Eur J Epidemiol (2013) 28:845–858
DOI 10.1007/s10654-013-9852-5
REVIEW
Whole grain and refined grain consumption and the risk
of type 2 diabetes: a systematic review and dose–response
meta-analysis of cohort studies
Dagfinn Aune • Teresa Norat • Pål Romundstad •
Lars J. Vatten
Received: 6 February 2013 / Accepted: 16 September 2013 / Published online: 25 October 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract Several studies have suggested a protective
effect of intake of whole grains, but not refined grains on
type 2 diabetes risk, but the dose–response relationship
between different types of grains and type 2 diabetes has
not been established. We conducted a systematic review
and meta-analysis of prospective studies of grain intake
and type 2 diabetes. We searched the PubMed database for
studies of grain intake and risk of type 2 diabetes, up to
June 5th, 2013. Summary relative risks were calculated
using a random effects model. Sixteen cohort studies were
included in the analyses. The summary relative risk per 3
servings per day was 0.68 (95 % CI 0.58–0.81, I2 = 82 %,
n = 10) for whole grains and 0.95 (95 % CI 0.88–1.04,
I2 = 53 %, n = 6) for refined grains. A nonlinear associ-
ation was observed for whole grains, pnonlinearity \ 0.0001,
but not for refined grains, pnonlinearity = 0.10. Inverse
associations were observed for subtypes of whole grains
including whole grain bread, whole grain cereals, wheat
bran and brown rice, but these results were based on few
studies, while white rice was associated with increased
risk. Our meta-analysis suggests that a high whole grain
intake, but not refined grains, is associated with reduced
Electronic supplementary material The online version of this
article (doi:10.1007/s10654-013-9852-5) contains supplementary
material, which is available to authorized users.
D. Aune
P. Romundstad
L. J. Vatten
Department of Public Health and General Practice, Faculty of
Medicine, Norwegian University of Science and Technology,
Trondheim, Norway
D. Aune (&)
T. Norat
Department of Epidemiology and Biostatistics, School of Public
Health, Imperial College London, St. Mary’s Campus, Norfolk
Place, Paddington, London W2 1PG, UK
e-mail: d.aune@imperial.ac.uk
type 2 diabetes risk. However, a positive association with
intake of white rice and inverse associations between
several specific types of whole grains and type 2 diabetes
warrant further investigations. Our results support public
health recommendations to replace refined grains with
whole grains and suggest that at least two servings of
whole grains per day should be consumed to reduce type 2
diabetes risk.
Keywords Whole grains
Refined grains
Cereals

Type 2 diabetes
Meta-analysis
Introduction
The prevalence of diabetes type 2 is rapidly increasing
worldwide, with an estimated 311 million persons living
with diabetes in 2011 and this number is expected to
increase to 552 million by 2030 [1]. Diabetes patients have
increased risk cardiovascular disease, some cancers, eye
and kidney disease [2]. Total medical costs of diabetes
were estimated at US$245 billion in 2012 in the US [3].
Changes in body weight and physical activity are likely
to contribute to these increased rates [4], but diet may also
influence diabetes risk, directly and indirectly through an
effect on obesity. Whole grains contain endosperm, germ,
and bran, in contrast to refined grains which have the germ
and bran removed during the milling process. Whole grains
have been hypothesized to reduce the risk of type 2 dia-
betes based on their content of fiber, vitamins and minerals
and phytochemicals which may improve insulin sensitivity
and glucose metabolism, and by reducing overweight and
obesity [5]. In contrast, refined grains may increase risk
because of their high glycemic index or glycemic load and
reduced fiber and nutrient content. Several studies of whole
123
846
grain intake in relation to type 2 diabetes risk have reported
inverse associations with higher intake [5–10], but some
found no significant association [11, 12]. Inverse associa-
tions have been reported with intake of specific whole grain
products as well, including brown bread [13–15], whole
grain breakfast cereals [13, 16] and brown rice [7],
although the results are not entirely consistent [17, 18]. In
contrast, most studies of refined grain intake have shown
no association overall [5, 12, 13, 19], although two sug-
gested inverse associations [8, 10], while high intake of
white bread [17] or white rice [7, 20, 21] has been asso-
ciated with increased risk, although not consistently
[17, 22]. Although two previous meta-analyses have been
conducted on whole grains and type 2 diabetes [23, 24], the
optimal intake of whole grains for prevention of type 2
diabetes is not established because the shape of the dose–
response relationship has not been investigated. In addi-
tion, there is increasing evidence suggesting that whole
grains reduces the risk of overweight and obesity and
weight gain [24–30], thus it is possible that body mass
index may be an intermediate factor more than a con-
founder, but it is not known how much of the association
that may be explained by reduced body fatness. We con-
ducted a systematic review and meta-analysis of the evi-
dence from prospective studies with the aim of clarifying
(1) the association between the intake of grains and dif-
ferent types of grains and type 2 diabetes risk, (2) the dose–
response relationship between intake of grains and specific
types of grains and type 2 diabetes risk, and (3) how much
of the association that may be explained by reduced body
fatness.
Methods
Search strategy
We conducted a comprehensive search in the PubMed
database up to June 5th, 2013 for studies of various food
groups and type 2 diabetes risk. The search terms relevant
to this analysis included ‘‘cereal OR breakfast cereal OR
grain OR whole grain OR rice OR bread’’ AND ‘‘diabe-
tes’’. The full search is provided in the Supplementary
Appendix. We also searched the reference lists of all the
studies that were included in the analysis and the reference
lists of published meta-analyses [23, 24].
Study selection
To be included, the study had to have a prospective design
and to investigate the association between the intake of
grains and type 2 diabetes risk. Estimates of the relative
risk (hazard ratio, risk ratio) had to be available with the
123
D. Aune et al.
95 % confidence intervals in the publication and for the
dose–response analysis, a quantitative measure of intake
and the total number of cases and person-years had to be
available in the publication. We identified 28 publications
that reported on intake of grains in relation to diabetes
[5–23, 31–39]. Three publications were excluded because
no risk estimates were provided [35, 36, 39], two publi-
cations were excluded because they were cross-sectional
studies [37, 38] and four because they were duplicates
[31–34]. One publication [23] was included only in the
sensitivity analysis with and without adjustment for BMI
because the most recent publication [7] from these two
studies did not provide results both adjusted and unadjusted
for BMI. In addition several publications from the same
studies reported on different grain items and all were
included in the analyses, but each study was only included
once in the analysis of the relevant grain variable.
Data extraction
We extracted the following data from each study: The first
author’s last name, publication year, country where the
study was conducted, the study name, follow-up period,
sample size, gender, age, number of cases, dietary assess-
ment method (type, number of food items and whether it
had been validated), exposure, quantity of intake, RRs and
95 % CIs for the highest versus the lowest grain intake and
variables adjusted for in the analysis.
Statistical methods
To take into account within and between studies hetero-
geneity we used random effects models to estimate sum-
mary RRs and 95 % CIs for the highest versus the lowest
level of grain intake and for the dose–response analysis
[40]. The average of the natural logarithm of the RRs was
estimated and the RR from each study was weighted by the
inverse of its variance. A two-tailed p \ 0.05 was con-
sidered statistically significant.
We used the method described by Greenland and
Longnecker [41] for the dose–response analysis and com-
puted study-specific slopes (linear trends) and 95 % CIs
from the natural logs of the RRs and CIs across categories
of grain intake. The method requires that the distribution of
cases and person-years or non-cases and the RRs with the
variance estimates for at least three quantitative exposure
categories are known. We estimated the distribution of
cases or person-years in studies that did not report these,
but reported the total number of cases/person-years [42].
The median or mean level of grain intake in each category
of intake was assigned to the corresponding relative risk for
each study. For studies that reported grain intake by ranges
of intake we estimated the midpoint for each category by
Whole grain and refined grain consumption 847

