Branched-Chain Amino Acid Intake and Risk of Incident Type 2 Diabetes: Results from the SUN Cohort

Background/Objectives: While many studies have explored the association between circulating branched-chain amino acids (BCAAs) and type 2 diabetes mellitus (T2DM), evidence on the prospective relationship between dietary BCAA intake and T2DM risk remains limited. We aimed to explore this relationship-both total and by dietary source-in a Mediterranean cohort. Methods: We used data from the SUN Project, a prospective and dynamic cohort of Spanish university graduates initiated in 1999. Dietary intake was assessed with a validated 136-item food frequency questionnaire at baseline and at 10 years. BCAA intake (valine, leucine, isoleucine) was estimated using the USDA amino acid database and adjusted for energy intake by the residual method. Participants were followed biennially through questionnaires to identify incident T2DM cases, confirmed by a supplementary questionnaire and medical report, following the ADA diagnostic criteria. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for potential confounders across four multivariable models. BCAA intake was modeled both categorically (tertiles) and continuously (per 0.5% energy or 5 g/day increase). Analyses were stratified by age and recruitment period. Results: After exclusions, 20,154 participants were included (mean follow-up: 14.67 ± 5.8 years), with 220 incident T2DM cases identified. For each 0.5% energy increment intake from BCAA, there was no association with T2DM (adjusted HR: 1.01; 95% CI: 0.69-1.20). Among men, the adjusted HR was 0.91, 95% CI: 0.69-1.20. Among women, it was 1.40, 95% CI: 0.94-2.09. In the overall cohort, higher BCAA intake showed a non-significant inverse association with the T2DM risk when comparing extreme tertiles (HR = 0.81; 95% CI: 0.48-1.37), which strengthened when repeated dietary measures were considered (HR = 0.70; 95% CI: 0.46-1.06, p-trend = 0.06). Analyses by BCAA sources (animal vs. plant) and stratified by sex, weight status, and age did not reveal consistent patterns, though exploratory findings suggested potential effect modification by sex and adiposity. Sensitivity analyses confirmed the lack of robust associations, with some subgroup-specific signals being limited by low event numbers and wide CIs. Conclusions: Given the power limitations and the modest, non-significant associations observed, these findings should be considered preliminary evidence that may help guide future research on the role of dietary BCAAs in glucose metabolism and diabetes risk.