metab 2010;95:323–7.
7. Solomon TP, Sistrun SN, Krishnan RK, et al. Exercise and diet enhance
fat oxidation and reduce insulin resistance in older obese adults. J Appl
Physiol 2008;104:1313–9.
8. Goodpaster BH, Katsiaras A, Kelley DE. Enhanced fat oxidation
through physical activity is associated with improvements in insulin
sensitivity in obesity. Diabetes 2003;52:2191–7.
9. Coker RH, Williams RH, Yeo SE, et al. The impact of exercise training
compared to caloric restriction on hepatic and peripheral insulin re-
sistance in obesity. J Clin Endocrinol Metab 2009;94:4258–66.
10. Dela F, von Linstow ME, Mikines KJ, Galbo H. Physical training may
enhance beta-cell function in type 2 diabetes. Am J Physiol Endocrinol
Metab 2004;287:E1024–31.
11. Slentz CA, Tanner CJ, Bateman LA, et al. Effects of exercise training in-
tensity on pancreatic beta-cell function. Diabetes Care 2009;32:1807–11.
12. Kahn SE, Larson VG, Beard JC, et al. Effect of exercise on insulin
action, glucose tolerance, and insulin secretion in aging. Am J Physiol
1990;258:E937–43.
13. Kirwan JP, Kohrt WM, Wojta DM, Bourey RE, Holloszy JO. Endurance
exercise training reduces glucose-stimulated insulin levels in 60- to
70-year-old men and women. J Gerontol 1993;48:M84–90.
14. Utzschneider KM, Carr DB, Barsness SM, Kahn SE, Schwartz RS.
Diet-induced weight loss is associated with an improvement in beta-cell
function in older men. J Clin Endocrinol Metab 2004;89:2704–10.
15. Brons C, Jensen CB, Storgaard H, et al. Impact of short-term high-fat
feeding on glucose and insulin metabolism in young healthy men.
J Physiol 2009;587:2387–97.
16. Del Prato S, Leonetti F, Simonson DC, Sheehan P, Matsuda M,
DeFronzo RA. Effect of sustained physiologic hyperinsulinaemia and
hyperglycaemia on insulin secretion and insulin sensitivity in man.
Diabetologia 1994;37:1025–35.
17. Hribal ML, Perego L, Lovari S, et al. Hyperglycemia impairs insulin
secretion by affecting insulin receptor expression, splicing, and signal-
9 of 10
ing in RIN beta cell line and human islets of Langerhans. FASEB J
2003;17:1340–2.
18. Fukagawa NK, Anderson JW, Hageman G, Young VR, Minaker KL.
High-carbohydrate, high-fiber diets increase peripheral insulin sen-
sitivity in healthy young and old adults. Am J Clin Nutr 1990;52:
524–8.
19. Salmeron J, Manson JE, Stampfer MJ, Colditz GA, Wing AL, Willett
WC. Dietary fiber, glycemic load, and risk of non-insulin-dependent
diabetes mellitus in women. JAMA 1997;277:472–7.
20. Rizkalla SW, Taghrid L, Laromiguiere M, et al. Improved plasma glu-
cose control, whole-body glucose utilization, and lipid profile on a low-
glycemic index diet in type 2 diabetic men: a randomized controlled trial.
Diabetes Care 2004;27:1866–72.
21. Pittas AG, Das SK, Hajduk CL, et al. A low-glycemic load diet facili-
tates greater weight loss in overweight adults with high insulin secretion
but not in overweight adults with low insulin secretion in the CALERIE
Trial. Diabetes Care 2005;28:2939–41.
22. Kirwan JP, O’Gorman D, Evans WJ. A moderate glycemic meal before
endurance exercise can enhance performance. J Appl Physiol 1998;84:53–9.
23. Febbraio MA, Keenan J, Angus DJ, Campbell SE, Garnham AP. Pre-
exercise carbohydrate ingestion, glucose kinetics, and muscle glycogen
use: effect of the glycemic index. J Appl Physiol 2000;89:1845–51.
24. Stevenson EJ, Thelwall PE, Thomas K, Smith F, Brand-Miller J, Trenell
MI. Dietary glycemic index influences lipid oxidation but not muscle or
liver glycogen oxidation during exercise. Am J Physiol Endocrinol
Metab 2009;296:E1140–7.
25. Solomon TP, Haus JM, Kelly KR, et al. Randomized trial on the effects
of a 7-d low-glycemic diet and exercise intervention on insulin resistance
in older obese humans. Am J Clin Nutr 2009;90:1222–9.
26. Botero D, Ebbeling CB, Blumberg JB, et al. Acute effects of dietary
glycemic index on antioxidant capacity in a nutrient-controlled feeding
study. Obesity (Silver Spring) 2009;17:1664–70.
27. Zhou J, Livak MF, Bernier M, et al. Ubiquitination is involved in
glucose-mediated downregulation of GIP receptors in islets. Am J
Physiol Endocrinol Metab 2007;293:E538–47.
28. Vollmer K, Gardiwal H, Menge BA, et al. Hyperglycemia acutely lowers
the postprandial excursions of glucagon-like Peptide-1 and gastric in-
hibitory polypeptide in humans. J Clin Endocrinol Metab 2009;94:
1379–85.
29. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method
for quantifying insulin secretion and resistance. Am J Physiol 1979;237:
E214–23.