calculating the average of the lower and upper bound.

When the highest or lowest category was open-ended we
assumed the open-ended interval length to be the same as
the adjacent interval. In studies that reported the intakes in
grams per day we used 30 g as a serving size for recal-
culation of the intakes to a common scale (servings per
day) [43]. We used 158 g as a serving size for intake of
white rice and brown rice consistent with a recent study
[44]. The dose–response results in the forest plots are
presented for a 3 serving per day increment [43]. We
examined a potential nonlinear dose–response relationship
between grain intake and type 2 diabetes by using frac-
tional polynomial models [45]. We determined the best
fitting second order fractional polynomial regression
model, defined as the one with the lowest deviance. A
likelihood ratio test was used to assess the difference
between the nonlinear and linear models to test for non-
linearity [46]. The intake in the reference category was
subtracted from the intake in each category for the linear
dose–response analysis, but not for the nonlinear dose–
response analysis.
Heterogeneity between studies was assessed by the Q
test and I2 [47]. I2 is the amount of total variation that is
explained by between study variation. I2 values of Fig. 1 Flow-chart of study selection
approximately 25, 50 and 75 % are considered to indicate
low, moderate and high heterogeneity, respectively. 0.71–0.78, I2 = 0 %, pheterogeneity = 0.43) (Supplementary
Publication bias was assessed with Egger’s test [48] and Figure 1). The summary RR per 3 servings per day was
Begg’s test [49] with the results considered to indicate 0.68 (95 % CI 0.58–0.81, I2 = 82 %, pheterogene-
publication bias when p \ 0.10. We conducted sensitivity ity \ 0.0001) (Fig. 2a). The summary RR ranged from 0.65
analyses excluding one study at a time to ensure that the (95 % CI 0.56–0.77) when excluding the EPIC-Potsdam
results were not simply due to one large study or a study study to 0.72 (95 % CI 0.63–0.83) when excluding the
with an extreme result, when there were at least 5 studies in Nurses’ Health Study 1. There was no evidence of small
the analysis. The statistical analyses were conducted using study bias with Egger’s test, p = 0.49 or with Begg’s test,
Stata, version 10.1 software (StataCorp, College Station, p = 0.37. There was evidence of a nonlinear association
TX, USA). between whole grain intake and type 2 diabetes risk,
pnonlinearity \ 0.0001, with a steeper reduction in risk when
increasing intake from low levels and most of the benefit
Results was observed up to an intake of two servings per day
(Fig. 2b, Supplementary Table 1).
We identified sixteen cohort studies (nineteen publications)
that were included in the analyses of grain intake and type Refined grains
2 diabetes risk [5–23] (Table 1; Fig. 1). Seven studies were
from the US, six were from Europe, two from Asia and one Six studies [5, 8, 12, 13, 19] reported on refined grain
was from Australia (Table 1). intake and type 2 diabetes and included 9,545 cases among
258,078 participants. The summary RR for high versus low
Whole grains intake of refined grains was 0.94 (95 % CI 0.82–1.09,
I2 = 64 %, pheterogeneity = 0.02) (Supplementary Figure 2).
Ten cohort studies (8 publications) [5–12] were included in The summary RR per 3 servings per day was 0.95 (95 % CI
the analysis of total whole grain intake and type 2 diabetes 0.88–1.04, I2 = 53 %, pheterogeneity = 0.06) (Fig. 3a). The
risk and included 19,829 cases among 385,868 participants. summary RR ranged from 0.93 (95 % CI 0.86–1.00) when
One of the studies only reported a continuous result and the Nurses’ Health Study 1 was excluded to 0.98 (95 % CI
was not included in the high versus low analysis [11]. The 0.90–1.08) when the Women’s Health Initiative was
summary RR for high versus low intake was 0.74 (95 % CI excluded. There was no evidence of small study bias with

