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Qualified health claim for whole-grain intake and risk of type 2
diabetes: an evidence-based review by the US Food and Drug
Administration
Sedigheh Yamini and Paula R. Trumbo
The objective of this review is to explain how the US Food and Drug Administration
(FDA) used its evidence-based review system to evaluate the scientific evidence for
a qualified health claim on the role of whole-grain consumption in reducing the
risk of type 2 diabetes. The labeling of health claims, including qualified health
claims, on conventional foods and dietary supplements requires premarket approval by the FDA. Health claims characterize the relationship between a substance
(food or food component) and a disease (eg, diabetes or cardiovascular disease) or
a health-related condition (eg, hypertension). This review describes the FDA’s evaluation of intervention and observational studies that characterize a relationship between whole grains and type 2 diabetes. This evidence-based review provides very
limited evidence to support a health claim of a relationship between intake of
whole grains and a reduced risk of type 2 diabetes.
INTRODUCTION
Type 2 diabetes is one of the most prevalent diseases in
the United States.1 The risk of developing type 2 diabetes
is associated with many factors, including obesity, race,
and ethnicity.1 Increased whole-grain consumption has
been reported to lower the risk of weight gain/obesity
and type 2 diabetes. Conflicting results reporting a beneficial effect or no effect have been reported for a relationship between whole grains and type 2 diabetes. The
majority of the studies evaluated foods that US Food and
Drug Administration (FDA) does not consider to be a
whole grain (eg, wheat germ, bran cereals, or pearled barley). In determining what foods should be considered
whole grains, the FDA is guided by its 2006 draft guidance entitled Whole Grain Label Statements.2 In this draft
guidance, the FDA describes whole grains as cereal grains
that consist of the intact, ground, cracked, or flaked caryopsis and whose principal anatomical components (the
starchy endosperm, germ, and bran) are present in the
same relative proportions as they exist in the intact caryopsis. The draft guidance listed the following examples of
cereal grains: amaranth, whole-grain barley, buckwheat,
bulgur, corn (including popcorn), millet, quinoa, rice,
rye, oats, sorghum, teff, triticale, wheat, brown rice, and
wild rice. The addition of individual parts of a whole
grain, such as bran, to a food does not make the food
“whole grain,” because such ingredients do not contain
the entire grain with all its components.
This review explains how the agency used its
evidence-based review system3 to evaluate a qualified
health claim regarding whole-grain consumption and type
2 diabetes, using the FDA’s definition of whole grain.
HEALTH CLAIMS
The Nutrition Labeling and Education Act of 1990 authorized the FDA to allow a health claim statement on
Affiliation: Sedigheh Yamini and Paula R. Trumbo are with the Office of Nutrition and Food Labeling, Center for Food Safety and Applied
Nutrition, US Food and Drug Administration, College Park, Maryland, USA.
Correspondence: S. Yamini, 5100 Campus Dr, HFS – 830, College Park, MD 20740, USA. Email: [email protected]. Phone: þ1-240402-1681.
Key words: diabetes, health claim, type 2 diabetes, whole grains.
Published by Oxford University Press on behalf of International Life Sciences Institute 2016. This work is written by US Government
employees and is in the public domain in the United States.
doi: 10.1093/nutrit/nuw027
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601
the labeling of conventional foods and dietary supplements that describes a relationship between a substance
(food or food component) and a disease (eg, cancer,
type 2 diabetes) or a health-related condition. A healthrelated condition is a condition (eg, hypertension) that
is essentially indistinguishable from a disease (eg, coronary heart disease) and/or is a surrogate marker for risk
of a specific disease (eg, insulin resistance for type 2 diabetes). The labeling of conventional foods and dietary
supplements with health claims requires premarket approval by the FDA. Health claims were first authorized
by the US Congress using the significant scientific
agreement (SSA) standard. The SSA standard is a rigorous standard that requires a high level of confidence in
the validity of a substance–disease relationship.3 An
SSA health claim is authorized through the rule-making
process. In contrast to SSA health claims, qualified
health claims are based on less scientific evidence and
are accompanied by qualifying language to reflect the
level of science supporting the claim. Qualified health
claims were established for the labeling of dietary supplements after court decisions regarding First
Amendment issues. The pivotal court ruling (Pearson v
Shalala) concluded that the First Amendment protection of commercial speech does not permit the agency
to reject health claims that it determines to be potentially misleading unless the agency also reasonably determines that a disclaimer would not eliminate the
potential deception.4 A subsequent FDA initiative resulted in the establishment of qualified health claims for
the labeling of conventional foods as well.5 Qualified
health claims are issued through letters of enforcement
discretion. When a letter of enforcement discretion has
been issued, the FDA does not object to the use of the
claim specified in the letter, provided the products that
bear the claim are consistent with the stated criteria.
Both SSAs and qualified health claims pertain to disease
risk reduction in the general US population or a target
subgroup (eg, women, children, or elderly) that does
not have the disease that is the subject of the claim.
EVIDENCE-BASED REVIEW OF HEALTH CLAIMS
BY THE FDA
A detailed and thorough premarket review of the scientific evidence is a key part of the process for evaluating
either authorized (SSA) or qualified health claims. In
2009, the FDA published a guidance document on the
evidence-based review system for the scientific review
of health claims.3 On the basis of this guidance, the
FDA reviews all scientific evidence (eg, supportive and
not supportive) related to a specific health claim that
the petitioner is required to provide in support of the
claim. Through a literature search, the agency identifies
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additional studies that it considers relevant to the petitioned health claim. The agency separates individual reports of human studies from other types of data and
information. The FDA focuses its review on reports of
interventional and observational studies in humans, because scientific conclusions about the substance–disease
relationship in humans can only be drawn from such
studies. In addition to individual reports of human
studies, the agency also considers data from other sources, such as meta-analyses, review articles, and animal
and in vitro studies. Although this type of data and information can assist the agency in understanding the
scientific issues about the substance, the disease or
health-related condition, or both, it cannot by itself support a health claim relationship.
The FDA evaluates the individual reports of human
studies to determine whether any scientific conclusions
can be drawn from each study. The human studies that
lack critical criteria, such as a control group or an appropriate statistical analysis, are eliminated from further review because they cannot be the basis for scientific
conclusions about the health claim relationship.6,7
Moreover, it is important that the study population is
relevant to the general US population or subgroup identified in the proposed claim. Therefore, each study is
evaluated to determine if the study population lives in an
area where malnutrition or inadequate intakes of the
specific substance are common and/or where the prevalence or etiology of the disease that is the subject of the
claim is different from that in the United States (eg, risk
factors for gastric cancer in certain Asian countries).3
Differences in nutrition, diet, and disease risk factors
between the United States and the country where a study
was conducted may mean that the study results cannot
be extrapolated to the US population or population
subgroup.3 Health claims are statements about reducing
the risk of a disease in people who do not already have
the disease that is the subject of the claim. The FDA may
consider evidence from studies in individuals diagnosed
with the disease that is the subject of the health claim
only if extrapolation of that evidence to individuals who
do not have the disease is scientifically appropriate.
The FDA rates the relevant human intervention
and observational studies for methodological quality.
