Effects of a low-fat dietary intervention on glucose, insulin,
and insulin resistance in the Women’s Health Initiative (WHI)
Dietary Modification trial1–3
James M Shikany, Karen L Margolis, Mary Pettinger, Rebecca D Jackson, Marian C Limacher, Simin Liu,
Lawrence S Phillips, and Lesley F Tinker
Background: Glycemic effects of the Women’s Health Initiative
(WHI) low-fat dietary intervention are unknown.
Objective: Our objective was to analyze the effects of the WHI
low-fat dietary intervention on serum glucose and insulin and in-
sulin resistance up to 6 y after random assignment.
Design: Postmenopausal WHI Dietary Modification trial interven-
tion (DM-I) and comparison (DM-C) participants with blood meas-
ures at least at baseline and year 1 (n = 2263) were included.
Anthropometric measures, dietary assessments, serum glucose and
insulin concentrations, homeostasis model assessment of insulin
resistance (HOMA-IR) measures, and quantitative insulin sensitiv-
ity check index (QUICKI) values were obtained at baseline, year 1,
year 3, and year 6. Changes in measures were compared between
groups at years 1, 3, and 6 overall and within stratified analyses.
Results: Mean (6SD) differences in changes at year 1 between the
DM-I and DM-C groups were as follows: glucose, 21.7 6 17.9 mg/
dL; insulin, 20.7 6 5.1 lIU/mL; HOMA-IR, 20.2 6 1.9; and
QUICKI, 0.004 6 0.019 (all P , 0.05). Similar findings resulted
from repeated-measures analyses comparing the intervention and
comparison groups over the 6 y. Whereas normoglycemic women
at baseline had a decrease in glucose at year 1 that was 1.9 6
17.2 mg/dL greater in the DM-I than in the DM-C group, diabetic
women had an increase in glucose that was 7.9 6 20.3 mg/dL greater
in the DM-I than in the DM-C group (P for interaction ,0.001).
Conclusions: A low-fat diet was not significantly associated with
adverse glycemic effects up to 6 y after random assignment in post-
menopausal women. However, diabetic women experienced adverse
glycemic effects of the low-fat diet. This trial is registered at clin-
icaltrials.gov as NCT00000611.Am J Clin Nutr 2011;94:75–85.
remains a major controversy in nutritional science. Low-fat diets
in general, and the Women’s Health Initiative (WHI) low-fat
dietary intervention in particular, have been criticized for their
potentialto substitute unhealthy carbohydrates forfat, potentially
contributing to hyperglycemia, hyperinsulinemia, and insulin
The WHI Dietary Modification (DM) trial was designed to test
the effects of a dietary pattern low in total fat, along with in-
creased vegetables, fruit, and grains, on primarily breast cancer
and colorectal cancer incidence in postmenopausal women
during a mean follow-up of 8.1 y. Despite the increased intake of
carbohydrate in the intervention group, and question of associ-
ated increased risk of diabetes, no increase in diabetes risk was
observed. Subgroup analysis suggested that greater decreases in
percentage of energy from total fat reduced diabetes risk (P for
trend = 0.04); however, that finding was not statistically sig-
nificant after adjustment for weight loss—a common effect of
eating a low-fat diet (2).
Details of the effects of the WHI diet intervention on glucose,
insulin, and insulin resistance have not been reported. The aim of
this report was to analyze the effect of the overall diet in-
tervention, and the specific effects of fiber and whole grain
intakes, and dietary glycemic index (GI) and glycemic load (GL)
on glucose, insulin, and insulin resistance in the WHI DM trial.
SUBJECTS AND METHODS
WHI DM trial
Details of the study design and methods were published pre-
viously (3). All women provided written informed consent, and
1From the Division of Preventive Medicine, School of Medicine, Univer-
sity of Alabama at Birmingham, Birmingham, AL (JMS); HealthPartners
Research Foundation, Minneapolis, MN (KLM); the Division of Public
Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
(MP and LFT); the Department of Internal Medicine, Division of Endocri-
nology, Diabetes and Metabolism, The Ohio State University, Columbus, OH
(RDJ); the Division of Cardiovascular Medicine, University of Florida Col-
lege of Medicine, Gainesville, FL (MCL); the Department of Epidemiology,
University of California, Los Angeles, Los Angeles, CA (SL); and the At-
lanta VA Medical Center and Division of Endocrinology, Department of
Medicine, Emory University School of Medicine, Atlanta, GA (LSP).
2Supported by the National Heart, Lung, and Blood Institute, National
Institutes of Health, US Department of Health and Human Services (contract
numbers N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13,
32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221).
3Address correspondence to JM Shikany, Division of Preventive Medi-
cine, School of Medicine, University of Alabama at Birmingham, 1530 3rd
Avenue S, MT 610, Birmingham, AL 35294. E-mail: email@example.com.
Received December 21, 2010. Accepted for publication April 15, 2011.
First published online May 11, 2011; doi: 10.3945/ajcn.110.010843.
Am J Clin Nutr 2011;94:75–85. Printed in USA. ? 2011 American Society for Nutrition
the study was approved by the National Institutes of Health and
the institutional review boards at each of the clinical centers and
women between the ages of 50 and 79 y were enrolled between
1993 and 1998 at 40 clinical centers across the United States (4).
Participants were assigned randomly to an intervention group
(40%, n = 19,541) or a usual-diet comparison group (60%, n =
29,294), stratified by clinical center site and age group.
