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Nutritional Epidemiology

Dietary Flavonoids and Flavonoid-Rich Foods Are Not Associated with Risk of Type 2 Diabetes in Postmenopausal Women¹

² Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN; ³ Exponent, Inc., Washington, DC; and ⁴ Department of Nutrition, University of Oslo, Oslo, Norway

^* To whom correspondence should be addressed. E-mail: jacobs{at}epi.umn.edu.

	ABSTRACT

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Flavonoids have anti-inflammatory and antioxidative effects and thus may protect against diabetes. Therefore, we hypothesized that consumption of flavonoids and specific food and beverage sources of flavonoids would be associated with reduced risk of incident diabetes. At baseline (1986), diet (by food frequency questionnaire) and health information were collected from 35,816 postmenopausal women free of diabetes. Self-reported incident diabetes was ascertained 5 times during the study (1987, 1989, 1992, 1997, and 2004). Cox proportional hazards regression was used to calculate hazard ratios for incident diabetes according to categories of total flavonoids and anthocyanidins, flavones, flavanones, flavonols, flavan-3-ol monomers, isoflavones, and proanthocyanidins. Hazard ratios according to intake categories of flavonoid-rich foods and beverages were also calculated (apples, pears, berries, broccoli, bran, citrus, tea, and red wine). Flavonoid consumption was not associated with diabetes risk after multivariable adjustment. Although other flavonoid-rich foods and beverages were not associated, red wine was inversely associated with diabetes. Women who reported drinking red wine 1 time/wk had a 16% reduced risk of diabetes than those drinking wine <1 time/wk [HR (95% CI): 0.84 (0.71, 0.99)], with parallel findings for white wine, beer, and liquor. In conclusion, these data do not support a diabetes-protective effect of flavonoids. The suggestive evidence of a protective effect of regular red wine consumption is shared with an inverse association between alcohol drinks in general and diabetes risk and may reflect the effects of nonflavonoid constituents that are common to all alcohol drinks.

	Introduction

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Several studies, although not all, have shown a reduced risk of cardiovascular disease in association with flavonoid intake (7); however, only 2 studies have evaluated the association between intake of various flavonoids and incident diabetes (13,14). Whereas the earlier of the 2 studies found suggestive, but nonsignificant relations between incident diabetes and the flavonols quercitin and myricetin (13), the more recent study found no association between diabetes and flavones, flavonols, or total flavonoid intake (14). Both studies reported significant inverse associations between the risk of diabetes and apple intake (a source of the flavonol, quercitin) in both populations. However, adjustment for quercitin in the study by Song et al. (14) did not attenuate the relative risk of diabetes attributed to apple consumption, suggesting that other compounds contained in apples or other factors associated with apple consumption may be important in mediating the observed relation between apple intake and diabetes risk.

The analyses presented here describe the association between flavonoid consumption and self-reported incident type 2 diabetes in the Iowa Women's Health Study. Our primary hypothesis was that consumption of each specific flavonoid subclass would be associated inversely with risk of self-reported incident diabetes. Our secondary hypothesis was that consumption of important food sources of flavonoids defined a priori would also be related inversely to incident diabetes.

	Methods

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    Subjects. The Iowa Women's Health Study is a prospective cohort study initiated in January 1986. Women 55–69 y of age, with valid 1985 Iowa drivers' licenses (n = 99,826), were sent a questionnaire in which they were asked questions about their education, diet, physical activity level, smoking habits, reproductive history, medication use, history of disease, height, weight, and waist and hip circumferences (15). Of the 41,836 women who completed the baseline questionnaire (41.9% of those randomly selected), 35,816 were included in the current analysis (85.6% of the original cohort). Women were excluded from analyses if they were not postmenopausal at baseline (n = 569), reported energy intake <600, >5000 kcal/d,⁵ or left >30 items on the food frequency questionnaire blank (n = 3,096), or reported a history of diabetes or medication for diabetes at baseline (n = 2752) (numbers not mutually exclusive). The study was approved by the University of Minnesota Institutional Review Board.