123
 Table 1 Cohort studies of grain intake and type 2 diabetes risk
848

Author, Study name Follow-up Study size, Dietary Exposure Quantity RR (95% CI) Adjustment for confounders
publication period gender, age, assessment
year [Ref. number of cases

123
no.], country

Ericson et al Malmo Diet 1991/ 27,140 m & w, Validated diet Fibre-rich bread 2.0 versus 0.1 0.85 (0.68–1.06) Age, dietary method, season, total energy,
2013 [12], and Cancer 1996–2006, age 45–74 history, FFQ and cereals, w portions/day education, smoking, alcohol, leisure time
Sweden Cohort 12 years years: 1,709 168 food Refined cereals, w 2.9 versus 0.7 1.07 (0.87–1.32) physical activity, BMI
follow-up cases items, portions/day
interview
Fibre-rich bread 2.3 versus 0.01 0.84 (0.68–1.04)
and cereals, m portions/day
Refined cereals, m 4.6 versus 1.1 1.02 (0.82–1.26)
portions/day
Parker et al Women’s 1993/ 72,215 w, age Validated FFQ, Whole grains C2.0 versus 0 0.79 (0.66–0.94) Age, energy intake, race/ethnicity, physical
2013 [10], Health 1998–2005, 50–79 years: 122 food serv/day activity, smoking status, pack-years of
USA Initiative 7.9 years 3,465 cases items Refined grains C6.0 versus \1.0 0.73 (0.58–0.93) cigarettes, alcohol, HRT, education, income,
Observational follow-up serv/day FH–DM, BMI, dairy, fruit, vegetables
Study
Von Ruesten European 1994/1998–NA, 23,531 m & w, Validated FFQ, Whole grain bread Per 50 g/day 0.92 (0.82–1.03) Age, sex, smoking status, pack-years of
et al 2013 Prospective 8 years age 35–65 148 food smoking, alcohol, leisure-time physical
[18], Investigation follow-up years: 837 items activity, BMI, WHR, prevalent
Germany into Cancer cases hypertension, high blood lipid levels,
and education, vitamin supplementation, non-
Nutrition– consumption of the food group, total energy,
Potsdam other food groups
study
Wirström et al NA 1992/1998–NA, 5,477 m & w, Validated FFQ, Whole grains [59.1 versus 0.71 (0.48–1.04) Age, sex, FH–DM, BMI, leisure-time physical
2013 [9], 8–10 years age 35–56 NA \30.6 g/day activity, smoking, education, blood pressure
Sweden follow-up years: 165 Per 30 g/day 0.88 (0.74–1.04)
cases
Soriguer et al The Pizarra 1997/ 605 m & w, age Validated FFQ, White rice 2–3/week versus 0.43 (0.19–0.95) Age, sex, BMI, abnormal glucose regulation
2013 [22], Study 1998–2003/ 18–65 years: NA B1/week
Spain 2004, 6 years 54 cases
follow-up
Sun et al 2010 Health 1986–2006, 20 39,765 m, age Validated FFQ, White rice C5/week versus 1.02 (0.77–1.34) Age, ethnicity, BMI, FH–DM, smoking status,
[7], USA Professionals years follow- 32–87 years: 131 food \1/month cigarettes per day, alcohol, multivitamins,
Follow-up up 2,648 cases items Brown rice C2/week versus 0.96 (0.82–1.12) physical activity, total energy, red meat,
Study \1/month fruits and vegetables, white rice or brown
rice in the respective analyses
Whole grain 47.1 versus 5.1 0.72 (0.63–0.83)
g/day
Bran 14.3 versus 0.6 0.69 (0.60–0.81)
g/day
Germ 2.3 versus 0.2 1.04 (0.89–1.21)
g/day
D. Aune et al.
 Table 1 continued
Author, Study name Follow-up Study size, Dietary Exposure Quantity RR (95% CI) Adjustment for confounders
publication period gender, age, assessment
year [Ref. number of cases
no.], country

Sun et al 2010 Nurses’ Health 1984–2006, 22 69,120 w, age Validated FFQ, White rice C5/week versus 1.11 (0.87–1.43) Age, ethnicity, BMI, FH–DM, smoking status,
[7], USA Study 1 years follow- 37–65 years: 116 food \1/month cigarettes per day, alcohol, multivitamins,
up 5,500 cases items Brown rice C2/week versus 0.83 (0.72–0.96) physical activity, menopausal status,
\1/month hormone use, OC use, total energy, red
meat, fruits and vegetables, white rice or
Whole grain 31.3 versus 3.6 0.70 (0.64–0.77) brown rice in the respective analyses
g/day
Bran 9.5 versus 0.6 0.77 (0.69–0.86)
g/day
Germ 1.5 versus 0.2 0.88 (0.79–0.97)
Whole grain and refined grain consumption

