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Whole Grains Reduced Diabetes Risk by 21% to 37%
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"Whole Grain, Bran, and Germ Intake and Risk of Type 2 Diabetes: A Prospective Cohort Study and Systematic Review"
PloS Medicine Aug 2007
Jeroen S. L. de Munter1,2, Frank B. Hu1,3,4, Donna Spiegelman3,5, Mary Franz1, Rob M. van Dam1,2,4*
1 Department of Nutrition, Harvard School of Public Health, Boston,
Massachusetts, United States of America, 2 Institute of Health Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands, 3 Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America, 4 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 5 Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America
"...From their analysis they calculated that a two-serving-per-day increment in whole grain consumption was associated with a 21% decrease in risk of type 2 diabetes...
The researchers found that women with the highest daily whole grain intake (median 31.2 g) in the first cohort had 37% lower relative risk of incident diabetes than women with the lowest intake (median 3.7 g) even after adjustment for potential confounders. In the second cohort, women with the highest, median 39.9 g daily whole grain intake had 32% lower odds of developing diabetes than women in the lowest, median 6.2 g daily intake quartile. After further adjustment for body mass index, higher whole grain consumption remained significantly linked to lower diabetes risk though the association was somewhat attenuated. Adjusting for magnesium intake did not appear to explain the association either.
But, bran appeared to be the most important constituent of whole grain for reducing diabetes risk with associations similar to those for total whole grain. Germ was not associated with lower diabetes incidence in the second cohort (P=0.95 for trend) or in the first cohort after adjustment for bran (RR 1.01, 95% CI 0.90 to 1.14, P=0.91 for trend).
....The median whole grain intake in the lowest and highest quintile of intake was, respectively, 3.7 and 31.2 g/d for NHSI and 6.2 and 39.9 g/d for NHSII.
.... After adjustment for potential confounders, the relative risks (RRs) for the highest as compared with the lowest quintile of whole grain intake was 0.63 (95% confidence interval [CI] 0.57-0.69) for NHSI and 0.68 (95% CI 0.57-0.81) for NHSII (both: p-value, test for trend <0.001). After further adjustment for body mass index (BMI), these RRs were 0.75 (95% CI 0.68-0.83; p-value, test for trend <0.001) and 0.86 (95% CI 0.72-1.02; p-value, test for trend 0.03) respectively...."
The analysis of two Nurses' Health Study cohorts and four other cohort studies showed a significant benefit to whole grain, particularly its bran component, in five of the studies.
Whole grain intake was inversely associated with risk of type 2 diabetes after adjustment for age and after adjustment for other potential confounders in both NHSI and NHSII (Table 2). Further adjustment for BMI, which may partly mediate the association with type 2 diabetes, substantially weakened the association, but significant inverse associations remained (Table 2). Further adjustment for magnesium intake did not substantially explain the inverse association for whole grain intake in either NHSI (RR 0.76, 95% CI 0.68-0.85 for extreme quintiles, p-value test for trend <0.001) or NHSII (RR 0.82, 95% CI 0.68-0.99, p-value 0.02). In the multivariate analysis, each 40 g increment in whole grain intake was associated with a RR of diabetes of 0.54 (95% CI 0.48-0.61) for NHSI and 0.64 (95% CI 0.54-0.76) for NHSII. After additional adjustment for BMI these RRs were 0.70 (95% CI 0.62-0.79) for NHSI and 0.83 (95% CI 0.70-0.98) for NHSII. BMI explained 42% (95% CI 33%-50%) of the association in NHSI and 57% (95% CI 29%-76%) of the association in NHSII.
Author Conclusions
Findings from prospective cohort studies consistently indicate that higher consumption of whole grains can contribute to the prevention of type 2 diabetes. Cross-sectional studies and short-term randomized trials have provided additional evidence for beneficial effects of whole grains on glucose homeostasis. Taken together, evidence for beneficial metabolic effects is stronger for consuming a variety of whole grains than for wheat bran in isolation. These data provide further support for recommendations to increase consumption of whole grains including whole wheat, whole oats, oatmeal, whole grain corn and popcorn, brown and wild rice, whole rye, whole grain barley, buckwheat, triticale, bulgur, millet, quinoa, and sorghum [49]. The US Department of Agriculture defines one serving of whole grains as 16 g of whole grain ingredients, the equivalent of the content of a one-ounce (28.4 g) slice of 100% whole wheat bread, but expressing whole grain intakes and the whole grain content of foods directly in grams rather than servings may also be a useful method to communicate amounts of whole grains. Educational efforts and clear information on whole grain contents on food labels can contribute to the recognition of foods high in whole grains by consumers. The consumption of whole grains in many populations is very low, an average of one serving per day for US adults [50] and even less in British adults [51], suggesting that increased consumption has the potential to contribute substantially to reducing risk of type 2 diabetes in these populations.