This quality rating is based on several criteria related
to study design (eg, use of a placebo-controlled vs a
non–placebo-controlled group), data collection (eg,
type of dietary assessment method), quality of the statistical analysis, type of outcome measured (eg, disease
incidence vs validated surrogate endpoint), and study
population characteristics other than relevance to the
US population (eg, selection bias and whether important information about the study subjects, such as age
or smoking status, was gathered and reported).3
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Finally, the agency rates the strength of the total
body of publicly available evidence by considering the
following: (1) the study type (eg, intervention, prospective cohort, case–control, cross-sectional); (2) the methodological quality rating assigned; (3) the quantity of
evidence (number of the various types of studies and
sample sizes); (4) whether the body of scientific evidence supports a health claim relationship for the US
population or target subgroup; (5) whether study results
supporting the proposed claim have been replicated;
and (6) the overall consistency of the total body of evidence. On basis of the totality of the scientific evidence,
the FDA then determines whether such evidence is
credible to support the substance–disease relationship,
and, if so, either authorizes an SSA health claim or,
through a letter of enforcement discretion, issues a
qualified health claim that reflects the level of scientific
evidence.3
SURROGATE ENDPOINTS FOR TYPE 2 DIABETES
The FDA uses surrogate endpoints that have been identified by the National Institutes of Health and the
FDA’s Center for Drug Evaluation and Research as
qualified biomarkers for predicting the risk of a disease.
In addition to the incidence of type 2 diabetes, the FDA
recognizes 3 surrogate endpoints for assessing type 2 diabetes risk for purposes of a health claim evaluation: (1)
fasting blood glucose concentration; (2) oral glucose tolerance; and (3) insulin resistance. Insulin resistance is
assessed by various measurements of insulin sensitivity,
including the euglycemic hyperinsulinemic clamp
method, the homeostasis model assessment (HOMA),
and the quantitative insulin sensitivity check index
(QUICK1).
CONSIDERATION OF THE QUALIFIED HEALTH CLAIM
BY THE FDA
A petition submitted to the FDA requested a qualified
health claim for the relationship between the consumption of whole grains and a reduced risk of type 2
diabetes in the general US population. The petition
cited 55 publications as evidence to substantiate the
risk-reduction relationship for the proposed claim, including 19 human intervention studies8–26 and 23 publications27–49 examining 24 observational studies to
evaluate the relationship between whole-grain consumption and reduction of risk of type 2 diabetes. In
addition to these individual studies, the petition cited
several publications50–59 on the history or consumption of whole grains, the history of agriculture, or the
world agriculture supply and demand; diabetes data
and trends; a position statement; 2 meta-analyses27,45;
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and 1 systematic review.60 The publication by de
Munter et al.,27 which included a meta-analysis, also
reported data from 2 observational studies: the Nurses’
Health Study I (NHS I) and the Nurses’ Health Study
II (NHS II). Similarly, the publication by Sun et al.45
included individual reports of 3 observational studies
– the NHS I, the NHS II, and the Health Professionals
Follow-Up Study (HPFS) – as well as a meta-analysis.
Therefore, the FDA considered each of these publications in both the meta-analysis category and the observational studies category.
In addition to the publications cited in the petition,
comments provided during the public comment period
for the petition identified 21 additional human intervention studies61–82 and 17 additional observational
studies83–99 that evaluated the relationship between
whole-grain intake and reduction of risk of type 2
diabetes.
Through a literature search, the agency identified 1
additional relevant intervention study100 that evaluated
the relationship between whole-grain intake and risk of
type 2 diabetes.
As mentioned above, the agency must be able to
review the critical elements of a study to determine
whether any scientific conclusions can be drawn.
Therefore, review articles, meta-analyses, and reports
of studies on a different substance or a disease that
was not the subject of the petition could not be
used.27,45,50–60
EVALUATION OF INTERVENTION STUDIES
The FDA evaluated 41 reports of intervention studies
that were designed to evaluate the relationship between
whole-grain intake and risk of type 2 diabetes.8–26,61–82
Some of these studies evaluated the effects of whole
grains as a category of food, while others were limited
to single forms of whole grains (eg, brown rice, oats).
Of the 41 intervention studies reviewed, scientific conclusions could not be drawn from 35 studies. For 31 of
these studies,8,10,11,14–17,19–21,23,25,62–66,68–80,82 the study
duration was too short (90 minutes to 12 hours) to
provide any information about the long-term effect of
whole-grain consumption on reduction of risk of type 2
diabetes. Such short-term studies were designed to assess the glycemic index or glycemic load of foods. The
glycemic index is a function of the food’s immediate effect on blood glucose levels rather than the long-term
effect of whole-grain consumption on the body’s ability
to metabolize glucose, such that lower blood glucose
levels may result in increased insulin sensitivity.
Therefore, the agency could not draw scientific conclusions from these studies.
603
The remaining 4 studies18,22,61,67 identified their
substances as whole grains that, on the basis of the
FDA definition, were not considered whole grains. For
example, Juntunen et al.18 considered rye bread made
with added rye bran (to increase the bread’s dietary fiber content) as whole grain. Another study22 did not
specify the composition of the foods studied in a manner clear enough for the FDA to determine whether
the foods were actually whole grains. Another study61
investigated the effects of the Nordic diet, which contains whole grains and other high-fiber plant foods like
fruits, berries, nuts, and vegetables. One intervention
study investigated legumes, seeds, and vegetables in
addition to whole grains.67 Because these 4 studies
may have evaluated substances other than, or in addition to, whole grains contained in the diet, no scientific conclusions could be drawn about whether,
specifically, whole grains may reduce the risk of type 2
diabetes.
Six intervention studies were available from which
scientific conclusions could be drawn about the relationship between whole-grain intake and risk of type 2
diabetes9,12,13,24,26,100 (Table 1). Andersson et al.9 conducted a high-quality randomized crossover intervention study of 30 Swedish overweight and obese (body
mass index [BMI] 28 6 2 kg/m2) men (n ¼ 8) and
women (n ¼ 22). These participants did not have type 2
diabetes but were at high risk, with 1 or more of the following symptoms: elevated serum insulin, elevated fasting blood glucose, elevated triglycerides, reduced highdensity lipoprotein, or borderline hypertension. The
subjects followed their habitual diets but were advised
to incorporate a fixed amount (112 g/d, or about 7 servings per day) of whole-grain foods (intervention group)
or refined-grain foods (control group) for a period of 6
weeks in each diet. The whole-grain products provided
were defined as foods for which whole grains (including
the bran, germ, and starchy endosperm), mainly in
milled form, provided 50% of the dry weight of the
product. Both whole grains and refined grains were
provided to the subjects during the study period.
Compliance with the dietary intervention was monitored by diaries, including a structured list to verify
daily portions eaten, and subjects adhered to their prescribed diets. Insulin sensitivity was directly measured
by the euglycemic hyperinsulinemic clamp method.
The subjects did not lose weight, and their insulin sensitivity and fasting blood glucose levels were not significantly different between the whole-grain and refinedgrain groups.
Brownlee et al.12 conducted a high-quality 16week parallel intervention study in 266 overweight
men and women (BMI >25 kg/m2) at 2 centers in the
United Kingdom. The subjects were randomly divided
604
into 3 groups: group 1 (control group) (n ¼ 100; no
dietary changes); group 2 (n ¼ 85; 60 g of whole grains
per day for 16 weeks); and group 3 (n ¼ 81; 60 g of
whole grains per day for 8 weeks followed by 120 g of
whole grains per day for 8 weeks). Whole-grain foods
were provided to the subjects, who were instructed to
substitute refined-grain foods with an equivalent
amount of whole grains. Seven-day food frequency
questionnaires were used to assess compliance, and on
average the subjects adhered to their assigned diets.
Fasting blood glucose and serum insulin were measured to calculate insulin resistance on the basis of
the QUICK1 method. There was no significant difference in fasting blood glucose or insulin resistance
between either of the intervention groups and the control group.