g/day
Sun et al 2010 Nurses’ Health 1991–2005, 14 88,343 w, age Validated FFQ, White rice C5/week versus 1.40 (1.09–1.80) Age, ethnicity, BMI, FH–DM, smoking status,
[7], USA Study 2 years follow- 26–45 years: 131 food \1/month cigarettes per day, alcohol, multivitamins,
up 2,359 cases items Brown rice C2/week versus 0.89 (0.75–1.07) physical activity, menopausal status,
\1/month hormone use, OC use, total energy, red
meat, fruits and vegetables, white rice or
Whole grain 40.0 versus 6.2 g/ 0.81 (0.70–0.94) brown rice in the respective analyses
day
Bran 12.1 versus 1.0 g/ 0.83 (0.71–0.97)
day
Germ 2.0 versus 0.3 g/ 1.04 (0.90–1.21)
day
Nanri et al Japan Public Cohort 1: 25,666 m & Validated FFQ, Rice, m 700 versus 280 1.19 (0.85–1.68) Age, study area, smoking status and cigarettes
2010 [21], Health 1995–2000 33,622 w, age 147 food g/day per day, alcohol, FH–DM, total physical
Japan Center-Based 45–75 years: items Bread 47.1 versus 0 0.85 (0.64–1.14) activity, hypertension, occupation, total
Prospective Cohort 2: 1,103 cases energy intake, coffee, calcium, magnesium,
1998–2003, 5 g/day
Study fruit, vegetables, fish, BMI
years follow- Noodles 225 versus 41.3 0.89 (0.68–1.17)
up g/day
Rice, w 560 versus 165 1.65 (1.06–2.57)
g/day
Bread 60 versus 4 g/day 0.99 (0.73–1.34)
Noodles 176.9 versus 29.0 1.15 (0.83–1.58)
g/day
Fisher et al European 1994/ 2,318 m & w, Validated FFQ, Whole grains, Per 50 g/day 0.86 (0.75–0.99) Age, sex, BMI, waist circumference,
2009 [11], Prospective 1998–2005, age 35–65 148 food rs7903146 CC education, occupational activity, sports,
Germany Investigation 7.1 years years: 724 items genotype smoking, alcohol, red meat, processed meat,
into Cancer follow-up cases Whole grains, Per 50 g/day 1.08 (0.96–1.23) low-fat dairy, butter, margarine, vegetable
and rs7903146 CT ? fat, total energy
Nutrition– TT genotype
Potsdam
study
849

123
 Table 1 continued
850

Author, Study name Follow-up Study size, Dietary Exposure Quantity RR (95% CI) Adjustment for confounders
publication period gender, age, assessment

123
year [Ref. number of cases
no.], country

de Munter Nurses’ Health 1984–2002, 18 73,327 w, age Validated FFQ, Whole grains 31.2 versus 3.7 0.75 (0.68–0.83) Age, smoking status, physical activity,
et al 2007 Study 1 years follow- 37–65 years: 116 food g/day alcohol, HRT, OC use, FH–T2DM, coffee,
[23], USA up 4,747 cases items Bran 9.6 versus 0.6 0.72 (0.65–0.80) sugar-sweetened soft drinks, fruit punch,
g/day total energy, processed meat, PUFA/SFA
ratio, BMI
Germ 1.5 versus 0.2 0.83 (0.75–0.92)
g/day
de Munter Nurses’ Health 1991–2003, 12 88,410 w age Validated FFQ, Whole grains 39.9 versus 6.2 0.86 (0.72–1.02) Age, smoking status, physical activity,
et al 2007 Study 2 years follow- 26–46 years: 131 food g/day alcohol, HRT, OC use, FH–T2DM, coffee,
[23], USA up 2,739 cases items Bran 12.0 versus 1.1 0.84 (0.71–1.00) sugar-sweetened soft drinks, fruit punch,
g/day total energy, processed meat, PUFA/SFA
ratio, BMI
Germ 1.9 versus 0.3 1.00 (0.85–1.17)
g/day
Villegas et al Shanghai 1996/ 64,117 w, age Validated FFQ, Rice 300 versus \200 1.78 (1.48–2.15) Age, energy intake, BMI, WHR, smoking
2007 [20], Women’s 2000–2004, 5 40–70 years: 77 food items g/day status, alcohol, physical activity, income
China Health Study years follow- 1,608 cases Staple food items Quintile 5 versus 1 1.37 (1.11–1.69) level, education level, occupation,
up (rice, noodles, hypertension
steamed bread,
bread)
Schulze et al European 1994/ 9,702 m Validated FFQ, Whole grain bread 80.2 versus 4.4 0.78 (0.62–0.97) Age, sex, BMI, sports activities, education,
2007 [14], Prospective 1998–2005, 7 &15,365 w, 146 food g/day cycling, occupational activity, smoking,
Germany Investigation years follow- age 35–65 items alcohol, total energy intake, waist
into Cancer up years: 844 circumference, PUFA:SFA ratio,
and cases MUFA:SFA ratio, carbohydrate, magnesium
Nutrition–
Potsdam
study
Simmons et al European 1993/ 25,633 m & w, Validated FFQ, Wholemeal/brown C1 versus \1 0.72 (0.53–0.97) Unadjusted
2007 [15], Prospective 1998–2000, age 40–79 bread portion/day
UK Investigation 4.6 years years: 417
into Cancer follow-up cases
and
Nutrition–
Norfolk study
Kochar et al Physicians’ 1981/ 21,152 m, mean FFQ, NA Breakfast cereals C7 versus 0 serv/ 0.69 (0.60–0.79) Age, smoking, vitamin intake, alcohol,
2007 [16], Health Study 1983–2002, age 53 years: week vegetables, physical activity BMI
USA 1 19.1 years 1,958 cases Whole grains C7 versus 0 serv/ 0.60 (0.50–0.71)
follow-up cereals week
Refined cereals C7 versus 0 serv/ 0.95 (0.73–1.30)
week
Van Dam et al Black Women’s 1995–2003, 8 41186 w, age Validated FFQ, Whole grains 1.29 versus 0.03 0.69 (0.60–0.79) Age, total energy, BMI, smoking status,
2006 [6], Health Study years follow- 21–69 years: 68 food items serv/day strenous physical activity, alcohol, parental
USA up 1,964 cases history of DM, education, coffee, sugar-
sweetened soft drink, processed meat, red
meat, low-fat dairy
D. Aune et al.
 Table 1 continued
Author, Study name Follow-up Study size, Dietary Exposure Quantity RR (95% CI) Adjustment for confounders
publication period gender, age, assessment
year [Ref. number of cases
no.], country

