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: < 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.