Causal role of genetically predicted impairment of branched-chain amino acid catabolism on insulin secretion and insulin resistance in type 2 diabetes

Background: Elevated branched-chain amino acids (BCAAs; leucine, valine, isoleucine) are linked to type 2 diabetes (T2D) risk, characterised by defective insulin secretion in pancreatic β-cell and peripheral insulin resistance. Causative interaction between BCAA metabolism and these two diabetic pathogenesis remains unclear. Methods: Using publicly available datasets from the European population, we conducted a meta-analysis of genome-wide association studies (GWAS), followed by multi-trait analysis of GWAS (MTAG), to identify genetic loci associated with BCAAs and their catabolites. Two-sample bidirectional Mendelian Randomisation (MR) examined putative causal associations of genetically determined BCAAs and their catabolites with 10 traits related to insulin and glucose metabolism. Sensitivity analyses evaluated robustness and specificity of observed associations. Results: MTAG identified 57.14%, 59.09%, and 63.41% novel genetic loci for circulating leucine, valine and isoleucine, respectively. Genetically elevated valine had a significant association with increased insulin fold change during oral glucose challenge test (OGTT) (β [95% CI] = 0.135 [0.045, 0.225]), False discovery rate adjusted p-value (p_FDR = 0.022), and suggestive association with fasting glucose level (β [95% CI] = 0.031 [0.004, 0.058], inverse-variance weighted p-value [p_IVW] = 0.025). In the reverse direction, genetically determined homeostasis model assessment of β-cell (HOMA-B) exhibited significant inverse associations with BCAAs (Leucine: β [95% CI] = −0.140 [−0.244, −0.036], p_FDR = 0.034; Valine: β [95% CI] = −0.147 [−0.255, −0.040], p_FDR = 0.030; Isoleucine: β [95% CI] = −0.149 [−0.248, −0.049], p_FDR = 0.020). Moreover, β-hydroxyisovalerate, a leucine-derived catabolite, was inversely related to 2-h glucose level after OGTT (β [95% CI] = −0.149 [−0.227, −0.071], p_FDR = 0.045). In the reverse direction, genetically predicted peak insulin response was suggestively associated with elevated isoleucine catabolite, 2-hydroxy-3-methylvalerate (β [95% CI] = 0.074 [0.018, 0.130], p_IVW = 9.20 × 10⁻³). Conclusions: Our genetic analysis indicates BCAA catabolism and insulin secretion/action interact with each other; their aberrance might form a vicious cycle promoting T2D progression.