EDITOR'S SUMMARY. The researchers drew on information recorded in a very large and continuing study in the US, the Nurses' Health Study, which began in 1976, when over 100,000 female registered US nurses completed and returned a mailed questionnaire to assess their health and lifestyle. More nurses were added in 1989. It is an example of what is known as a "cohort study." Every two years, questionnaires have been mailed to the nurses. Questions asked include the nurses' age, weight, their diet, whether they smoke, their use of oral contraception; and their personal history of diabetes, cardiovascular disease, and cancer. The researchers calculated each nurse's whole grain intake in grams per day. They found that by 2004 about 6,500 of them had developed type 2 diabetes. From an analysis of the data it was clear that the greater the consumption of whole grains the lower the risk of getting type 2 diabetes.
An additional part of the study was that the researchers searched the medical literature for other cohort studies that examined whole grain intake in relation to risk of type 2 diabetes. (This type of research is called a "systematic review," and it requires that researchers define clearly in advance the kind of studies they are looking for and how they will analyze the data.) They found five such studies. They added together the results of all the studies, including their own. This gave a total of nearly 11,000 cases of type 2 diabetes, out of around 286,000 people. From their analysis they calculated that a two-serving-per-day increment in whole grain consumption was associated with a 21% decrease in risk of type 2 diabetes.
Scientists say that association can never prove causation. (That would require a different sort of study called a trial, where two similar groups of people would be given either a diet high in whole grains or one that was low.) Nevertheless, the research does strongly suggest that a healthy diet that reduces the risk of developing type 2 diabetes should include the consumption of several servings of whole grains daily. The authors do point out that people who choose to eat a lot of whole grains also tend to have a healthy lifestyle in other respects, and that it was hard to calculate intake accurately. However, they do not consider that these limitations to their study would have affected the overall result too seriously.
Mechanisms
Adjustment for BMI substantially weakened the observed association between whole grain intake and risk of type 2 diabetes in our study, suggesting that a relation between whole grain intake and diabetes risk may be partly mediated by effects on body weight. Higher whole grain intake was associated with reduced weight gain in several cohort studies [15,46], but data from randomized trials are currently lacking.
The definition of whole grains used in the cohort studies did not require an intact kernel. Given the commercial availability of grains in the US, whole grain intake in the cohorts probably largely consisted of "shredded whole grains" such as whole wheat bread, which have glycemic indices that are similar to refined grains such as white bread [47]. Therefore, a low dietary glycemic index or glycemic load seems an unlikely explanation for the observed inverse association between whole grain intake and diabetes risk.
Whole grains are an important source of cereal fiber, vitamins, minerals, lignans, and other phytochemicals [10]. Magnesium intake improved glucose metabolism in some short-term clinical trials [12] and was inversely associated with risk of type 2 diabetes in several cohort studies [9,39]. However, magnesium intake did not explain the inverse association between whole grain intake and risk of type 2 diabetes in the current study. Higher cereal fiber intake has generally been associated with a lower risk of type 2 diabetes in cohort studies [39]. Furthermore, intake of purified insoluble cereal fiber intake for 3 d increased insulin sensitivity in a randomized cross-over study [11]. In a shorter trial, intake of these fibers stimulated the acute secretion of glucose-dependent insulinotropic polypeptide and insulin and reduced the glucose response to a meal the following day [48]. Intake of lignans reduced the development of diabetes mellitus in animal studies, possibly through their antioxidant or (anti) estrogenic effects [13]. Further mechanistic studies are needed to elucidate effects of whole grain constituents or combinations on glucose metabolism.
ABSTRACT
Background
Control of body weight by balancing energy intake and energy expenditure is of major importance for the prevention of type 2 diabetes, but the role of specific dietary factors in the etiology of type 2 diabetes is less well established. We evaluated intakes of whole grain, bran, and germ in relation to risk of type 2 diabetes in prospective cohort studies.