Hodge et al Melbourne 1990/1994–NA, 31,641 m & w, FFQ, 121 food Cereal C41 versus \20 1.05 (0.73–1.52) Age, sex, country of birth, physical activity,
2004 [17], Collaborative 4 years age 40–69 items times/week FH–DM, alcohol intake, education, weight
Australia Cohort Study follow-up years: 365 Breakfast cereal C7.0 versus \0.01 1.01 (0.75–1.35) change in the last 5 years, energy intake,
cases times/week BMI, WHR

Rice C2.5 versus \1.0 0.93 (0.68–1.27)

times/week
Bread C18.0 versus \6.0 1.12 (0.79–1.58)
times/week
White bread C7.0 versus \0.5 1.13 (0.86–1.50)
Whole grain and refined grain consumption

times/week
Whole-meal bread C17.5 versus \0.5 0.86 (0.63–1.18)
times/week
Savory cereal C1.5 versus \0.5 1.22 (0.89–1.69)
products times/week
Pasta C3.0 versus \0.5 0.86 (0.60–1.23)
times/week
Other cereal C11.0 versus \2.0 0.79 (0.56–1.10)
times/week
Montonen Finnish Mobile 1966/ 2,286 m & Dietary history Total grain 340–1535 versus 0.38 (0.19–0.77) Age, sex, geographic area, smoking, BMI,
et al 2003 Clinic Health 1972–1995, 2,030 w, age interview, 10–181 g/day intake of energy, fruit, berries and
[8], Finland Examination 23 years 40–69 years: [100 food Whole grain 238–1321 versus 0.65 (0.36–1.18) vegetables
Survey follow-up 52/102 cases items 0–109 g/day
Rye 182–1026 versus 0.65 (0.36–1.18)
0–58 g/day
Other whole grain 76–632 versus 0–5 1.14 (0.69–1.87)
g/day
Refined grain 111–567 versus 0.62 (0.36–1.06)
0–45 g/day
Refined grain from 91–389 versus 0.69 (0.41–1.17)
wheat 0–33 g/day
Fung et al Health 1986–1998, 12 42,898 m, age Validated FFQ, Whole grains 3.2 versus 0.4 0.70 (0.57–0.85) Age, period, physical activity, energy intake,
2002 [19], Professionals years follow- 40–75 years: 131 food serv/day missing FFQ, smoking, FH–DM, alcohol
USA Follow-up up 1,197 cases items Refined grains 4.1 versus 0.8 1.08 (0.87–1.33) intake, fruit intake, vegetable intake, BMI
Study
851

123
 Table 1 continued
852

Author, Study name Follow-up Study size, Dietary Exposure Quantity RR (95% CI) Adjustment for confounders
publication period gender, age, assessment

123
year [Ref. number of cases
no.], country

Liu et al 2000 Nurses’ Health 1984–1994, 10 75,521 w, age FFQ, 126 food Total grain Quintile 5 versus 1 0.75 (0.63–0.89) Age, BMI, physical activity, cigarette
[13], USA Study 1 years follow- 38–63 years: items Whole grain 2.70 versus 0.13 0.73 (0.63–0.85) smoking, alcohol intake, FH–DM 2 in a 1st
up 1,879 cases serv/dayay degree relative, use of multivitamins or
vitamin E supplements, total energy intake
Refined grain Quintile 5 versus 1 1.11 (0.94–1.30)
Refined/whole Quintile 5 versus 1 1.26 (1.08–1.46)
grain ratio
Dark bread C1/day versus 0.77 (0.66–0.90)
almost never
Whole-grain C1/day versus 0.66 (0.55–0.80)
breakfast cereal almost never
Popcorn C1/day versus 0.88 (0.59–1.31)
almost never
Cooked oatmeal C1/day versus 0.73 (0.35–1.54)
almost never
Brown rice 5–6/week versus 0.47 (0.15–1.45)
almost never
Wheat germ 5–6/week versus 0.85 (0.52–1.37)
almost never
Bran 5–6/week versus 0.54 (0.41–0.72)
almost never
Other grains \1/week versus 0.77 (0.63–0.94)
almost never
Meyer et al Iowa Women’s 1986–1992, 6 35,988 w, age Validated FFQ, Total grains 41.5 versus 9.5 0.68 (0.54–0.87) Age, total energy intake, BMI, WHR,
2000 [5], Health Study years follow- 55–69 years: 127 food serv/week education, pack-years of smoking, alcohol
USA up 1,141 cases items Whole grains 20.5 versus 1.0 0.79 (0.65–0.96) intake, physical activity
serv/week
Refined grains 29.5 versus 3.5 0.87 (0.70–1.08)
serv/week

adj. adjustment, BMI body mass index, DM diabetes mellitus, FFQ food frequency questionnaire, FH family history, m men, NA not available, WHR waist-to-hip ratio, w women
D. Aune et al.
Whole grain and refined grain consumption 853

A A
Relative Risk Relative Risk
Study (95% CI) Study (95% CI)
Ericson, 2013 0.77 ( 0.63, 0.94)
Parker, 2013 0.83 ( 0.69, 0.99) Ericson, 2013 0.98 ( 0.85, 1.13)

Wirström, 2013 0.68 ( 0.41, 1.12) Parker, 2013 0.89 ( 0.82, 0.96)
Sun, 2010, HPFS 0.66 ( 0.55, 0.79)
Montonen, 2003 0.66 ( 0.43, 1.00)
Sun, 2010, NHS1 0.46 ( 0.39, 0.56)
Sun, 2010, NHS2 0.69 ( 0.54, 0.88) Fung, 2002 1.03 ( 0.86, 1.22)
Fisher, 2009 0.96 ( 0.81, 1.13)
Liu, 2000 1.07 ( 0.95, 1.20)
van Dam, 2006 0.41 ( 0.30, 0.56)
Montonen, 2003 0.75 ( 0.48, 1.17) Meyer, 2000 0.93 ( 0.79, 1.08)

