Insulin resistance is a major cause of type 2 diabetes (T2D), heart attacks, strokes and cancer. These chronic metabolic diseases disproportionately affect veterans, especially black veterans. Targeting insulin resistance by treating obesity is effective but the major clinical options, low calorie diets or bariatric surgery, are difficult to sustain and scale for the over 40% of veterans afflicted with obesity. Thiazolidinediones (TZDs), specifically target insulin resistance and have proven clinically effective in preventing T2D, heart attacks and strokes, but serious side effects have limited their clinical use. New therapeutic targets to treat insulin resistance are needed. In theory, ‘omics’ approaches such as genome wide association studies (GWAS) of surrogate measures of insulin resistance or mining the transcriptomic response caused by weight loss/ TZD treatment could provide a source of novel target genes, but both approaches have limitations including identifying specific genes/mechanisms for GWAS and distinguishing correlation from causation in gene expression studies. Importantly, existing GWAS studies contain predominantly European samples and thus bias against genetic discovery in African ancestry individuals. Ultimately, the dozens to hundreds of genes nominated by ‘omics’ approaches must be sifted by functional investigation for biological mechanism and therapeutic translation. Even when a potential insulin sensitizing effector gene is validated in the lab, credentialing its relevance to human insulin sensitivity necessitates drug development and human trials, another poorly scalable process that usually results in failure for lack of efficacy. However, the recent accumulation of genome sequences in large, clinically characterized populations has revealed that nature has performed countless human trials in the form of millions of naturally occurring, protein-altering genetic variants scattered throughout almost every gene in the genome. High-throughput functional assays are the key to unlocking these opportunities: 1) identifying novel candidate genes for insulin resistance and 2) leveraging nature’s clinical trials for assessing therapeutic potential. In this application, we propose to utilize a newly developed massively parallel adipocyte differentiation/ lipid accumulation assay in an integrative genomic approach to: Aim 1: Systematically identify novel insulin resistance genes incorporating African ancestry specific genetic discovery in the VA population and Aim 2: Determine the clinical effect of novel insulin resistance genes on metabolic disease in humans using data from 488,000 sequenced individuals. This work will identify novel insulin sensitivity genes relevant to the VA population and include African ancestry-specific genes. It will also provide critical information on the human, clinical consequence of modulating function of selected genes to enable therapeutic translation.