We are in the midst of an unprecedented obesity epidemic, which is causing an epidemic of type 2 diabetes (T2D). Obesity causes insulin resistance, resulting in an increased demand for insulin from pancreatic -cells. Genetic factors play a critical role in determining whether or not the -cells are capable of responding to the increased demand for insulin. In individuals where this insulin demand is not met, diabetes results and likely reflects some aspect of -cell impairment (development, proliferation, survival or insulin secretion). We positionally cloned Sorcs1, a gene that contributes to obesity-induced T2D. SORCS1 is associated with T2D and diabetes complications in humans. We derived Sorcs1 knockout (KO) mice and when obese, they develop diabetes. Pancreatic -cells from obese Sorcs1 KO mice have a severe deficiency in insulin granules, due to a dramatic increase in the post-translational degradation of insulin. We have shown that Sortilin, a protein related to Sorcs1, which is known to target proteins to the lysosome for degradation, binds to insulin. The pro-domain of Sorcs1 also binds to Sortilin and inhibits its activity. Our preliminary studies show that overexpression of Sortilin in -cells, in contrast to -cells overexpressing Sorcs1, decreases cellular insulin content. We hypothesize that Sorcs1 inhibits the ability of Sortilin to promote insulin degradation. The proposed studies will elucidate the role of Sorcs1 and Sortilin in determining the intracellular fate of insulin. We have identified two coding SNPs in human Sortilin (SORT1); one associated with reduced insulin levels and the other with elevated cholesterol. We will characterize these SNPs in SORT1 to understand their association with these distinct phenotypes. We will evaluate an allelic variant in mouse Sorcs1 that is associated with reduced insulin. Our proposed studies will elucidate a newly identified branch point that determines whether insulin is packaged in insulin granules, or is diverted towards degradation. We will characterize mutations in Sortilin and Sorcs1 that are associated with decreased insulin in humans and in mice. Insights from our work may provide clues to the development of novel therapeutic approaches aimed at preserving the insulin reserve of pancreatic -cells.