Meyer, 2000 0.77 ( 0.63, 0.93) Overall 0.95 ( 0.88, 1.04)

Overall 0.68 ( 0.58, 0.81)

.25 .5 .75 1 1.5

.25 .5 .75 1 1.5
Relative Risk
Relative Risk

B
B 1.2
1.2

1.0
1.0

0.8
0.8
RR
RR

0.6 0.6

0.4 0.4

0 1 2 3 4 5 0 1 2 3 4 5 6 7
Whole grains (serving/day) Refined grains (servings/day)

Best fitting fractional polynomial Best fitting fractional polynomial

95% confidence interval 95% confidence interval

Fig. 2 Whole grains and type 2 diabetes. Summary estimates were Fig. 3 Refined grains and type 2 diabetes. Summary estimates were
calculated using a random-effects model calculated using a random-effects model

Egger’s test, p = 1.00 or with Begg’s test, p = 1.00. There
was no evidence of a nonlinear association between refined
grain intake and type 2 diabetes risk, pnonlinearity = 0.10
(Fig. 3b, Supplementary Table 2).
Total grains and subtypes of grains
Fewer studies had reported on total grains and subtypes of
grains. The summary RR for high versus low total grain
intake was 0.74 (95 % CI 0.58–0.93) [5, 8, 13, 17] with
moderate heterogeneity, I2 = 60 %, pheterogeneity = 0.06
(Supplementary Figure 3). The summary RR per 3 servings
per day was 0.83 (95 % CI 0.75–0.91, I2 = 36 %, phetero-
geneity = 0.19) (Supplementary Figure 4a). There was evi-
dence of a nonlinear association between total grain intake
and type 2 diabetes, pnonlinearity = 0.001, and the reduction
in risk was steeper at the lower and higher end of the
intake, with a slight flattening at intermediate intakes
(Supplementary Figure 4b, Supplementary Table 3). The
summary RR for high versus low intake was 0.82 (95 % CI
0.72–0.94, I2 = 50 %, pheterogeneity = 0.11, n = 4) for
whole grain bread [5, 13, 14, 17], 0.66 (95 % CI 0.57–0.77,
I2 = 35 %, pheterogeneity = 0.21, n = 3) for whole grain
cereals [5, 13, 16], 0.76 (95 % CI 0.69–0.84, I2 = 30 %,
pheterogeneity = 0.24, n = 3) for wheat bran [7], 0.97 (95 %
CI 0.86–1.10, I2 = 59 %, pheterogeneity = 0.09, n = 3) for
wheat germ [7], 0.89 (95 % CI: 0.81–0.97, I2 = 0 %,
pheterogeneity = 0.40, n = 3) for brown rice [7], 1.17 (95 %
CI: 0.93–1.47, I2 = 78 %, pheterogeneity \ 0.0001, n = 7)
for white rice [7, 17, 20–22], and 0.82 (95 % CI 0.56–1.18,
n = 2) for total cereals [16, 17] (Table 2). Nonlinear
associations were observed for whole grain bread, pnonlin-
earity = 0.01, whole grain cereals, pnonlinearity \ 0.0001,
wheat bran, pnonlinearity = 0.007, and brown rice, pnonlinear-
ity = 0.02, and consistent with the analysis of overall
whole grain intake, the reduction in risk was steepest when
increasing the intake from low levels (Supplementary
Figure 5a-d). We were not able to fit a nonlinear curve for