Giacco et al.13 performed a moderate-quality randomized crossover study in 15 healthy overweight/
obese (BMI, 27.4 6 3.0 kg/m2) Italian men (n ¼ 12) and
women (n ¼ 3). After a 2-week run-in period, the subjects were randomly assigned to follow 2 isocaloric diets
for 3 weeks each. The subjects were advised not to modify their habitual intake of nongrain foods (meats, dairy
products, eggs, fish, fruits, and vegetables) during the
study. The only difference between the 2 diets was the
inclusion of a fixed amount of whole-wheat (ie, wholegrain) foods or refined-wheat foods (control) as the
main carbohydrate source at all meals. Both whole
grains and refined grains were provided to the subjects.
Compliance with the diets was evaluated using a 7-day
food record at the start of the study, during the study,
and at the end of the study. The subjects’ compliance
with both diets was good. There was no significant difference in fasting blood glucose or insulin resistance
(calculated by HOMA) between the whole-grain and
refined-grain groups.
Rave et al.24 conducted a moderate-quality randomized crossover study in 31 obese (BMI,
33.9 6 2.7 kg/m2) German men (n ¼ 13) and women
(n ¼ 18) with elevated fasting blood glucose levels but
without a diagnosis of type 2 diabetes. The participants
in the whole-grain group consumed a diet containing
whole-grain double-fermented wheat for 4 weeks, and
those in the control group consumed a diet containing
a nutrient-dense, high-fiber meal-replacement product
that contained no whole grains (the reference meal),
also for 4 weeks. The whole-grain group replaced at
least 2 daily meals with either the double-fermented
wheat or the reference meal, with the target consumption being 200 g of the assigned product per day. Both
the whole-grain and the reference meals were provided
in a powder form and were prepared in portions equivalent in calorie content. Subjects in the whole-grain
group were instructed to dissolve the whole-grain
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605
Study design
4-wk randomized, crossover
Rave et al. (2007)24
12-wk randomized, parallel
Study population
30 overweight/obese men
and women at risk of type
2 diabetes in Sweden
316 overweight and obese
men and women in the
UK; 81–85 in each intervention group and 100 in
control group
15 healthy normal-weight/
overweight/obese men
and women in Italy
31 obese men and women at
risk of type 2 diabetes in
Germany
43 normal-weight/overweight/moderately obese
men and women in the
USA
206 normal-weight/overweight/moderately obese
men and women in the UK
Abbreviations: NA, not available; , no effect at P < 0.05.
Tighe et al. (2010)100
Saltzman et al. (2001)26 6-wk randomized, parallel
3-wk randomized, crossover
Giacco et al. (2010)13
Brownlee et al. (2010)12 16-wk randomized, controlled, parallel
Andersson et al. (2007)9 6-wk randomized, crossover
Reference
Table 1 Summary of intervention studies on whole grains and type 2 diabetes
70–80 g of whole-wheat
bread plus 30–40 g of
whole-grain cereals; or 1
serving of whole-wheat
food and 2 servings of oats
(no amount given)
45 g/1000 kcal rolled oats
200 g/d (double-fermented
whole wheat)
NA
60–120 g/d
112 g/d
Whole-grain intake level
Beneficial effect after adjustment for body-weight loss
(P < 0.049)
Insulin resistance
Fasting blood
glucose
Results
NA
NA
NA
NA
NA
NA
Oral glucose tolerance test
powder in water, skim milk, or yogurt, while those in
the reference-meal group were instructed to dissolve
the powder in skim milk. All subjects were interviewed
by a dietitian during the first, second, and third week of
the study to assess compliance with the study diet,
changes in body weight, and any potential adverse
events. In addition, they recorded their daily food intake each day, using a standardized questionnaire. All
participants adhered to their prescribed diets. After 4
weeks, each group showed a loss in body weight, lower
fasting blood glucose levels, and improved insulin resistance (calculated by HOMA), but there were no significant differences between the groups. After statistical
adjustment for body weight reduction, insulin resistance was significantly reduced in the whole-grain
group compared with the control group (P < 0.049).
Notably, the powdered, double-fermented whole-grain
product used in this study was significantly different
from the whole-grain products generally available for
purchase in the United States.101
The study by Saltzman et al.26 was a moderatequality 8-week parallel intervention that included 43
healthy US adults with a BMI of 26.4 6 3.3 kg/m2. The
8-week protocol was divided into a 2-week weightmaintenance phase (phase 1), during which habitual
diets were consumed, followed by a 6-week weight-loss
phase (phase 2). During phase 2, the subjects consumed
1 of 2 reduced-calorie diets (weight-maintenance calories minus 1000 kcal/d). The intervention group
(n ¼ 22) received a diet that included 45 g of rolled
whole-grain oats (roughly equivalent to 1.5 servings of
oatmeal) per 1000 kcal. The control group (n ¼ 21) received a diet equivalent in calories to the intervention
group diet, but without oats. The 2 diets were matched
for insoluble fiber, fat, protein, and carbohydrate content. All foods and calorie-containing beverages were
provided to the subjects, who were required to eat at
least 4 meals per week in the metabolic research unit,
with the other meals provided as take-out. The subjects’
compliance with both diets was good. There was no significant difference in fasting blood glucose or insulin
resistance (calculated by HOMA) between the intervention and control groups.
Tighe et al.100 conducted a high-quality, randomized, parallel controlled hypocaloric 12-week intervention study in the United Kingdom in men (n ¼ 102)
and women (n ¼ 104) with a BMI (kg/m2) between 18.5
and 35. After a 4-week run-in period on a refined-grain
diet, subjects (stratified by age, sex, and BMI) were randomly assigned to 1 of 3 groups. The first group (control) (n ¼ 63) consumed a diet that included refined
cereals and white bread. The second group (n ¼ 73)
replaced 3 servings of refined grains with whole-wheat
foods (70–80 g of whole-grain bread plus 30–40 g of
606
whole-grain cereal), and the third group (n ¼ 70)
replaced 3 servings of refined grains with 1 serving of
whole-wheat food plus 2 servings of whole-grain oats.
All refined and whole-grain products were provided to
the subjects. Compliance was determined by dietary assessment on 3 occasions during the intervention period.
The subjects’ compliance with the diets was good.
There was no significant difference in fasting blood glucose levels or insulin resistance (calculated by HOMA)
between the whole-grain groups and the control group.
EVALUATION OF OBSERVATIONAL STUDIES
The FDA reviewed 40 articles27–49,83–99 reporting on 41
observational studies. The articles contained a total of
44 analyses evaluating the association between wholegrain intake and risk of type 2 diabetes. Two of these articles examined more than 1 observational study and
contained more than 1 analysis. Specifically, the publication by de Munter et al.27 evaluated the association
between whole-grain consumption and incidence of
type 2 diabetes on the basis of data from 2 prospective
cohort studies, the NHS I and the NHS II. The authors
analyzed data for whole-grain consumption and its association with type 2 diabetes separately for each of
these studies. Sun et al.45 analyzed data from 3 prospective cohort studies, ie, the 2 reported by de Munter
et al.27 (NHS I and NHS II) and the HPFS, to evaluate
the association between brown rice intake and risk of
type 2 diabetes. They also analyzed the association between whole-grain intake and risk of type 2 diabetes using data from the HPFS. In total, the FDA evaluated 44
individual analyses from the 40 articles on 41 observational studies.
