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 on circulating blood-based metabolites to shed light on potential mediators of the insulin resistance to cardiometabolic disease relationship. Research Design and Methods: We used 53 single nucleotide polymorphisms associated with insulin resistance from a recent genome-wide association study to explore their effects on circulating lipids and metabolites. We used published summary-level data from two genome-wide association studies (GWASs) of European individuals; data on the exposure (insulin resistance) were obtained from meta-GWASs of 188,577 individuals and data on the outcomes (58 metabolic measures assessed by NMR) were taken from a GWAS of 24,925 individuals. Results: One standard deviation (SD) genetically elevated insulin resistance (equivalent to 55% higher geometric mean of fasting insulin, 0.89 mmol/L higher triglycerides and 0.46 mmol/L lower HDL-C) was associated with higher concentrations of all branched-chain amino acids, 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 insulin resistance causally impacts on each individual branched-chain amino acid and inflammation. Taken together with existing studies, this implies that branched-chain amino acid metabolism lies on a causal pathway from adiposity and insulin resistance to type 2 diabetes.