123
854
Table 2 Subtypes of grains and type 2 diabetes risk
Type of grain High versus low comparison
2
N RR (95 % CI) I Pheterogeneity
Whole grain bread 4 0.81 (0.74–0.89) 0 0.60
Whole grain breakfast cereal 3 0.72 (0.55–0.93) 77.8 0.01
Brown rice 3 0.89 (0.81–0.97) 50 0.11
Wheat bran 3 0.76 (0.69–0.84) 30 0.24
Wheat germ 3 0.97 (0.86–1.10) 59 0.09
White rice 7 1.17 (0.93–1.47) 78.1 \0.0001
white rice, possibly due to large differences in the intake
between studies.
Subgroup and sensitivity analyses
There was no significant heterogeneity between subgroups
in analyses of whole grains and type 2 diabetes stratified by
gender, duration of follow-up, geographic area, number of
cases and adjustment for confounding factors and inverse
associations were apparent in most subgroups, although
they were not always statistically significant (Table 3).
Although the test for heterogeneity was not significant,
pheterogeneity = 0.15, the association appeared to be slightly
stronger in the American studies than among the European
studies.
Because BMI may be an intermediate variable we also
restricted the analysis to the five studies (four publications)
that had presented risk estimates both adjusted and not
adjusted for BMI [10, 12, 19, 23]. The summary RR per 3
servings per day increase in whole grain intake was 0.69
(0.60–0.80, I2 = 58 %, pheterogeneity = 0.05) with BMI
adjustment (and this was similar to the result from the main
analysis) and 0.53 (95 % CI 0.41–0.69, I2 = 88 %, pheter-
ogeneity \ 0.001) without BMI adjustment (Fig. 4a) and
there were similar differences in the results by BMI
adjustment in the nonlinear analysis (Fig. 4b).
Discussion
Our meta-analysis supports the hypothesis that a high
whole grain and total grain intake protects against type 2
diabetes with a 32 and 17 % reduction in the relative risk
per 3 servings per day, but we found no association
between overall refined grain intake and type 2 diabetes
risk. There was evidence of a nonlinear inverse association
between whole grains and total grains and type 2 diabetes
with most of the reduction observed when increasing the
intake up to 2 servings per day for whole grain intake,
while for total grains there was also a steep reduction in
relative risk when increasing intake from low levels,
123
D. Aune et al.
Dose-response analysis
Dose N RR (95 % CI) I2 Pheterogeneity
Per 3 serv/day 3 0.74 (0.56–0.98) 44.1 0.17
Per 1 serv/day 3 0.73 (0.59–0.91) 80.3 0.006
Per 0.5 serv/day 3 0.87 (0.78–0.97) 26.1 0.26
Per 10 g/day 3 0.79 (0.72–0.87) 49.1 0.14
Per 2 g/day 3 0.98 (0.87–1.11) 50.1 0.14
Per 1 serv/day 6 1.23 (1.15–1.31) 21.4 0.27
followed by a slight flattening of the curve with interme-
diate intakes and a steeper reduction at higher intakes.
However, the inverse association with high total grain
intake should be interpreted with caution as it was based on
relatively few studies, and is likely to be driven by higher
whole grain intake since there was no association with
overall refined grain intake. A positive association was
observed with intake of white rice. In addition, we found
that several subtypes of whole grains including whole grain
cereals, brown bread and brown rice were associated with
reduced risk, but these analyses were based on few studies
and need further confirmation.
Our meta-analysis has limitations which affect the
interpretation of the results. The main limitation is the low
number of cohort studies available apart from the total
whole grain analysis. Further studies are therefore needed
before firm conclusions can be made for the remaining
exposures. Although it is possible that the inverse associ-
ation between whole grain intake and type 2 diabetes could
be due to unmeasured or residual confounding by other
lifestyle factors we found that the association persisted in
several subgroup analyses where such factors had been
adjusted for. There was high heterogeneity in the dose–
response analysis of whole grains and type 2 diabetes,
although not in the comparison of the highest versus the
lowest intake. There was less heterogeneity in studies
conducted among men than among women, but there was
no significant heterogeneity between these subgroups, or
when stratified by number of cases, duration of follow-up
or adjustment for confounding factors. A slightly stronger
association was observed in the American studies than
among the European studies, but there was also no sig-
nificant heterogeneity by geographic location, suggesting
that this finding could be due to chance. Because of the low
number of studies our ability to test for publication bias
may have been limited, however, there was no indication of
asymmetry in the funnel plots. In addition, because of the
low number of studies with very high intakes of whole
grains and total grains, the results in the high ranges ([3
servings for whole grains, and [7 servings for total grains)
were based on relatively few datapoints and should be
Whole grain and refined grain consumption 855

Table 3 Subgroup analyses of whole intake and type 2 diabetes, dose–response

Whole grains, 3 servings per day
n RR (95 % CI) I2 (%) Pah Pbh

All studies 10 0.68 (0.58–0.81) 81.9 \0.0001

Duration of follow-up
\10 years follow-up 5 0.72 (0.56–0.93) 82.3 \0.0001 0.26
C10 years follow-up 5 0.65 (0.53–0.79) 75.3 0.003
Sex
Men 3 0.70 (0.61–0.81) 0 0.53 0.43/0.723
Women 7 0.64 (0.51–0.80) 82.0 \0.0001
Men and women 2 0.93 (0.79–1.09) 1.5 0.31
Geographic location
Europe 4 0.84 (0.72–0.97) 23.8 0.27 0.15
America 6 0.62 (0.51–0.77) 84.0 \0.0001
Number of cases
Cases \1,000 3 0.88 (0.73–1.06) 13.6 0.31 0.32
Cases 1,000–\2,000 3 0.64 (0.46–0.89) 84.5 0.002
Cases C2.000 4 0.65 (0.50–0.83) 85.1 \0.0001
Adjustment for confounders
Body mass index Yes 10 0.68 (0.58–0.81) 81.9 \0.0001 NC
No 0
Physical activity Yes 9 0.68 (0.57–0.81) 83.9 \0.0001 0.78
No 1 0.75 (0.48–1.17)
Smoking Yes 10 0.68 (0.58–0.81) 81.9 \0.0001 NC
No 0
Alcohol Yes 8 0.68 (0.56–0.82) 85.9 \0.0001 0.84
No 2 0.72 (0.52–1.01) 0 0.78
Coffee Yes 1 0.41 (0.30–0.56) 0.07
No 9 0.72 (0.61–0.84) 78.7 \0.0001
Red and/or processed meat Yes 5 0.61 (0.46–0.83) 90.5 \0.0001 0.23
No 5 0.78 (0.71–0.87) 0 0.94
Dairy products Yes 3 0.70 (0.47–1.05) 90.9 \0.0001 0.94
No 7 0.67 (0.57–0.78) 69.0 0.004
Fruits and/or vegetables Yes 5 0.66 (0.53–0.82) 80.6 \0.0001 0.74
No 5 0.71 (0.55–0.91) 82.0 \0.0001
Energy intake Yes 9 0.68 (0.57–0.82) 83.9 \0.0001 0.99
No 1 0.68 (0.41–1.12)
a
P for heterogeneity within each subgroup
2
P for heterogeneity between subgroups with meta-regression analysis
3
P for heterogeneity between men and women (excluding studies with both genders)
NC not calculable

interpreted with caution. Measurement errors in the expo-
sure assessment are known to bias effect estimates, but
because we only included prospective cohort studies such
measurement errors are most likely to have resulted in
attenuation of the association between whole grain intake
and type 2 diabetes risk. None of the studies published to
date have corrected their results for measurement error.
The definition of whole grains differed in some of the
studies (Supplementary Table 4) with several American
studies considering breakfast cereals to be made of whole
grains if the product contained C25 % whole grain or bran
by weight [5, 7, 13, 19, 23], while one Swedish study used
C50 % as a cut-off point [9]. Several other studies did not
state how whole grains were defined, thus it is difficult to
assess whether the differing definitions might have influ-
enced the results. Further studies using biomarkers of

123
856 D. Aune et al.