Scientific conclusions could not be drawn from 38
of the articles on observational studies 28–44,46–49,83–99
for 1 or more of the following reasons: (1) the whole
grains measured in these studies were not consistent
with the FDA’s definition of whole grain2; (2) the study
report failed to specify what foods were considered to
be whole grain; or (3) the studies evaluated dietary patterns and not only whole grains. In the majority of these
studies, bran, germ, and/or dietary fiber added separately to food was considered part of the whole-grain
food group. As mentioned above, a substance containing only parts (eg, bran, germ, or dietary fiber) of the
caryopsis of a cereal grain is not whole grain because it
does not consist of the intact, ground, cracked, or flaked
caryopsis and does not have anatomical components
present in the same relative proportions as they exist in
the intact caryopsis. Therefore, the FDA could not draw
scientific conclusions about the association between
whole-grain intake and risk of type 2 diabetes from
these 38 studies.
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Table 2 Summary of observational studies on whole grains and type 2 diabetes
Reference
de Munter et al. (2007)
Sun et al. (2010)45
27
Study design
Study population
2 cohort studies: NHS I and NHS II;
whole grains; validated FFQ
NHS I – 18-y follow-up
Healthy women in the USA with no
history of disease
Participants ¼ 73 327
Overall cases ¼ 4747
NHS II – 12-y follow-up
Participants ¼ 88 410
Overall cases ¼ 1739
Cohort study – HPFS
Healthy men in the USA with no
history of disease
Participants ¼ 39 765
Overall cases ¼ 2648
Whole grains; validated FFQ; 20-y
follow-up
Sun et al. (2010)45
3 cohort studies (HPFS, NHS I, NHS
II); brown rice; validated FFQ
HPFS: 20-y follow-up
Healthy men and women in the
USA
Participants ¼ 39 765 men
Overall cases ¼ 2648
NHS I: 22-y-follow-up
Participants ¼ 69 120 women
Overall cases ¼ 5500
NHS II: 14-y follow-up
Participants ¼ 88 343 women
Overall cases ¼ 2359
Intake level
Median intake
Q1 (reference intake) ¼ 3.7 g
Q2 ¼ 8.4 g
Q3 ¼ 13.2 ga
Q4 ¼ 19.5 ga
Q5 ¼ 31.2 ga
Q1 ¼ 6.2 g
Q2 ¼ 12.6 g
Q3 ¼ 18.6 g
Q4 ¼ 26.1 ga
Q5 ¼ 39.9 g
Median intake
Q1 ¼ 5.1 g
Q2 ¼ 12.6 ga
Q3 ¼ 20.4 ga
Q4 ¼ 29.9 ga
Q5 ¼ 47.1 ga
1 serving/wk to 1 serving/
1 serving mo (0.6 g)
2 servings/wk (3.5 g)
1 serving/wk to 1 serving/
1 serving mo (0.6 g)b
2 servings/wk (3.5 g)b
1 serving/wk to 1 serving/
1 serving mo (0.6 g)
2 servings/wk (3.5 g)
Abbreviations: FFQ, food frequency questionnaire; HPFS, Health Professionals Follow-up Study; NHS, Nurses’ Health Study; Q, quintile.
effect at each quintile compared with Q1 (reference intake).
Beneficial effect compared with <1 serving per month.
a
Beneficial
b
There were 6 analyses of 3 observational studies
that evaluated the association between whole-grain intake and risk of type 2 diabetes (de Munter et al.,27 examining NHS I and NHS II, and Sun et al.,45 examining
HPFS, NHS I, and NHS II) from which scientific conclusions could be drawn (Table 2). As mentioned above,
the HPFS study reported by Sun et al.45 included analyses of 2 diet–disease associations: the association between intake of whole grains, which include brown rice,
and risk of type 2 diabetes, and the association between
intake of brown rice and risk of type 2 diabetes.
de Munter et al.27 analyzed data from 2 high-quality
prospective cohort studies (NHS I and NHS II). The NHS
I followed 73 327 women (aged 37–65 years) and the NHS
II 88 410 women (aged 26–46 years). About 4747 (NHS 1)
and 1739 (NHS II) cases of type 2 diabetes were identified
in these studies. Whole grains included both intact and
pulverized forms containing the expected proportion of
bran, germ, and endosperm for the particular type of grain.
Whole-grain intake from all sources was assessed using a
validated food frequency questionnaire. In the NHS I, after
adjustment for appropriate confounders, including BMI,
higher whole-grain intake was associated with a significant
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reduction in risk of type 2 diabetes for the 3 highest quintiles (Q) of intake (median whole-grain intake, 13.2 g/d or
higher). Specifically, relative risk (RR) and 95% confidence
intervals (95%CIs) were 0.84 (95%CI, 0.77–0.92), 0.79
(95%CI, 0.72–0.87), and 0.75 (95%CI, 0.68–0.83) in Q3
(median whole-grain intake, 13.2 g/d), Q4 (19.5 g/d), and
Q5 (31.2 g/d), respectively, when compared with Q1 (3.7 g/
d). The RR and 95%CI in Q2 (median whole-grain intake,
8.4 g/d), which did not show a significantly reduced risk of
type 2 diabetes compared with Q1, were 0.92 and 0.84–
1.00. In the NHS II, after adjustment for all relevant confounders, including BMI, a significant association was
found between whole-grain intake and reduced risk of
type 2 diabetes in Q4 (median whole-grain intake, 26.1 g/
d) compared with Q1 (6.2 g/d) (RR ¼ 0.81; 95%CI, 0.69–
0.95). However, no significant association was observed in
Q5 (39.9 g/d) compared with Q1 (RR ¼ 0.86; 95%CI, 0.72–
1.02). Similarly, no significant association was observed in
Q2 (12.6 g/d) (RR ¼ 0.94; 95%CI, 0.82–1.08) or Q3 (18.6 g/
d) (RR ¼ 0.90; 95%CI, 0.78–1.08) compared with Q1.
Thus, unlike the NHS I, the NHS II did not indicate a consistent dose–response association between whole-grain intake and reduction in risk of type 2 diabetes.
607
Sun et al.45 analyzed data from the HPFS, the NHS
I, and the NHS II to evaluate the association between
consumption of brown rice (a whole grain) and incidence of type 2 diabetes. These studies were of high
quality and followed 39 675 men (aged 32–87 years)
from the HPFS, 69 120 women (aged 37–65 years) from
the NHS I, and 88 343 women (aged 26–45 years) from
the NHS II. The numbers of type 2 diabetes cases in
these studies were 2648 (HPFS), 5500 (NHS I), and
2359 (NHS II), respectively. In the NHS I, after adjustment for appropriate confounders, there was a significantly reduced risk of type 2 diabetes for those who
consumed from 1 serving per month to 1 serving per
week of brown rice compared with those at the lowest
level of intake (<1 serving/month) (RR ¼ 0.92; 95%CI,
0.87–0.98) as well as for those who consumed 2 or more
servings per week compared with those at the lowest
level of intake (RR ¼ 0.83; 95%CI, 0.72–0.96). There
was no significant association between brown rice consumption and incidence of type 2 diabetes in the NHS
II or the HPFS. Sun et al.45 also analyzed intake of all
whole grains using the same definition as de Munter
et al.27 After adjustment for appropriate confounders,
there was a significant association between quintiles of
whole-grain intake and reduced risk of type 2 diabetes
in Q2 (12.6 g/d) (RR ¼ 0.82; 95%CI, 0.73–0.92], Q3
(20.4 g/d) (RR ¼ 0.86; 95%CI, 0.77–0.97), Q4 (29.9 g/d)
(RR ¼ 0.78; 95%CI, 0.69–0.88), and Q5 (47.1 g/d)
(RR ¼ 0.72; 95%CI, 0.63–0.83) compared with Q1
(5.1 g/d).
STRENGTH OF THE SCIENTIFIC EVIDENCE
The evidence for a relationship between whole-grain intake and type 2 diabetes risk was derived from 6 intervention studies9,12,13,24,26,100 and 2 publications27,45 that
together contain a total of 6 analyses of 3 prospective
cohort studies.