    Incident type 2 diabetes. In 1987 (91% response rate), 1989 (90%), 1992 (83%), 1997 (79%), and 2004 (69%) women from the baseline cohort were mailed questionnaires designed to assess their current health status. Self-reported incident cases of diabetes were determined from participant responses to the following question: "(since previous contact) were you diagnosed for the first time by a doctor as having sugar diabetes?" Over the 5 follow-up surveys, 3395 women reported having diabetes (1987, n = 363; 1989, n = 342; 1992, n = 474; 1997 n = 750; and 2004, n = 1466).

    Diet assessment. The participants' usual diet was assessed at baseline with a 127-item semiquantitative FFQ (16,17). Women were asked the frequency with which they consumed various foods during the previous year (portion sizes given in parentheses). Frequency categories ranged from never or less than once per month to 6 or more times per day. The questionnaire included 15 questions addressing fruit intake, 29 addressing vegetable intake, and questions each for chocolate, bran added to foods, tea, red wine, white wine, beer, and liquor. Certain flavonoid-rich foods (e.g., berries, onions) were not queried specifically, although participants were given the opportunity to report foods consumed at least weekly that were not included in the questionnaire. Nutrient composition values for foods on the FFQ were obtained from the Harvard University Food Composition Database (18).

    Flavonoid intake. Flavonoid levels of individual foods assessed in the FFQ were derived from 3 flavonoid databases developed by the USDA Nutrient Data Laboratory (NDL) (19–21), providing data for the following flavonoid classes: anthocyanidins, flavones, flavanones, flavonols, flavan-3-ols (monomers), isoflavones, plus proanthocyanidins (condensed tannins or flavan-3-ols polymers). The flavonoid content of each participant's diet was calculated by multiplying the reported consumption frequency by the flavonoid content of each food as assessed by responses to the FFQ. Questions containing multiple flavonoid-containing foods (e.g., fresh apples or pears; raisins or grapes) were assigned a value weighted according to the mean per capita consumption of each food in 1986 (22). In the absence of such data, the Continuing Survey of Food Intake by Individuals was used (23).

    Statistical analysis. For those women not reporting diagnosis of diabetes, person-time-at-risk was calculated from baseline to the date of the last completed follow-up survey, date of death, or end of the study period. For those reporting a diagnosis of diabetes, person-time-at-risk was calculated from the sum of the known disease-free period and half of the period during which the diagnosis was made. Mortality status was updated annually through linkage with the State Health Registry of Iowa. The National Death Index was used for nonrespondents and those no longer living in Iowa.

Participant characteristics and nutrient intakes were calculated according to flavonoid intake quintiles (Proc GLM, SAS Institute, version 9.1). Cox proportional hazards regression was used to determine the hazard ratio for type 2 diabetes according to baseline flavonoid intake (SAS Proc TPHREG), using the lowest intake category as the referent. Due to skewed distribution and low intake in the majority of women, anthocyanidin intake was modeled as a 3-level variable according to predefined categories: 0 mg/d, >0–0.042 mg/d, and >0.042 mg/d; all others were analyzed in quintiles. Tests for trend across categories were performed by assigning each category its median flavonoid intake value and treating the variable as a continuous term. We also calculated hazard ratios according to intake of specific foods and food groups high in flavonoids and shown in previous studies to be related to diabetes (13,14) or shown in this cohort to be related to cardiovascular disease (24) (P. J. Mink, unpublished data): fresh apples and pears, berries (strawberries, blueberries, and other reported berries), broccoli, bran added to foods, citrus fruits, juices (grapefruit, grapefruit juice, oranges, and orange juice), tea, and red wine. Hazard ratios for incident diabetes were calculated according to consumption frequency categories, which varied depending on the spread of the data (<1 time/wk vs. 1/wk for each of berries, broccoli, bran, tea, and red wine; <1 time/wk, 1–2 times/wk, and >2 times/wk for apples; <5 times/wk, 5–8 times/wk, and >8 times/wk for citrus fruits and juices). We adjusted all risk analyses for the following confounders: age (y), energy (kcal/d), education level (less than, equal to, or greater than a high school degree), physical activity (low, medium, high), BMI (kg/m²), waist:hip ratio, smoking status (current, former, or never), pack years (0, 1–19, 20–39, 40+ y), regular use of multivitamin supplements (yes/no), current use of hormone therapy (yes/no). Tests for interaction with flavonoid intake for risk of diabetes were performed by adding a cross-product term to the multivariable model. The following modifying variables were considered: BMI, waist:hip ratio, smoking status, family history of diabetes, and physical activity.