Methods and Findings
We followed 161,737 US women of the Nurses' Health Studies (NHSs) I and II, without history of diabetes, cardiovascular disease, or cancer at baseline. The age at baseline was 37-65 y for NHSI and 26-46 y for NHSII. Dietary intakes and potential confounders were assessed with regularly administered questionnaires. We documented 6,486 cases of type 2 diabetes during 12-18 y of follow-up. Other prospective cohort studies on whole grain intake and risk of type 2 diabetes were identified in searches of MEDLINE and EMBASE up to January 2007, and data were independently extracted by two reviewers. The median whole grain intake in the lowest and highest quintile of intake was, respectively, 3.7 and 31.2 g/d for NHSI and 6.2 and 39.9 g/d for NHSII. After adjustment for potential confounders, the relative risks (RRs) for the highest as compared with the lowest quintile of whole grain intake was 0.63 (95% confidence interval [CI] 0.57-0.69) for NHSI and 0.68 (95% CI 0.57-0.81) for NHSII (both: p-value, test for trend <0.001). After further adjustment for body mass index (BMI), these RRs were 0.75 (95% CI 0.68-0.83; p-value, test for trend <0.001) and 0.86 (95% CI 0.72-1.02; p-value, test for trend 0.03) respectively. Associations for bran intake were similar to those for total whole grain intake, whereas no significant association was observed for germ intake after adjustment for bran. Based on pooled data for six cohort studies including 286,125 participants and 10,944 cases of type 2 diabetes, a two-serving-per-day increment in whole grain consumption was associated with a 21% (95% CI 13%-28%) decrease in risk of type 2 diabetes after adjustment for potential confounders and BMI.
Conclusions
Whole grain intake is inversely associated with risk of type 2 diabetes, and this association is stronger for bran than for germ. Findings from prospective cohort studies consistently support increasing whole grain consumption for the prevention of type 2 diabetes.
Funding: This study was funded by research grants CA50385 and DK58845 from the National Institutes of Health. The study sponsors did not have any role in the study design; collection, analysis, and interpretation of data; writing of the paper; and decision to submit it for publication.
Competing Interests: The authors have declared that no competing interests exist.
Academic Editor: Leif C. Groop, Clinical Research Centre, Sweden
Introduction
The prevalence of type 2 diabetes is increasing rapidly worldwide [1]. Control of body weight by balancing energy intake and energy expenditure is of major importance for the prevention of type 2 diabetes, but the role of specific dietary factors in the etiology of type 2 diabetes is less well established [2]. Evidence is accumulating that consumption of whole grains may reduce risk of chronic diseases including various types of cancer [3], cardiovascular diseases [4], and type 2 diabetes [5-9]. Foods are considered to be whole grains if all components of the kernel, i.e., the bran, germ, and endosperm, are present in their natural proportions. Both the fiber-rich bran outer coating and the inner germ are rich in micronutrients and phytochemicals, whereas the endosperm middle layer mainly consists of starch. In the refining process, components of the grain that are part of the bran and germ are lost, including fiber, minerals, vitamins, lignans, and other phytochemicals [10]. These components may offer important health benefits, including beneficial effects on glucose metabolism [11-13].
In most previous studies, foods are defined as whole grains if at least 25% is whole grain or bran by weight [14]. We used a recently developed food composition database of the grams of whole grains per food to directly calculate each participant's whole grain intake in grams per day [15]. This approach avoids the use of an arbitrary cut-point to classify a food as a whole grain food. In addition, our food composition database now includes bran and germ separately; these whole grain constituents have not to our knowledge been studied in relation to risk of type 2 diabetes before. The endosperm is fairly stable at about 80% of the entire grain, but the proportions of bran and germ can vary by cereal type.
We previously reported data on whole grain intake and risk of type 2 diabetes after 10 y of follow-up [5]. Here, we extend this analysis to 18 y of follow-up, include data from the Nurses' Health Study (NHS) II, use the quantitative whole grain variable, and evaluate the role of the bran and germ constituents separately. Furthermore, we combine our results with those from previous cohort studies in a meta-analysis to systematically evaluate the strength of the epidemiological evidence for a relation between whole grain intake and risk of type 2 diabetes.
