Type 2 diabetes (T2D) occurs when pancreatic beta-cells are unable to produce enough insulin to meet the increased demand for insulin brought about by insulin resistance. Most of the genetic loci that have been discovered through genome-wide association studies in humans point to defects that affect beta-cell mass or beta-cell function. Using mouse genetics, we positionally cloned a diabetes susceptibility locus and identified the causal gene, Sorcs1. Subsequent studies show that Sorcs1 is involved in T2D and diabetes complications in humans. Sorcs1 is a member of the Vacuolar protein sorting-10 (Vps10) gene family. Vps10 was originally discovered in yeast where it is a receptor for carboxypeptidase Y and is essential for its transport to the vacuole. We derived a mouse with a deletion of the Sorcs1 gene. When made obese, the mouse develops severe diabetes. This is due to a defect in the production of insulin granules and a dramatic increase in the post-translational degradation of insulin. The luminal domain of SORCS1, when expressed in a beta-cell line, acted as a dominant-negative, leading to deficiency of insulin secretory granules (SGs). Using syncollin-dsRed5TIMER adenovirus, we found that the loss of Sorcs1 function greatly impairs the rapid replenishment of SGs following secretagogue challenge. Thus, in metabolically stressed mice, Sorcs1 is important for insulin SGs replenishment, and under chronic challenge by insulin secretagogues, loss of Sorcs1 leads to diabetes. Our preliminary studies point to a second vps10 protein, Sortilin, which plays an important role in post-translational degradation of proteins, by targeting to the lysosome. It is shown that Sorcs1 binds to Sortilin and inhibits its activity. Thus, we hypothesize that the loss of Sorcs1 function de-represses Sortilin, leading to increased insulin degradation. Using adenoviral overexpression and CRISPR knockout, we show that Sortilin plays a novel role in post-translational degradation of insulin in beta-cells.