Genetic Support for a Causal Role of Insulin Resistance on Circulating Branched-Chain Amino Acids and Inflammation

OBJECTIVE Insulin resistance has deleterious effects on cardiometabolic disease. We used Mendelian randomization analyses to clarify the causal relationships of insulin resistance (IR) on circulating blood-based metabolites to shed light on potential mediators of the IR to cardiometabolic disease relationship. RESEARCH DESIGN AND METHODS We used 53 single nucleotide polymorphisms associated with IR from a recent genome-wide association study (GWAS) to explore their effects on circulating lipids and metabolites. We used published summary-level data from two GWASs of European individuals; data on the exposure (IR) were obtained from meta-GWASs of 188,577 individuals, and data on the outcomes (58 metabolic measures assessed by nuclear magnetic resonance) were taken from a GWAS of 24,925 individuals. RESULTS One-SD genetically elevated IR (equivalent to 55% higher geometric mean of fasting insulin, 0.89 mmol/L higher triglycerides, and 0.46 mmol/L lower HDL cholesterol) was associated with higher concentrations of all branched-chain amino acids (BCAAs)-isoleucine (0.56 SD; 95% CI 0.43, 0.70), leucine (0.42 SD; 95% CI 0.28, 0.55), and valine (0.26 SD; 95% CI 0.12, 0.39)-as well as with higher glycoprotein acetyls (an inflammation marker) (0.47 SD; 95% CI 0.32, 0.62) (P < 0.0003 for each). Results were broadly consistent when using multiple sensitivity analyses to account for potential genetic pleiotropy. CONCLUSIONS We provide robust evidence that IR causally affects each individual BCAA and inflammation. Taken together with existing studies, this implies that BCAA metabolism lies on a causal pathway from adiposity and IR to type 2 diabetes.