RESULTS
Nurses' Health Study I and II
We documented 4,747 cases of type 2 diabetes during 1,235,403 person-years of follow-up in the NHSI and 1,739 cases during 1,040,136 person-years in NHSII. Table 1 describes the characteristics of the study population according to whole grain consumption. Higher intakes of whole grain were associated with higher physical activity, a lower BMI, a lower likelihood of smoking, and a lower consumption of alcohol, soft drinks, and processed meats. Correlations with whole grain intake for NHSI and NHSII respectively were 0.75 and 0.75 for bran, 0.57 and 0.66 for germ, 0.79 and 0.77 for cereal fiber, and 0.53 and 0.53 for magnesium.
Whole grain intake was inversely associated with risk of type 2 diabetes after adjustment for age and after adjustment for other potential confounders in both NHSI and NHSII (Table 2). Further adjustment for BMI, which may partly mediate the association with type 2 diabetes, substantially weakened the association, but significant inverse associations remained (Table 2). Further adjustment for magnesium intake did not substantially explain the inverse association for whole grain intake in either NHSI (RR 0.76, 95% CI 0.68-0.85 for extreme quintiles, p-value test for trend <0.001) or NHSII (RR 0.82, 95% CI 0.68-0.99, p-value 0.02). In the multivariate analysis, each 40 g increment in whole grain intake was associated with a RR of diabetes of 0.54 (95% CI 0.48-0.61) for NHSI and 0.64 (95% CI 0.54-0.76) for NHSII. After additional adjustment for BMI these RRs were 0.70 (95% CI 0.62-0.79) for NHSI and 0.83 (95% CI 0.70-0.98) for NHSII. BMI explained 42% (95% CI 33%-50%) of the association in NHSI and 57% (95% CI 29%-76%) of the association in NHSII.
Table 3 shows the results for bran and germ intake in relation to risk of type 2 diabetes. Associations for bran intake were similar to those for total whole grain intake, whereas associations with diabetes risk were weaker for germ intake. The correlation between bran and germ intake was 0.30 for NHSI and 0.37 for NHSII. Because associations in the fully adjusted model were significant for both bran and germ intake, we modeled bran and germ intake simultaneously for NHSI. After mutual adjustment, bran intake was significantly associated with a lower risk of type 2 diabetes (RR 0.70; 95% CI 0.62-0.79 for extreme quintiles; p-value, test for trend <0.001), whereas germ intake was not (RR 1.01; 95% CI 0.90-1.14; p-value, test for trend 0.91).
Meta-Analysis
Characteristics of the six prospective cohort studies included in the meta-analysis are shown in Table 4. The cohorts included men and women, predominantly white or black populations, and participants from the United States and Finland. In addition to our cohorts, Cox proportional hazards analysis was used in three studies, but it was not reported whether the proportional hazards assumption was met [6,8,9]. Pooled logistic regression analysis was used in the other study [7]. Based on data from all studies combined, including 286,125 participants and 10,944 cases of type 2 diabetes, the pooled RR was 0.79 (95% CI 0.72-0.87) for each two-serving-per-day increment in whole grain intake (Figure 2). Although all studies were consistent with a substantial inverse association, there was significant heterogeneity in results (I2 68%, 95% CI 23%-86%; p-value, test for homogeneity 0.009). In the meta-regression analysis, a higher median whole grain intake of a study population (logarithmically transformed) was significantly associated with a weaker inverse association between whole grain intake and risk of type 2 diabetes (p-value, 0.03). The original heterogeneity was explained by this association: after median whole grain intakes of the population were accounted for, little heterogeneity in studies results remained (I2 5%, 95% CI 0%-80%; p-value, test for homogeneity 0.38). Similarly, after excluding the two studies that had a substantially lower [9] or higher [8] median whole grain intakes than the other studies (Table 4), the test for homogeneity was not significant anymore (p-value 0.15), while the pooled RR did not change (0.79; 95% CI 0.72-0.86). We also conducted a sensitivity analysis excluding one study at the time and calculating the pooled estimate for the remaining studies. The pooled RRs ranged from 0.76 (95% CI 0.70-0.84) after excluding the Finnish study [8] to 0.81 (95% CI 0.74-0.89) after excluding the Black Women's Health Study [9], indicating that the overall results were not unduly influenced by any one study. Visual inspection of the funnel plot (unpublished data) and the Begg (p-value 0.35) and Egger (p-value 0.30) tests did not suggest publication bias.