	Results

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Age, education, physical activity level, supplement use, and hormone therapy were positively associated with flavonoid intake (P 0.002, Table 1). In contrast, smoking prevalence, BMI, and waist:hip ratio were inversely associated with intake (P < 0.001). Neither family history of diabetes (P = 0.26) nor self-reported hypertension (P = 0.20) differed across flavonoid quintiles.

Intake of each apples, berries, broccoli, bran, citrus fruits or juices, and tea was not associated with incident diabetes after multivariable adjustment (data not shown). In contrast, multivariable analysis for red wine showed that women who reported drinking red wine at least once per week had a 16% reduced risk of developing diabetes compared with women who did not drink red wine or who drank infrequently (<1 time/wk) [HR (95% CI): 0.84 (0.71, 0.99); Table 4]. Modeling red wine consumption in categories of abstainers vs. drinkers produced similar results. To determine whether the association was independent of flavonoid content, we further adjusted the analysis for each of the flavonoid subclasses present in high levels in wine: total flavonoid, anthocyanidins, flavan-3-ol monomers, proanthocyanidins, and total proantocyanidins. None of these adjustments markedly changed the hazard ratio associated with wine drinking. Adjustment for potential confounding food and nutrient variables that may cluster with a healthy lifestyle also did not attenuate the relation observed between red wine intake and risk of diabetes (fiber, whole grains, iron, magnesium, vitamin E, vitamin A, vitamin C, ß-carotene, vegetable fat, and polyunsaturated fat). To evaluate whether these results were unique to red wine vs. true of all alcoholic beverages, we adjusted the above analyses for total alcohol intake [sum of red wine (10.8 g alcohol), white wine (10.8 g alcohol), beer (13.2 g alcohol), and liquor (15.1 g alcohol)], and found the association attenuated [HR (95% CI): 0.94 (0.83, 1.05)]. When the same analyses were repeated separately for each of the other alcoholic beverages, results mirrored those of red wine (Table 4). Similarly, analysis of total alcohol intake in relation to diabetes risk (categorized as 0 g/d, 1–14 g/d, 15 g/d) were analogous [HR (95% CI): 0.83 (0.77, 0.90) for 1–14 g/d; 0.66 (0.55, 0.79) for 15 g/d]. These data were robust to adjustment for specific alcoholic beverage types (data not shown).

	Discussion

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In this study of predominantly white, postmenopausal women, we did not observe evidence of an independent association of flavonoid consumption with incident diabetes. Overall, our results are in contrast to those of Knekt et al. (13), who reported that intakes of the flavonols quercetin and myricetin were inversely associated with risk of type 2 diabetes in Finnish men and women aged 40 y, but are consistent with the results of Song et al. (14), who found no association between risk of diabetes and total flavonoids nor individual flavonols and flavones in U.S. women aged 45 y. Both the Knekt and Song studies reported suggestive inverse associations between apple consumption and risk of type 2 diabetes, whereas we observed no such inverse associations with diabetes risk and specific foods high in flavonoids (including apples among others). Methodological differences among the 3 studies (13,14) may have contributed to the inconsistent findings.

In all 3 studies (13,14), most women reported their perimenopausal or early postmenopausal diets, which may have been poor reflections of lifetime dietary exposures of likely importance to disease risk (28–31). Accuracy of the dietary data may have varied among studies because of the use of FFQs in ours and Song's (14) studies vs. the more comprehensive dietary history method in the Finnish study (13). Specific sources of flavonoids (e.g., onions or berries) may have been missed or measured less accurately in studies [like ours and Song's (14)] that relied on data from FFQs, potentially biasing estimates toward the null. Furthermore, because all 3 studies were conducted in culturally and geographically unique regions, differences among populations in dietary patterns or flavonoid content of identical foods may have influenced results. Lastly, differences in the comprehensiveness of flavonoid databases used in each study complicate comparison.