Of the 6 intervention studies evaluated, 5 reported
no significant relationship between whole-grain intake
and incidence of type 2 diabetes.9,12,13,26,100 These 5
studies were of moderate or high quality and consisted
of randomized controlled trials that examined types of
whole-grain products (eg, whole-wheat bread, oatmeal)
typically purchased by US consumers.101 The studies by
Brownlee et al.12 and Tighe et al.100 were both of high
quality and had the longest study durations (16 weeks
and 12 weeks, respectively) and the largest number of
subjects. Brownlee et al.12 had 266 subjects, with about
80 to 100 in each of 3 groups, while Tighe et al.100 had
206 subjects, with about 70 per group. Both studies included both men and women.
The study by Rave et al.24 was a 6-week, moderatequality, randomized controlled weight-loss study. After
608
adjustment for the amount of weight loss, there was no
significant reduction in fasting blood glucose in the
whole-grain group compared with the control group,
but a significant improvement in insulin resistance was
observed in the whole-grain group compared with the
control group (P < 0.049). There are serious doubts
about this study’s applicability to whole-grain consumption in the general US population. The whole-grain
product in this study was a dry powder derived from
double-fermented wheat and was consumed in large
quantities (total of 200 g/d) as a meal replacement. This
product is significantly different from the whole-grain
products available to consumers for purchase in the US
marketplace. Commonly available whole-grain products
in the US marketplace are neither double fermented
nor in powder form.101 Moreover, since the study subjects followed a diet designed to cause weight loss, the
study does not rule out the possibility that the benefit
would only be observed during a period of caloric reduction, such as dieting, and not when whole grains are
consumed as part of a weight-maintenance or highcalorie diet.
The results of the 6 analyses of the 3 observational
studies from which scientific conclusions could be
drawn were mixed. All 3 prospective cohort studies
showed a significant association between whole-grain
intake and reduced risk of type 2 diabetes (NHS I, NHS
II, HPFS).27,45 However, when Sun et al.45 analyzed the
association between brown rice consumption and incidence of type 2 diabetes in the same 3 prospective cohort studies (NHS I, NHS II, and HPFS), the only study
that showed a significant association between brown
rice intake and reduced risk of type 2 diabetes was the
NHS I. No association between brown rice intake and
risk of type 2 diabetes was found in the NHS II or the
HPFS. Thus, the findings of the brown rice studies were
not consistent.
In general, results from large, well-designed, randomized controlled intervention studies provide the
strongest evidence for the claimed effect, regardless of
existing observational studies on the same relationship.
Intervention studies are designed to avoid selection bias
and avoid findings that are due to chance or other confounders of disease.102 Although the evaluation of substance/disease relationships often involves both
intervention and observational studies, observational
studies generally cannot be used to rule out the findings
from more reliable intervention studies.102 One intervention study would not be sufficient to rule out consistent findings of observational studies. However, when
several randomized controlled intervention studies are
consistent in showing or not showing a substance/disease relationship, they take precedence over the findings
of any number of observational studies.3,103 This is
Nutrition ReviewsV Vol. 74(10):601–611
R
because intervention studies are designed and controlled to test whether there is evidence of a cause-andeffect relationship between a substance and a reduced
risk of a disease, whereas observational studies are only
able to identify possible associations. There are numerous examples – such as vitamin E and cardiovascular
disease, and b-carotene and lung cancer – for which associations identified in observational studies have been
publicized. However, when randomized controlled intervention studies were later conducted to test these
possible associations, the intervention studies found no
evidence to support the relationships.3,104
Consistency of findings among similar and different
study designs is important for evaluating the strength of
the scientific evidence.3,105 The majority of the intervention studies included in FDA’s evaluation did not show a
significant relationship between whole-grain consumption and reduced risk of type 2 diabetes. Only 1 intervention study24 showed a significant relationship. It is
doubtful, however, whether the results of that study apply
to the general US population because the powdered,
double-fermented wheat product tested in that study is
markedly different in composition and conditions of use
from whole-grain products typically used in the United
States. Further, the reported individual findings of Rave
et al.24 have not been replicated in any other intervention
studies, and replication of scientific findings is important
in order to substantiate results.3,106
CONCLUSION
On the basis of the agency’s evidence-based review, there
are 4 analyses of 3 observational studies and 1 intervention study supporting an association between consumption of whole grains and reduced risk of type 2 diabetes,
while 5 intervention studies and 2 additional analyses of
observational studies found no evidence of such a relationship. Among the observational studies, the results of
analyses examining intake of whole grains of all types
were generally consistent, with 3 analyses finding a significant association between whole-grain consumption and
reduced risk of type 2 diabetes at some level of intake.
However, of the 3 analyses that were limited to brown
rice, only 1 found a significant association between brown
rice intake and reduced risk of type 2 diabetes. The sole
intervention study24 suggesting a causal relationship is
not well suited to assess whether whole-grain foods commonly consumed in the United States reduce the risk of
type 2 diabetes, as it examined the effects of a whole-grain
product in an unusual form (powdered mix containing
double-fermented whole wheat), at a very high intake
level (200 g/d), and under atypical conditions of use
(meal replacement to be mixed with a liquid and substituted for 2 of the day’s 3 meals). Moreover, the results
Nutrition ReviewsV Vol. 74(10):601–611
R
of relevant studies are not consistent within or across
study types, and the prospective cohort studies suggesting a link between whole-grain intake and reduced risk
of type 2 diabetes are undermined by several randomized controlled intervention studies that measured surrogate endpoints of type 2 diabetes risk and found that
whole-grain intake had no effect.
On the basis of its scientific review, the FDA, on
September, 2013, issued a letter of enforcement discretion for the use of the following claim: “Whole grains
may reduce the risk of type 2 diabetes, although the
FDA has concluded that there is very limited scientific
evidence for this claim.”107
Since the FDA issued the letter of enforcement discretion on whole grains and risk of type 2 diabetes, several systematic reviews or meta-analyses on this topic
have been published. As noted above, the FDA does not
rely on published systematic reviews and/or metaanalyses but instead conducts evidence-based reviews of
the scientific data. Two individual cohort studies have
been published since the completion of the FDA review.
In one,108 it was not clear how whole grain was defined.
In the other, the impact of whole grains on the progression of normal glucose tolerance to type 2 diabetes was
not significant in either men (OR ¼ 0.72; 95%CI, 0.44–
1.16) or women (OR ¼ 0.68; 95%CI, 0.35–1.33).109 The
FDA has not conducted a detailed review of these studies using the evidence-based review system.
Nevertheless, a preliminary appraisal indicates that the
findings of these studies do not appear to contradict the
conclusions of the earlier review supporting the issuance of the letter of enforcement discretion.107
Acknowledgments
Declaration of interest. The authors have no relevant
interests to declare.
REFERENCES
1.
2.
3.
4.
5.
6.
Centers for Disease Control and Prevention. Diabetes Report Card, 2014, Atlanta,
GA: Centers for Disease Control and Prevention, US Dept. of Health and Human
Services,
2015.
http://www.cdc.gov/diabetes/pdfs/library/diabetesreport
card2014.pdf. Accessed October 7, 2015.
US Food and Drug Administration. Draft Guidance for Industry and FDA Staff:
Whole Grain Label Statements. http://www.fda.gov/Food/GuidanceRegulation/
GuidanceDocumentsRegulatoryInformation/LabelingNutrition/ucm059088.htm.
Published February 17, 2006. Accessed October 7, 2015.