Eligibility criteria included consumption of a baseline a diet
with a total fat intake ?32% of total energy, as assessed by
a food-frequency questionnaire (FFQ). Major exclusions for the
WHI included prior breast or colorectal cancer, other cancers
(except nonmelanoma skin cancer) in the past 10 y, medical
conditions with a predicted survival ,3 years, and compliance
concerns such as alcoholism. Additional DM trial-specific ex-
clusions included type 1 diabetes and frequent consumption of
meals prepared away from home.
The DM intervention was designed to promote dietary
change, with the goals of reducing intake of total fat to 20% of
energy and increasing vegetable and fruit consumption to ?5
servings and grains to ?6 servings daily (5). The intervention
did not include total energy reduction or weight-loss goals. The
intensive behavioral-modification program involved 18 group
sessions in the first year and quarterly maintenance sessions
thereafter, led by specially trained and certified nutritionists.
Group activities were supplemented during the intervention
period by individual contacts, completed by telephone or mail.
Each participant was assigned her own fat gram goal, calcu-
lated on the basis of height. Participants self-monitored total fat
gram intake and also servings of vegetables, fruit, and grains. No
formal intervention regarding saturated fat, cholesterol, trans fatty
acids, or other known atherogenic factors was provided.
Comparison-group participants received a copy of the Di-
etary Guidelines for Americans (6) and other health-related
materials available to all WHI participants (such as informa-
tion about Pap tests and breast exams and guides to quitting
smoking), but had no contact with the nutrition interventionists.
Interested and eligible women were allowed to join 1, 2, or all 3
of the WHI clinical trial components: DM trial, Hormone Ther-
apy trial, or Calcium and Vitamin D trial (7). Of the total DM
enrollment of 48,836, 10,553 (21.6%) participated in only the DM
trial, 8050 (16.5%) in the DM and the Hormone Therapy trial,
25,210 (51.6%) in the DM and the Calcium and Vitamin D trial,
and 5017 (10.3%) in all 3 trials.
Participants were followed from the date of entry until the
trial’s planned completion date, loss to follow-up, the time that
aparticipant requested no further contact,or death,regardless of
their compliance with the dietary intervention. DM trial par-
ticipants were contacted by clinic staff at 6-mo intervals to
provide information on health outcomes.
All DM participants completed an FFQ, designed specifically
for the study, at baseline and at 1 y (8). Thereafter, one-third of
the participants completed the FFQ each year in a rotating
sample; completion rates were 100% at baseline and 81%
thereafter. Data on dietary intake for the year 6 follow-up were
computed from the FFQs administered from years 5 through 7,
thus including all participants. The methods for assigning GI
and GL values used in the WHI FFQ were reported elsewhere
(9).Briefly,GI valuesweretaken frompublished reports orwere
imputed from GI values of foods with similar composition and
preparation, by using glucose as the reference standard. A
composite GI was computed by a weighted average for FFQ line
items with multiple foods. The GL was computed by multi-
plying the GI by grams of carbohydrate consumed according to
the number and frequency of servings and portion size.
The current study uses data from the 5.8% (n = 2816) subset of
DM trial participants for whom blood samples were collected,
and serum was analyzed at baseline and years 1, 3, and 6. The
subsample for blood sample collection was randomly chosen
from all 40 WHI clinical centers, with oversampling of minority
women and Hormone Therapy trial participants, where the odds
for selection were 6-fold higher than for white women and higher
among the Hormone Therapy trial participants (8.6% sampling
rate) than among the DM participants (4.3% sampling rate).
Excluded from the analyses were participants without glucose and
insulin results at least at baseline and year 1 (n = 504), who self-
reported taking insulin at baseline (n = 46) (although participants
with diabetes at baseline not taking insulin were included), with
baseline insulin .170 lIU/mL (n = 1), and having a change in
insulin between baseline and year 1 .100 lIU/mL (n = 2), which
resulted in a final analytic cohort of 2263 participants.
Blood samples were collected in the fasting state (?12 h) and
were maintained at 4?C for up to 1 h until plasma or serum was
separated from cells. Centrifuged aliquots were stored in
freezers (at 270?C) within 2 h of collection and sent on dry ice
to the central repository, where storage at 270?C was main-
tained. Serum glucose was measured by using the hexokinase
method on the Hitachi 747 analyzer (Boehringer Mannheim
Diagnostics, Indianapolis, IN) (10). Serum insulin was mea-
sured by using a step-wise sandwich enzyme-linked immuno-
assay procedure on an ES 300 analyzer (Boehringer Mannheim
Diagnostics, Indianapolis, IN) (11). Insulin resistance was
calculated from fasting glucose and insulin according to the
homeostasis model assessment of insulin resistance (HOMA-
IR) (12). We also conducted analyses using another method of
calculating insulin sensitivity—the quantitative insulin sensi-
tivity check index (QUICKI) (13).
by randomization assignment with the use of chi-square tests.
Means and standard deviations were computed fornutrient intake
data from the FFQ, physical activity levels collected from
standardized questionnaires, physical measurements, and labo-
ratory data at baseline, year 1, year 3, and year 6. Differences in
means between intervention and comparison groups for baseline,
year 1, year 3, and year 6 were computed and tested for signifi-
cance by using a 2-sample paired t test. Because of non-normal
distributions, means and t tests of insulin and HOMA-IR were
SHIKANY ET AL
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LOW-FAT DIET, GLUCOSE, AND INSULIN IN THE WHI