Insulin resistance is a heritable cause of multiple epidemic metabolic disorders such as type 2 diabetes (T2D), atherosclerotic cardiovascular disease (ASCVD) and fatty liver (NAFLD) with few direct treatments. To discover novel insulin-sensitizing effector genes, we conducted combined and sex-stratified genome-wide association study (GWAS) for triglyceride to HDL-cholesterol ratio (TG/HDL), a surrogate marker of insulin resistance, in 382,129 individuals from the UK Biobank. We identified 251 independent loci, of which 62 were more strongly associated with TG/HDL compared to TG or HDL alone distinguishing them as insulin-resistance loci. Genetic fine mapping was applied to prioritize causal genes, and directions of effect and tissue specificity was determined for causal genes by examination of patterns of heritable variation in gene expression as well as protein coding variant aggregation from exome sequencing. Corroboration of directions of effect and target tissue was performed via transcriptomic analysis of participant tissue samples from insulin sensitizing clinical trials. We highlight two phospholipase encoding genes PLA2G12A and PLA2G6 which liberate arachidonic acid and improve insulin sensitivity, and VGLL3, a pro-fibrotic, transcriptional co-factor that increases insulin resistance partially through enhanced adiposity. Finally, we identify TNFAIP8, an anti-apoptotic factor that promotes insulin resistance in females by increasing visceral adiposity. In summary our study identifies several new modulators of insulin resistance with potential to serve as biomarkers or pharmacological targets.