US Food and Drug Administration. Guidance for Industry: Evidence-Based
Review System for the Scientific Evaluation of Health Claims – Final. http://www.
fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/
LabelingNutrition/ucm073332.htm. Published January 2009. Accessed
September 10, 2015.
Pearson v Shalala, 172 F.3d 72. 98-5043 (DC Cir, US Court of Appeals, January 15,
1999).
US Food and Drug Administration. Consumer Health Information for Better
Nutrition Initiative. Task Force Report. http://www.fda.gov/food/ingredientspack
aginglabeling/labelingnutrition/ucm096010.htm. Published July 10, 2003.
Accessed October 7, 2015.
Spilker B. Guide to Clinical Studies. New York, NY: Raven Press; 1991.
609
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
610
Federal Judicial Center. Reference Manual on Scientific Evidence. 2nd ed.
Washington, DC: National Academies Press; 2000.
Alminger M, Eklund-Jonsson C. Whole-grain cereal products based on a highfibre barley or oat genotype lower post-prandial glucose and insulin responses
in healthy humans. Eur J Nutr. 2008;47:294–300.
Andersson A, Tengblad S, Karlstrom B, et al. Whole-grain foods do not affect insulin sensitivity or markers of lipid peroxidation and inflammation in healthy,
moderately overweight subjects. J Nutr. 2007;137:1401–1407.
Behall KM, Scholfield DJ, Hallfrisch J. The effect of particle size of whole-grain
flour on glucose, insulin, glucagon and thyroid-stimulating hormone in humans.
J Am Coll Nutr. 1999;18:591–597.
Behall KM, Scholfield DJ, Hallfrisch J. Comparison of hormone and glucose responses of overweight women to barley and oats. J Am Coll Nutr. 2005;24:182–188.
Brownlee IA, Moore C, Chatfield M, et al. Markers of cardiovascular risk are not
changed by increased whole-grain intake: the WHOLEheart study, a randomized,
controlled dietary intervention. Br J Nutr. 2010;104:125–134.
Giacco R, Clemente G, Cipriano D, et al. Effects of the regular consumption of
wholemeal wheat foods on cardiovascular risk factors in healthy people. Nutr
Metab Cardiovas Dis. 2010;20:186–194.
Granfeldt Y, Eliasson AC, Bjorck I. An examination of the possibility of lowering
the glycemic index of oat and barley flakes by minimal processing. J Nutr.
2000;130:2207–2214.
Hallfrisch J, Scholfield DJ, Behall KM. Physiological responses of men and women
to barley and oat extracts (Nu-trimX). II. Comparison of glucose and insulin responses. Cereal Chem. 2003;80:80–83.
Hlebowicz J, Lindstedt S, Bjorgell O, et al. The botanical integrity of wheat products influences the gastric distention and satiety in healthy subjects. Nutr J.
2008;7:12–20.
Hlebowicz J, Jonsson JM, Lindstedt S, et al. Effect of commercial rye whole-meal
bread on postprandial blood glucose and gastric emptying in healthy subjects.
Nutr J. 2009;16:26. doi:10.1186/1475-2891-8-26.
Juntunen KS, Laaksonen DE, Poutanen KS, et al. High-fiber rye bread and insulin
secretion and sensitivity in healthy postmenopausal women. Am J Clin Nutr.
2003;77:385–391.
Liljeberg H, Granfeldt YE, Bjorck IM. Products based on a high fiber barley genotype, but not on common barley or oats, lower postprandial glucose and insulin
responses in healthy humans. J Nutr. 1996;126:458–466.
Nilsson AC, Ostman EM, Granfeldt Y, et al. Effect of cereal test breakfasts differing
in glycemic index and content of indigestible carbohydrates on daylong glucose
tolerance in healthy subjects. Am J Clin Nutr. 2008;87:645–654.
Nilsson AC, Ostman EM, Hoist JJ, et al. Including indigestible carbohydrates in
the evening meal of healthy subjects improves glucose tolerance, lowers inflammatory markers, and increases satiety after a subsequent standardized breakfast.
J Nutr. 2008;138:732–739.
Pereira MA, Jacobs DR, Pins JJ, et al. Effect of whole grains on insulin sensitivity
in overweight hyperinsulinemic adults. Am J Clin Nutr. 2002;75:848–855.
Priebe MG, Wang H, Weening D, et al. Factors related to colonic fermentation of
nondigestible carbohydrates of a previous evening meal increase tissue glucose
uptake and moderate glucose-associated inflammation. Am J Clin Nutr.
2010;91:90–97.
Rave K, Roggen K, Dellweg S, et al. Improvement of insulin resistance after diet
with a whole-grain based dietary product: results of a randomized, controlled
cross-over study in obese subjects with elevated fasting blood glucose. Br J Nutr.
2007;98:929–936.
Rosen LAH, Blanco Silva LO, Andersson UK, et al. Endosperm and whole grain
rye breads are characterized by low post-prandial insulin response and a beneficial blood glucose profile. Nutr J. 2009;8:42–53.
Saltzman E, Das SK, Lichtenstein AH, et al. An oat-containing hypocaloric diet reduces systolic blood pressure and improves lipid profile beyond effects of weight
loss in men and women. J Nutr. 2001;131:1465–1470.
de Munter JS, Hu FB, Spiegelman D, et al. Whole grain, bran, and germ intake
and risk of type 2 diabetes: a prospective cohort study and systematic review.
PLoS Med. 2007;4:1385–1395.
Esmaillzadeh A, Mirmiran P, Azizi F. Whole-grain consumption and the metabolic
syndrome: a favorable association in Tehranian adults. Eur J Clin Nutr.
2005;59:353–362.
Fung TT, Hu FB, Pereira MA, et al. Whole-grain intake and the risk of type 2 diabetes: a prospective study in men. Am J Clin Nutr. 2002;76:535–540.
Kochar J, Djoussé L, Gaziano JM. Breakfast cereals and risk of type 2 diabetes in
the Physicians’ Health Study I. Obesity (Silver Spring). 2007;15:3039–3044.
Liu S, Manson JE, Stampfer MJ, et al. A prospective study of whole-grain intake
and risk of type 2 diabetes mellitus in US women. Am J Public Health.
2000;90:1409–1415.
Lutsey PL, Jacobs DR, Kori S, et al. Whole grain intake and its cross-sectional association with obesity, insulin resistance, inflammation, diabetes and subclinical
CVD: The MESA Study. Br J Nutr. 2007;98:397–405.
Masters RC, Liese AD, Haffner SM, et al. Whole and refined grain intakes are related to inflammatory protein concentrations in human plasma. J Nutr.
2010;140:587–594.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
Meyer KA, Kushi LH, Jacobs DR Jr, et al. Carbohydrates, dietary fiber, and incident
type 2 diabetes in older women. Am J Clin Nutr. 2000;71:921–930.
McKeown NM, Meigs JB, Liu S, et al. Whole-grain intake is favorably associated
with metabolic risk factors for type 2 diabetes and cardiovascular disease in the
Framingham Offspring Study. Am J Clin Nutr. 2002;76:390–398.
McKeown NM, Meigs JB, Liu S, et al. Carbohydrate nutrition, insulin resistance
and the prevalence of the metabolic syndrome in the Framingham Offspring
Cohort. Diabetes Care. 2004;27:538–546.
Montonen J, Knekt P, Jarvinen R, et al. Whole-grain and fiber intake and the incidence of type 2 diabetes. Am J Clin Nutr. 2003;77:622–629.
Newby PK, Maras J, Bakun P, et al. Intake of whole grains, refined grains, and cereal fiber measured with 7-d diet records and associations with risk factors for
chronic disease. Am J Clin Nutr. 2007;86:1745–1753.
