Higher habitual intakes of flavonoids and flavonoid-rich foods are associated with a lower incidence of type 2 diabetes in the UK Biobank cohort

Type 2 diabetes (T2D) is a major non-communicable disease with substantial global health and economic consequences. While modifiable risk factors like obesity are key contributors, diet plays a crucial role in prevention. Plant-based diets, rich in flavonoids, have shown promise in reducing T2D risk. Flavonoids, a class of polyphenolic compounds found in various fruits, vegetables, and beverages, have been linked to favorable health effects. These compounds are categorized into six subclasses, each with varying bioavailability and bioactivity. Previous studies have indicated inverse associations between certain flavonoid subclasses and T2D incidence, with short-term trials showing improvements in insulin sensitivity and lipid profiles. This study aimed to investigate the association between a flavonoid-rich diet, represented by a novel Flavodiet Score (FDS), and incident T2D risk in the large UK Biobank cohort, further exploring potential mediating mechanisms and the contribution of specific foods and flavonoid subclasses.

Numerous studies have explored the relationship between flavonoid intake and T2D risk. A meta-analysis of prospective cohort studies reported inverse associations between higher dietary intakes of several flavonoid subclasses (flavanols, flavonols, flavan-3-ols, and isoflavones) and T2D risk. However, findings on flavanone intakes remain inconsistent, with some studies showing inverse associations and others showing positive associations. These discrepancies may be attributed to the inclusion of fruit juices, which are high in flavanones but also have a high glycemic load. Studies on individual flavonoid-rich foods, such as tea, berries, and apples, have also indicated protective effects against T2D. Short-term randomized controlled trials (RCTs) have provided evidence that increased intakes of certain flavonoid subclasses, like anthocyanins and flavan-3-ols, can improve insulin sensitivity, insulin resistance, and lipid profiles. Mechanistic studies have suggested that the protective effects of flavonoids might be mediated through various pathways, including reduced inflammation, oxidative stress, and improved glucose metabolism.

This prospective cohort study utilized data from the UK Biobank, a large-scale population-based study. After exclusions for incomplete dietary data, implausible energy intakes, withdrawal of consent, pre-existing conditions (diabetes, CVD, cancer), and pregnancy, the final analysis included 113,097 participants. Flavonoid intakes were estimated from at least two 24-hour dietary assessments using the USDA database. A novel Flavodiet Score (FDS) was developed, summing the number of servings of ten flavonoid-rich foods (tea, red wine, apples, berries, grapes, oranges, grapefruit, peppers, onions, and dark chocolate). The FDS was categorized into sex-specific quartiles. Reproducibility of the FDS was assessed using intraclass correlation coefficients (ICCs). The relationship between the FDS, individual flavonoid-rich foods (categorized into quartiles), and flavonoid subclasses (also categorized into quartiles) with incident T2D was analyzed using multivariable Cox proportional hazards regression models. Model 1 adjusted for sociodemographic factors (sex, education, age, and region), while Model 2 further adjusted for BMI, waist circumference, ethnicity, physical activity, smoking status, alcohol intake, energy intake, polypharmacy index, multimorbidity index, Townsend deprivation index, family history of diabetes, hypercholesterolemia, hypertension, menopausal status, polygenic risk score for T2D, number of dietary assessments, and intakes of whole grains, sugar-sweetened beverages, red and processed meat, and coffee. Sensitivity analyses were conducted, and mediation analyses explored potential mediating pathways (BMI, IGF-1, C-reactive protein, cystatin C, urate, GGT, ALT) using biomarker measurements. Bonferroni correction was applied to adjust for multiple comparisons in food and subclass analyses.

During a median follow-up of 12 years, 2628 incident T2D cases were identified. In multivariable-adjusted models, a higher FDS (Q4 vs. Q1), representing an average of 6 servings of flavonoid-rich foods per day, was associated with a 26% lower T2D risk (HR: 0.74, 95% CI: 0.66–0.84, Ptrend <0.001). A 1-point increase in the FDS was associated with a 5% lower risk (HR: 0.95, 95% CI: 0.93–0.97, Ptrend <0.001). Excluding red wine from the FDS only marginally attenuated the associations. Food-based analyses showed that higher intakes of black or green tea (21% lower risk, HR: 0.79, 95% CI: 0.70–0.90, Ptrend <0.001 after Bonferroni correction), berries (15% lower risk, HR: 0.85, 95% CI: 0.74–0.98, Ptrend = 0.01), and apples (12% lower risk, HR: 0.88, 95% CI: 0.79–0.98, Ptrend = 0.03) were associated with lower T2D risk. After Bonferroni correction, only tea intake remained statistically significant. Analyses of flavonoid subclasses showed that higher intakes of anthocyanins, flavan-3-ols, flavonols, flavones, polymers, and proanthocyanidins were associated with 19–28% lower risks of T2D after multivariable adjustment and Bonferroni correction. Subgroup analyses showed no significant heterogeneity across different strata of potential effect modifiers. Mediation analyses suggested that the association between FDS and T2D risk was partially mediated by lower BMI, lower levels of C-reactive protein, lower cystatin C and urate levels (indicators of kidney function), and lower GGT and ALT levels (indicators of liver function), cumulatively accounting for 28% of the observed association.

This study provides robust evidence from a large prospective cohort that a diet rich in flavonoid-rich foods, as captured by the FDS, is associated with a lower risk of T2D. The findings are consistent with previous studies showing inverse associations between flavonoid subclasses and T2D risk. The observed associations are not solely explained by overall dietary quality, highlighting the specific benefits of these foods. The significant mediation by body fatness and inflammatory markers underscores the role of flavonoids in modulating weight and inflammation pathways. The partial mediation by kidney and liver function suggests potential protective effects on these organs. While some limitations exist, such as the predominantly White-European population and reliance on self-reported dietary data, the large sample size and long follow-up strengthen the study's conclusions.

This study demonstrates a significant association between a higher Flavodiet Score and a reduced risk of T2D in a large prospective cohort. The protective effects may be mediated by the beneficial impacts of flavonoids on obesity, inflammation, and kidney and liver function. Encouraging increased consumption of specific flavonoid-rich foods, such as tea, berries, and apples, could contribute to T2D prevention. Future research could focus on exploring the underlying mechanisms further and investigating the generalizability of these findings to diverse populations.

The study's limitations include the predominantly White-European ancestry of the UK Biobank participants, limiting the generalizability of findings. Self-reported dietary data may be subject to recall bias and potential misreporting. The mediation analyses showed modest effects, suggesting that additional, unmeasured mediators might be involved. Despite multivariable adjustment, residual confounding cannot be entirely ruled out.