Branched-chain amino acids and type 2 diabetes: a bidirectional Mendelian randomization analysis

Genetic studies have suggested that the branched-chain amino acids (BCAAs) valine, leucine, and isoleucine have a causal association with type 2 diabetes (T2D). However, inferences are based on a limited number of genetic loci associated with BCAAs.

Instrumental variables (IVs) for each BCAA were constructed and validated using large well-powered data sets and their association with T2D was tested using a two-sample inverse-variance weighted Mendelian randomization approach. Sensitivity analyses were performed to ensure the accuracy of the findings. A reverse association was assessed using instrumental variables for T2D.

Estimated effect sizes between BCAA IVs and T2D, excluding outliers, were as follows: valine (β = 0.14 change in log-odds per SD change in valine, 95% CI: -0.06 to 0.33, p = 0.17), leucine (β = 0.15, 95% CI: -0.02 to 0.32, p = 0.09), and isoleucine (β = 0.13, 95% CI: -0.08 to 0.34, p = 0.24). In contrast, T2D IVs were positively associated with each BCAA, i.e., valine (β = 0.08 per SD change in levels per log-odds change in T2D, 95% CI: 0.05 to 0.10, p = 1.8 × 10^-9 ), leucine (β = 0.06, 95% CI: 0.04 to 0.09, p = 4.5 × 10^-8 ), and isoleucine (β = 0.06, 95% CI: 0.04 to 0.08, p = 2.8 × 10^-8 ).

These data suggest that the BCAAs are not mediators of T2D risk but are biomarkers of diabetes.