Although we found no evidence of an inverse association between flavonoids and risk of type 2 diabetes, we did find an inverse association between diabetes and red wine consumption. The Iowa Women's Health Study has previously reported an inverse association between total alcohol intake and diabetes risk with fewer years of follow-up (26), and other studies conducted in women also support the diabetes-protective associations of wine or alcohol (32–36). Various mechanisms have been proposed to explain observations suggesting a protective effect of wine for diabetes (37–40). These reported effects are thought to be related to the flavonoid (41), resveratrol (42), or ethanol (43) component of red wine. Our finding that the reduced risk of diabetes associated with red wine consumption was independent of flavonoid intake but not of total alcohol intake, suggests that nonflavonoid constituents are responsible. Alternatively, it may be that the food and beverage matrix is needed to confer the protective effects of certain food or beverage constituents (44,45). Similarly, our lack of significant association between risk of diabetes and intake of flavonoids or flavonoid-rich foods may be in part due to a need for synergy among foods. Many have reported inverse associations between diabetes risk and dietary patterns, which for the most part, include flavonoid-rich fruits and vegetables (46–49). The small effects of flavonoids may be undetectable with the type of reductive approach utilized in the current investigation.

We acknowledge some limitations to our analysis. First, these results may be biased by the overall low intake of flavonoids and flavonoid-rich foods, and it is possible that biological effect thresholds were not reached at the level of intake observed in our cohort. Second, these results may be influenced by an inadequate determination of incident diabetes. Although self-reported diabetes has been shown in studies of health professionals to be highly valid (50), the validity of self-report in population-based studies like ours is less sound (51). Third, whereas long-term follow-up can be advantageous in terms of accruing outcomes, the advantage can be lost with regard to dietary exposures measured only at baseline, potentially increasing exposure misclassification over time and attenuating risk estimates. Although we found no evidence to support this when we stratified analyses by follow-up year, it may be that cases were too few in early follow-ups to detect meaningful associations. Furthermore, we may have missed subjects with diabetes who died before periodic follow-ups; although this is less of an issue with a more slowly developing disease like diabetes, important comorbidities can result rapidly in death. Lastly, even though we observed significant inverse associations between risk of diabetes and consumption of alcoholic beverages (including red wine), these findings should be interpreted cautiously, given the number of comparisons made and the relatively crude categorization of consumption. Healthy diet and lifestyle characteristics often cluster with drinking and are difficult to fully account for in observational investigations, which may be particularly problematic in our study where drinking prevalence (any alcoholic beverage) was relatively low (41.4%). Moreover, given that only 4.1% of our cohort (and 0.7% of cases) consumed >2 alcoholic beverages per week, our analyses using multiple intake categories cannot fully evaluate the possibility of increased risk of diabetes at higher intake levels (32,33,52,53).

In conclusion, despite the substantial size of our cohort and the use of a comprehensive flavonoid database, we did not find flavonoid intake to be associated with a reduced risk of diabetes in postmenopausal women. These findings may be due to a true absence of a protective effect of these compounds with regard to type 2 diabetes, or alternatively, the result of improper timing and quality of dietary assessment, insufficient diabetes assessment, or failure to adequately account for the collective contribution of other dietary constituents. Lastly, our findings provide evidence that regular consumers of alcoholic beverages like red wine have a significantly reduced risk of developing diabetes compared with those who do not, or irregularly, consume alcohol. Diet represents a complex myriad of exposures that are likely to have both beneficial and harmful effects with regard to diabetes risk. Although we found no evidence of the protective effect of only one food constituent, flavonoids, in relation to diabetes risk, ours is one of few studies that have evaluated this association. The conflicting results among current studies suggests that further research in this area is warranted, perhaps with greater focus on potential synergies among foods, lifestyle, and other environmental or genetic factors.

	ACKNOWLEDGMENTS

 
The authors thank Dr. Aaron R. Folsom for providing the Iowa Women's Health Study data and Ching Ping Hong, MS, for statistical consultation and assistance in data preparation prior to analysis.

	FOOTNOTES

 
¹ The Iowa Women's Health Study was supported by grant R01 CA39742 from the National Cancer Institute. Funding for this particular work was provided by training grant T32 HL07779 from the National Heart, Lung, and Blood Institute (J.A.N.). Additional grants were provided by the International Life Sciences Institute (ILSI) to the University of Minnesota (D.R.J. and L.J.H.) and to Exponent (P.J.M., C.G.S., and L.M.B.) to facilitate assignment of flavonoid values and data analysis. None of the sponsors were involved in writing this article.

⁵ 1 kcal = 4.184 kJ.

Manuscript received 31 July 2006. Initial review completed 6 September 2006. Revision accepted 19 September 2006.

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