Longitudinal associations of branched-chain amino acids with type 2 diabetes and markers of insulin secretion and sensitivity in Japanese Americans

Abstract

Background and aims: To prospectively investigate the associations of branched-chain amino acids (BCAA) with incident diabetes and estimates of insulin secretion and sensitivity.Methods and results: We conducted a secondary analysis among participants free from diabetes in the Japanese American Community Diabetes Study (n=349). For the biomarker study, participants were assessed for diabetes at baseline and 5–6 years of follow-up and estimates of insulin sensitivity and secretion were obtained. Baseline plasma samples in adults free from diabetes were assayed for BCAA levels. We fit logistic regression models to examine associations of BCAA with incident diabetes at 5–6 years and linear regression models to examine associations with estimates of insulin secretion (oral disposition index, oDI) and insulin sensitivity (Matsuda index and HOMA2-%S) at baseline and 5–6 years. Models were adjusted for age, sex, BMI, and smoking status (Model 2); and for age, sex, BMI, smoking status, and family history of T2D (Model 3). For the oDI and Matsuda index, we fit sex-stratified models and examined whether associations depended on sex on a multiplicative scale. Results: The mean age was 56.5. 50.7% (n=177) were men. Higher valine was associated with higher odds of incident diabetes (OR for a 1SD change 1.06, 95% CI 1.03, 1.09, Model 2). After adjustment, no BCAA was associated with oDI at baseline or follow-up. Higher isoleucine was associated with lower Matsuda index at baseline (β for 1SD change -0.02, 95%CI – (0.03, -0.01, Model 2)). Higher isoleucine and valine were associated with lower HOMA2-%S at baseline (β for 1SD change -0.43, 95%CI (-0.62, -0.23), and -0.58, 95%CI (-0.82, -0.35), Model 2, respectively). No BCAA was associated with Matsuda index or HOMA2%S at follow-up. Associations were similar in models with and without adjustment for family history of T2D. In men, no BCAA was associated with oDI or Matsuda index at baseline. In women, higher isoleucine was associated with lower Matsuda index at baseline (β for 1SD change: -0.04, 95%CI (-0.06, -0.02), Model 2, p for interaction >0.05). Conclusion: Higher valine was associated with a higher risk of incident diabetes at 5–6 years. Higher isoleucine and valine were associated with lower insulin sensitivity (isoleucine with Matsuda index and HOMA2-%S, valine with HOMA2-%S only) at baseline but not at follow up. Results were similar with and without adjustment for family history of T2D. Associations may differ by sex. More research is needed to characterize the roles of sex and genetic variation in associations of circulating BCAA with diabetes risk and insulin secretion and sensitivity measures.