The results of the nonlinear analysis stratified by adjustment

A for BMI suggest that reduced body fatness may explain a
larger part of the association at higher levels compared with
Relative Risk
Study (95% CI) lower levels of whole grain intake as the association
with BMI adjustment
Ericson, 2013 0.77 ( 0.63, 0.94) appeared to have a more linear shape in analyses without
Parker, 2013 0.76 ( 0.64, 0.91)
de Munter, 2007, NHS1 0.53 ( 0.43, 0.64)
adjustment for BMI than when adjusted for BMI. Whole
de Munter, 2007, NHS2 0.73 ( 0.55, 0.97) grains are an important source of cereal fiber, phytochemi-
Fung, 2000 0.70 ( 0.57, 0.85)
Subtotal 0.69 ( 0.60, 0.80) cals, vitamins and minerals. High whole grain intake has
no BMI adjustment
been associated with greater insulin sensitivity and lower
Ericson, 2013 0.75 ( 0.62, 0.91) fasting insulin concentration and this was observed for dark
Parker, 2013 0.60 ( 0.50, 0.72)
de Munter, 2007, NHS1 0.35 ( 0.29, 0.42) breads, and in particular high-fiber cereals [51]. Intake of
de Munter, 2007, NHS2 0.48 ( 0.36, 0.64)
Fung, 2000 0.56 ( 0.46, 0.68) cereal fiber, but not fruit or vegetable fiber, has been asso-
Subtotal 0.53 ( 0.41, 0.69)
ciated with reduced type 2 diabetes risk in a meta-analysis of
prospective studies [14]. Greater intake of soluble fiber
.1 .25 .5 .75 1 1.5 reduces the rate of gastric emptying and leads to a slower
Relative Risk blood glucose and insulin response [52–54]. However,
whole grains contain more insoluble fiber, thus other
B mechanisms are probably involved than just the latter.
Intake of rye bread has been shown to result in a lower
1.2 postprandial insulin response and this was found to be
1.0
independent of its fiber content [55]. In addition, high intake
of whole grains may reduce risk of type 2 diabetes by
0.8 reducing concentrations of inflammatory markers including
RR plasminogen activator inhibitor type 1 and C-reactive pro-
0.6
tein [56–60] and liver enzymes including gamma-gluta-
myltransferase and aspartate aminotransferase [56], as
higher concentrations of these proteins may increase type 2
diabetes risk [61–63]. In addition, a high intake of whole
0.4
0 1 2 3 4
grains and cereal fiber has been associated with greater
Whole grains (serv/day) blood concentrations of adiponectin [57, 64], a cytokine that
increases insulin sensitivity and reduces inflammation [65].
without BMI adjustment 95% CI
with BMI adjustment 95% CI Further studies are needed to explore potential mechanisms
that could explain the nonlinear associations observed.
Fig. 4 Whole grains and type 2 diabetes, with and without adjust- Our meta-analysis also has several strengths. Because
ment for BMI. Summary estimates were calculated using a random-
effects model we based our analysis on prospective cohort studies recall
bias is not likely to explain our findings, and the possibility
for selection bias is reduced. Although the number of
whole grain intake could be useful to assess the impact of studies was moderate they included up to 19,800 cases and
measurement errors in the dietary assessment [50] and any 385,000 participants and we therefore had adequate sta-
further studies on dietary whole grain intake should report tistical power to detect moderate associations. We con-
the definition of whole grain foods used in the analysis for ducted several subgroup analyses and observed that the
comparison between studies. inverse association persisted in most subgroup analyses,
A protective effect of whole grain consumption against and the findings were also robust in sensitivity analyses
type 2 diabetes is biologically plausible and several mech- where each study was excluded one at a time. We quan-
anisms may operate to reduce the risk. Several studies have tified the association between grain intake and type 2 dia-
reported inverse associations between whole grain intake betes by conducting linear and nonlinear dose–response
and prospective weight gain [25–30] and we found that the analyses and found that most of the benefit of whole grains
size of the association between whole grains and type 2 on type 2 diabetes risk is observed with an intake of at least
diabetes was about 1/3 stronger when the analyses were not 2 servings per day (60 g/day). However, if whole grains
adjusted for BMI compared with adjustment for BMI reduce body fatness and body mass index is a mediating
(RR = 0.53 vs. 0.69, respectively) [10, 12, 19, 23]. Thus, factor, further reductions in the risk may be observed with
reduced body fatness may explain part, but not all of the higher intakes. Increasing whole grain intakes is also likely
protective effect of whole grains against type 2 diabetes risk. to reduce the risk of cardiovascular disease [66],

123
Whole grain and refined grain consumption
overweight and obesity [24–30] and colorectal cancer [43],
and it is possible that there are greater benefits for these
outcomes with even higher intakes.
In summary, our meta-analysis suggests that a high intake
of whole grains, but not refined grains, is associated with
reduced type 2 diabetes risk. However, a positive association
with intake of white rice and inverse associations between
several specific types of whole grains and type 2 diabetes
warrant further investigations. Our results support public
health recommendations to replace refined grains with whole
grains and suggest that at least two servings of whole grains
per day should be consumed to reduce type 2 diabetes risk.
Acknowledgement DA designed the project, conducted the literature
search and analyses and wrote the first draft of the paper. DA, TN, PR,
LJV interpreted the data and revised the subsequent drafts for important
intellectual content and approved the final version of the paper to be
published. The authors declare that there is no duality of interest
associated with this manuscript. This project has been funded by Liai-
son Committee between the Central Norway Regional Health Authority
(RHA) and the Norwegian University of Science and Technology
(NTNU). We thank Ulrika Ericson for clarifying the definition of high-
fibre cereals and breads in the Malmö Diet and Cancer cohort.
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