Sahyoun NR, Jacques PF, Zhang XL, et al. Whole-grain intake is inversely associated with the metabolic syndrome and mortality in older adults. Am J Clin Nutr.
2006;83:124–131.
Salmeron J, Ascherio A, Rimm EB, et al. Dietary fiber, glycemic load, and risk of
NIDDM in men. Diabetes Care. 1997;20:545–550.
Salmeron J, Manson JE, Stampfer MJ, et al. Dietary fiber, glycemic load,
and risk of non-insulin-dependent diabetes mellitus in women. JAMA.
1997;277:472–477.
Schulze MB, Liu S, Rimm EB, et al. Glycemic index, glycemic load, and dietary fiber intake and incidence of type 2 diabetes in younger and middle-aged
women. Am J Clin Nutr. 2004;80:348–356.
Steffen LM, Jacobs DR, Murtaugh MA, et al. Whole grain intake is associated with
lower body mass and greater insulin sensitivity among adolescents. Am J
Epidemiol. 2003;158:243–250.
Stevens J, Ahn K, Juhaeri HD, et al. Dietary fiber intake and glycemic index and
incidence of diabetes in African American and white adults. Diabetes Care.
2002;25:1715–1721.
Sun Q, Spiegelman D, van Dam RM, et al. White rice, brown rice, and risk of type
2 diabetes in US men and women. Arch Intern Med. 2010;170:961–969.
Valachovicova M, Krajcovicova-Kudlackova M, Blazicek P, et al. No evidence of insulin resistance in normal weight vegetarians. A case control study. Eur J Nutr.
2006;45:52–54.
van Dam RM, Rimm EB, Willett WC, et al. Dietary patterns and risk for type 2 diabetes mellitus in U.S. men. Ann Intern Med. 2002;136:201–209.
van Dam RM, Hu FB, Rosenberg L, et al. Dietary calcium and magnesium, major
food sources, and risk of type 2 diabetes in U.S. black women. Diabetes Care.
2006;29:2238–2243.
Wolever TM, Bolognesi C. Source and amount of carbohydrate affect postprandial glucose and insulin in normal subjects. J Nutr. 1996;126:2798–2806.
Badr A, Muller K, Schafer-Pregl R, et al. On the origin and domestication history
of barley (Hordeum vulgare). Mol Biol Evol. 2000;17:499–510.
Lin BH, Yen ST. The U.S. Grain Consumption Landscape: Who Eats Grain, in What
Form, Where, and How Much? Washington, DC: US Dept. of Agriculture,
Economic Research Service. 2007. Economic Research Report no. 50.
Pringle H. Neolithic agriculture: the slow birth of agriculture. Science.
1998;282:1446. doi:10.1126/science.282.5393.1446.
US Department of Agriculture, Agricultural Marketing Service, Economic
Research Service, Farm Service Agency. World Agricultural Supply and Demand
Estimates. http://www.usda.gov/oce/commodity/wasde/latest.pdf. Published
July 12, 2016. Accessed September 10, 2015.
Dietary Guidelines Advisory Committee. Report of the Dietary Advisory
Committee on Dietary Guidelines for Americans. http://www.health.gov/dietarygui
delines/dga2005/report/default.htm. Part D Science Base, Section 6: Selected Food
Groups (pp 1, 10–11, 15–18), and Part G, Appendix G-3, Summary Tables from
Systematic Review (pp 107–109). Published 2005. Accessed September 10, 2015.
US Department of Agriculture, US Department of Health and Human Services.
Dietary Guidelines for Americans, 2010. http://www.cnpp.usda.gov/sites/default/
files/dietary_guidelines_for_americans/PolicyDoc.pdf. Chapter 1: Introduction (p
6), and Chapter 4: Foods and Nutrients to Increase (p 36). Published December
2010. Accessed September 10, 2015.
US Department of Health and Human Services, Food and Drug Administration.
Draft Guidance for Industry: Diabetes Mellitus: Developing Drugs and
Therapeutic Biologics for Treatment and Prevention. http://www.fda.gov/down
loads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM071624.pdf. Published February 2008. Accessed September 10, 2015.
US Department of Agriculture Nutrition Evidence Library (NEL), Dietary
Guidelines Advisory Committee (DGAC). NEL Evidence-based Systematic
Reviews, Carbohydrates, Whole Grains. What is the Relationship Between Whole
Grain Intake and Body Weight, 2010. http://www.nel.gov/conclusion.cfm?conclu
sion_statement_id¼250273. Accessed September 10, 2015.
Centers for Disease Control and Prevention. Diabetes Data and Trends; Data
from the National Health Interview Survey. Atlanta, GA: National Center for
Health Statistics, Division of Health Interview Statistics; 2009.
American Diabetes Association. Position statement: nutrition recommendations
and interventions for diabetes. Diabetes Care. 2008;31(suppl 1):S61–S78.
Nutrition ReviewsV Vol. 74(10):601–611
R
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
Priebe MG, van Binsbergen J, de Vos R, et al. Whole grain foods for the prevention of type 2 diabetes mellitus. Cochrane Database Syst Rev.
2008;(1):CD006061. doi:10.1002/14651858.CD006061.pub2.
Adamsson V, Reumark A, Fredriksson IB, et al. Effects of a healthy Nordic diet on
cardiovascular risk factors in hypercholesterolaemic subjects: a randomized controlled trial (NORDIET). J Intern Med. 2011;269:150–159.
Anderson GH, Cho CE, Akhavan T, et al. Relation between estimates of cornstarch
digestibility by the Englyst in vitro method and glycemic response, subjective appetite, and short-term food intake in young men. Am J Clin Nutr. 2010;9:932–939.
Casiraghi MC, Garsetti M, Testolin G, et al. Post-prandial responses to cereal products enriched with barley beta-glucan. J Am Coll Nutr.
2006;25:313–320.
d’Emden MC, Marwick TH, Dreghorn J, et al. Post-prandial glucose and insulin responses to different types of spaghetti and bread. Diabetes Res Clin Pract.
1987;3:221–226.
Holt SH, Miller JB. Particle size, satiety and the glycaemic response. Eur J Clin
Nutr. 1994;48:496–502.
Ito Y, Mizukuchi A, Kise M, et al. Postprandial blood glucose and insulin responses to pre-germinated brown rice in healthy subjects. J Med Invest.
2005;52:159–164.
Jang Y, Lee JH, Kim OY, et al. Consumption of whole grain and legume powder
reduces insulin demand, lipid peroxidation, and plasma homocysteine concentrations in patients with coronary artery disease: randomized controlled clinical
trial. Arterioscler Thromb Vasc Biol. 2001;21:2065–2071.
Jenkins DJ, Wolever TM, Jenkins AL, et al. Low glycemic response to traditionally
processed wheat and rye products: bulgur and pumpernickel bread. Am J Clin
Nutr. 1986;43:516–520.
Jenkins DJ, Wesson V, Wolever TM, et al. Wholemeal versus wholegrain breads:
proportion of whole or cracked grain and the glycaemic response. BMJ.
1988;297:958–960.
Jensen MK, Koh-Banerjee P, Hu FB, et al. Intakes of whole grain, bran, and germ
and the risk of coronary heart disease in men. Am J Clin Nutr. 2004;80:1492–1499.
Karupaiah T, Aik CK, Heen TC, et al. A transgressive brown rice mediates favourable glycaemic and insulin responses. J Sci Food Agric. 2011;91:1951–1956.
Kim H, Stote KS, Behall KM, et al. Glucose and insulin responses to whole grain
breakfasts varying in soluble fiber, beta-glucan: a dose response study in obese
women with increased risk for insulin resistance. Eur J Nutr. 2009;48:170–175.