30. Eaton RP, Allen RC, Schade DS, Erickson KM, Standefer J. Prehepatic
insulin production in man: Kinetic analysis using peripheral connecting
peptide behavior. J Clin Endocrinol Metab 1980;51:520–8.
31. Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, Mari A, DeFronzo
RA. Thiazolidinediones improve beta-cell function in type 2 diabetic
patients. Am J Physiol Endocrinol Metab 2007;292:E871–83.
32. Holst JJ, Vilsboll T, Deacon CF. The incretin system and its role in type
2 diabetes mellitus. Mol Cell Endocrinol 2009;297:127–36.
33. Meier JJ, Hucking K, Holst JJ, Deacon CF, Schmiegel WH, Nauck MA.
Reduced insulinotropic effect of gastric inhibitory polypeptide in first-
degree relatives of patients with type 2 diabetes. Diabetes 2001;50:
2497–504.
34. Fritsche A, Stefan N, Hardt E, Haring H, Stumvoll M. Characterisation
of beta-cell dysfunction of impaired glucose tolerance: evidence for
impairment of incretin-induced insulin secretion. Diabetologia 2000;43:
852–8.
35. Kjems LL, Holst JJ, Volund A, Madsbad S. The influence of GLP-1 on
glucose-stimulated insulin secretion: effects on beta-cell sensitivity in
type 2 and nondiabetic subjects. Diabetes 2003;52:380–6.
36. Meneilly GS, Ryan AS, Minaker KL, Elahi D. The effect of age and
glycemic level on the response of the beta-cell to glucose-dependent
insulinotropic polypeptide and peripheral tissue sensitivity to endoge-
nously released insulin. J Clin Endocrinol Metab 1998;83:2925–32.
37. Kashyap SR, Daud S, Kelly KR, et al. Acute effects of gastric bypass
versus gastric restrictive surgery on beta-cell function and insulinotropic
hormones in severely obese patients with type 2 diabetes. Int J Obes
(Lond) 2010;34:462–71.
38. Poitout V, Robertson RP. Glucolipotoxicity: fuel excess and beta-cell
dysfunction. Endocr Rev 2008;29:351–66.
39. Xu G, Kaneto H, Laybutt DR, et al. Downregulation of GLP-1 and GIP
receptor expression by hyperglycemia: possible contribution to impaired
incretin effects in diabetes. Diabetes 2007;56:1551–8.
10 of 10 SOLOMON ET AL
40. Mooney MH, Abdel-Wahab YH, Morgan LM, O’Harte FP, Flatt PR.
Detection of glycated gastric inhibitory polypeptide within the intestines
of diabetic obese (ob/ob) mice. Endocrine 2001;16:167–71.
41. Solomon TP, Haus JM, Kelly KR, Rocco M, Kashyap SR, Kirwan JP.
Improved pancreatic b-cell function in type 2 diabetics following life-
style-induced weight loss is related to glucose-dependent insulinotropic
polypeptide. Diabetes Care 2010;33:1561–6.
42. Kelly KR, Brooks LM, Solomon TP, Kashyap SR, O’Leary VB, Kirwan
JP. The glucose-dependent insulinotropic polypeptide and glucose-
stimulated insulin response to exercise training and diet in obesity. Am J
Physiol Endocrinol Metab 2009;296:E1269–74.
43. Pereira MA, Swain J, Goldfine AB, Rifai N, Ludwig DS. Effects of
a low-glycemic load diet on resting energy expenditure and heart disease
risk factors during weight loss. JAMA 2004;292:2482–90.
44. McKeown NM, Meigs JB, Liu S, et al. Dietary carbohydrates and car-
diovascular disease risk factors in the Framingham offspring cohort.
J Am Coll Nutr 2009;28:150–8.
45. Das SK, Gilhooly CH, Golden JK, et al. Long-term effects of 2
energy-restricted diets differing in glycemic load on dietary adherence,
body composition, and metabolism in CALERIE: a 1-y randomized
controlled trial. Am J Clin Nutr 2007;85:1023–30.
46. Bouche C, Rizkalla SW, Luo J, et al. Five-week, low-glycemic index
diet decreases total fat mass and improves plasma lipid profile in mod-
erately overweight nondiabetic men. Diabetes Care 2002;25:822–8.
47. Pittas AG, Roberts SB, Das SK, et al. The effects of the dietary glycemic
load on type 2 diabetes risk factors during weight loss. Obesity (Silver
Spring) 2006;14:2200–9.
48. Levitan EB, Mittleman MA, Wolk A. Dietary glycemic index, dietary
glycemic load and mortality among men with established cardiovascular
disease. Eur J Clin Nutr 2009;63:552–7.
49. Wolever TM, Gibbs AL, Mehling C, et al. The Canadian Trial of Car-
bohydrates in Diabetes (CCD), a 1-y controlled trial of low--
glycemic-index dietary carbohydrate in type 2 diabetes: no effect on
glycated hemoglobin but reduction in C-reactive protein. Am J Clin Nutr
2008;87:114–25.
50. Kirwan JP, Barkoukis H, Brooks LM, Marchetti CM, Stetzer BP,
Gonzalez F. Exercise training and dietary glycemic load may have
synergistic effects on insulin resistance in older obese adults. Ann Nutr
Metab 2009;55:326–33.
51. Cheong SH, McCargar LJ, Paty BW, Tudor-Locke C, Bell RC. The First
Step First Bite Program: guidance to increase physical activity and daily
intake of low-glycemic index foods. J Am Diet Assoc 2009;109:1411–6.