Discussion
In our prospective studies in over 150,000 women in their 20s through 60s at baseline, we observed a substantial inverse association between whole grain intake and risk of type 2 diabetes. Associations for total whole grain and bran intake were stronger than for germ intake, and we did not observe an independent association for germ intake after adjustment for bran intake. Based on a meta-analysis of six cohort studies, a two-servings-per-day increment in whole grain intake was associated with a 21% decrease in risk of type 2 diabetes.
Strengths and Limitations
Strengths of our study included the prospective design and high rates of follow-up, which minimize the probability of recall bias or selection bias. Our study and the other studies included in the meta-analysis also had several potential limitations. First, although potential confounding was considered in detail, residual confounding by additional unmeasured or imperfectly measured confounders cannot be excluded. Particularly, higher whole grain intake tends to be associated with a healthier lifestyle, and incomplete adjustment for lifestyle factors could have led to overestimation of the strength of the inverse associations between whole grain intake and risk of type 2 diabetes. However, the consistency of findings across different cohorts and studies of different designs (see below) reduces the likelihood that residual confounding can fully explain the findings. Second, some measurement error in the assessment of dietary intakes is inevitable. Because of the prospective study design, misclassification of whole grain intake was unlikely to differ by case status and probably weakened the observed inverse association between whole grain intake and diabetes risk. We used averages of multiple repeated measurements of dietary intakes to reduce measurement error and better represent long-term diet [23]. Third, diabetes was assessed by self-report confirmed by a supplementary questionnaire, because screening for blood glucose was not feasible given the size of the cohorts. Data from our validation study using medical records suggest that reporting of diabetes is accurate for this population of registered nurses. Although underdiagnosis of diabetes is likely, it was probably limited in this cohort with ready access to medical care.
In the meta-analysis, the assessment of whole grain intake and its classification varied between the different included cohorts (Table 4). The use of an FFQ with less-detailed questions on whole grain foods [9] and the use of a classification that weighted all foods with at least 25% of whole grains equally [6-8] may have contributed to measurement error. In addition, the level of whole grain intakes differed substantially for the different cohorts. For example, the intake of whole grains and rye bread in particular was substantially higher for the Finnish population than for the US populations. Our results suggest that the benefit of adding a serving of whole grains may be greater for populations with a low intake than for those who already have a high intake, but this finding requires further research. Given the measurement error in the assessment of whole grain intake, the potential for residual confounding, and the difference in characteristics of the study populations, the estimated magnitude of associations should be interpreted with caution. However, all cohort studies were consistent with a substantial protective effect of whole grain consumption in relation to type 2 diabetes and excluding any one study did not substantially change the pooled estimate. Publication bias can affect the findings of any meta-analysis, but standard tests did not indicate the presence of publication bias in the current analysis.
Relation to Other Studies
The findings from cohort studies are consistent with the direct association between whole grain consumption and insulin sensitivity that has been observed in cross-sectional studies in adolescent [32] and adult US populations [33-36]. Higher whole grain consumption was also associated with lower fasting and postload plasma glucose concentrations in one cross-sectional study [37], but not in two other studies [32,33]. In population of adults in Iran, whole grain consumption was inversely associated with newly detected abnormal glucose metabolism and type 2 diabetes [38]. Although all studies that quantified total whole grain consumption were included in our meta-analysis, two studies evaluated whole grain bread consumption in relation to type 2 diabetes. Whole grain bread intake was associated with a significantly lower risk of type 2 diabetes in a German cohort (RR 0.78, 95% CI 0.62-0.97 for 80 versus <4 g/d) [39], but not in an Australian cohort (RR 0.86, 95% CI 0.63-1.18 for highest versus lowest quartile) possibly due to the low reproducibility of the assessment of bread consumption in that cohort [40].
In a randomized cross-over trial in hyperinsulinemic overweight adults, consumption of whole grains (mostly whole wheat, rolled oats, and brown rice) for 6 wk increased insulin sensitivity as compared with refined grains [41]. Results of intervention studies of wheat bran have been mixed, with beneficial effects on glucose tolerance in studies in persons with [42] and without glucose intolerance [43], but no improvement in glycemic control in individuals with established type 2 diabetes [44]. In a randomized cross-over trial in postmenopausal women, consumption of high-fiber rye bread for 8 wk did not alter insulin sensitivity as compared with white wheat bread, but enhanced acute insulin response [45].
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