Lakshmi KB, Vimala V. Hypoglycemic effect of selected sorghum recipes. Nutr
Res. 1996;16:1651–1658.
Liljeberg H, Granfeldt Y, Bjorck I. Metabolic responses to starch in bread containing intact kernels versus milled flour. Eur J Clin Nutr. 1992;46:561–575.
Liljeberg H, Bjorck I. Bioavailability of starch in bread products. Postprandial glucose and insulin responses in healthy subjects and in vitro resistant starch content. Eur J Clin Nutr. 1994;48:151–163.
Losso JN, Holliday DL, Finley JW, et al. Fenugreek bread: a treatment for diabetes
mellitus. J Med Food. 2009;12:1046–1049.
Noriega E, Bouix O, Brun JF, et al. Glycaemic and insulinaemic responses to
white, brown and germinated rices in healthy subjects. Diabetes Nutr Metab.
1993;6:215–221.
Oosthuizen W, Venter CS, Nell TA, et al. The effect of extrusion processing on the
glycaemic index of dry bean products. S Afr J Clin Nutr. 2005;18:244–249.
Panlasigui LN, Thompson LU. Blood glucose lowering effects of brown rice in
normal and diabetic subjects. Int J Food Sci Nutr. 2006;57:151–158.
Priebe MG, Wachters-Hagedoorn RE, Heimweg JA, et al. An explorative study of
in vivo digestive starch characteristics and postprandial glucose kinetics of
wholemeal wheat bread. Eur J Nutr. 2008;47:417–423.
Rosén LA, Ostman EM, Björck IM. Effects of cereal breakfasts on postprandial glucose, appetite regulation and voluntary energy intake at a subsequent standardized
lunch; focusing on rye products. Nutr J. 2011;10:7. doi:10.1186/1475-2891-10-7.
Thondre PS, Wang K, Rosenthal AJ, et al. Glycaemic response to barley porridge
varying in dietary fibre content. Br J Nutr. 2012;107:719–724.
Anderson AL, Harris TB, Tylavsky FA, et al. Dietary patterns, insulin sensitivity and
inflammation in older adults. Eur J Clin Nutr. 2012;66:18–24.
Azadbakht L, Mirmiran P, Esmaillzadeh A, et al. Dietary diversity score
and cardiovascular risk factors in Tehranian adults. Public Health Nutr.
2006;9:728–736.
Deshmukh-Taskar PR, O’Neil CE, Nicklas TA, et al. Dietary patterns associated
with metabolic syndrome, sociodemographic and lifestyle factors in young
adults: the Bogalusa Heart Study. Public Health Nutr. 2009;12:2493–2503.
Nutrition ReviewsV Vol. 74(10):601–611
R
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
Fisher E, Boeing H, Fritsche A, et al. Whole-grain consumption and transcription
factor-7-like 2 (TCF7L2) rs7903146: gene–diet interaction in modulating type 2
diabetes risk. Br J Nutr. 2009:101:478–481.
Fung TT, Rimm EB, Spiegelman D, et al. Association between dietary patterns
and plasma biomarkers of obesity and cardiovascular disease risk. Am J Clin
Nutr. 2001;73:61–67.
Ghattas LA, Hanna LM, Tapozada ST, et al. Some complementary hypoglycemic
supplements from grain and legumes for the management of type 2 diabetes
mellitus. J Med Sci. 2008;8:102–103.
Hsu TF, Kise M, Wang MF, et al. Effects of pre-germinated brown rice on blood
glucose and lipid levels in free-living patients with impaired fasting glucose or
type 2 diabetes. J Nutr Sci Vitaminol (Tokyo). 2008;54:163–168.
Hur IY, Reicks M. Relationship between whole-grain intake, chronic disease risk indicators, and weight status among adolescents in the National
Health and Nutrition Examination Survey, 1999–2004. J Acad Nutr Diet.
2012;112:46–55.
Jacobs DR, Meyer KA, Kushi LH, et al. Whole-grain intake may reduce the risk of
ischemic heart disease death in postmenopausal women: the Iowa Women’s
Health Study. Am J Clin Nutr. 1998;68:248–257.
Jensen MK, Koh-Banerjee P, Franz M, et al. Whole grain, bran, and germ in relation to homocysteine and markers of glycemic control, lipids, and inflammation.
Am J Clin Nutr. 2006;83:275–283.
Liese AD, Roach AK, Sparks KC, et al. Whole-grain intake and insulin sensitivity:
the Insulin Resistance Atherosclerosis Study. Am J Clin Nutr. 2003;78:965–971.
Liu E, McKeown NM, Newby PK, et al. Cross-sectional association of dietary patterns with insulin-resistant phenotypes among adults without diabetes in the
Framingham Offspring Study. Br J Nutr. 2009;102:576–583.
McGeoch SC, Holtrop G, Fyfe C, et al. Food intake and dietary glycaemic index in
free-living adults with and without type 2 diabetes mellitus. Nutrients.
2011;3:683–693.
McIntosh GH, Noakes M, Royle PJ, et al. Whole-grain rye and wheat foods and
markers of bowel health in overweight middle-aged men. Am J Clin Nutr.
2003;77:967–974.
Nettleton JA, Schulze MB, Jiang R, et al. A priori-defined dietary patterns and
markers of cardiovascular disease risk in the Multi-Ethnic Study of
Atherosclerosis (MESA). Am J Clin Nutr. 2008;88:185–194.
Nettleton JA, Steffen LM, Ni H, et al. Dietary patterns and risk of incident type 2
diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA). Diabetes Care.
2008;31:1777–1782.
Steemburgo T, Dall’Alba V, Almeida JC, et al. Intake of soluble fibers has a protective role for the presence of metabolic syndrome in patients with type 2 diabetes. Eur J Clin Nutr. 2009;63:127–133.
Tighe P, Duthie G, Vaughan N, et al. Effect of increased consumption of wholegrain foods on blood pressure and other cardiovascular risk markers in healthy
middle-aged persons: a randomized controlled trial. Am J Clin Nutr.
2010;92:733–740.
Kranz S, Dodd KW, Juan W, et al. Comparison of main contributors to dietary fiber and whole grain in Americans’ diet: NHANES 2003–2010 [abstract 1065.11].
FASEB J. 2013;27(suppl 1).
Sempos CT, Liu K, Ernst ND. Food and nutrient exposures: what to consider
when evaluating epidemiologic evidence. Am J Clin Nutr. 1999;69:1330S–1338S.
Lichtenstein AH, Russell RM. Essential nutrients: food or supplements? JAMA.
2005;294:351–358.
Barton S. Which clinical studies provide the best evidence? The best RCT still
trumps the best observational study. Br Med J. 2000;321:255–256.
Wilson EB. An Introduction t Scientific Research. New York, NY: Dover
Publications; 1990: 46–48.
Hill AB. The environment and disease: association or causation? Proc R Soc Med.
1965;58:295–300.
US Food and Drug Administration. Whole Grains and a Reduced Risk of Diabetes
Mellitus Type 2. http://www.fda.gov/downloads/Food/IngredientsPackaging
Labeling/LabelingNutrition/UCM368051.pdf. Published September 11, 2013.
Accessed September 10, 2015.
Parker ED, Liu SM, Van Horn L, et al. The association of whole grain consumption
with incident type 2 diabetes: the Women’s Health Initiative Observational
Study. Ann Epidemiol. 2013;23:321–327.
Wirstrom T, Hilding A, Gu HF, et al. Consumption of whole grain reduces risk of
deteriorating glucose tolerance, including progression to prediabetes. Am J Clin
Nutr. 2013;97:179–187.
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