Project Summary/Abstract It is estimated that 1 in 4 Veterans suffer from diabetes, and, in the Veteran population, this is largely Type 2 diabetes. This condition drives heart disease, stroke, retinopathy, nephropathy and neuropathy, all of which are a cause of significant morbidity and mortality among our Veterans. As such, understanding the biology of diabetes, discovering novel molecules that regulate b-cell function and developing innovative therapeutic approaches will have a significant impact on the health of our aging veteran population. Type 2 diabetes is characterized by both a loss of insulin sensitivity and, ultimately, a relative loss of insulin-secretion from the pancreatic b-cell. Insulin secretion from the pancreatic b-cell is triggered by Ca2+ influx through voltage-gated Ca2+ channels (VGCC) to trigger insulin vesicle fusion with the b-cell plasma membrane. We recently reported that SWELL1 (LRRC8a), a member of the Leucine Rich Repeat Containing protein family, is required for ICl,SWELL in β-cells. SWELL1-mediated ICl,SWELL activates upon b-cell swelling induced by glucose import, and this generates a depolarizing current contributing to VGCC activation, thereby regulating insulin secretion and systemic glycemia. Indeed, mice with SWELL1-deficient β-cells exhibit impaired glucose- stimulated insulin secretion and glucose intolerance. Moreover, we find that ICl,SWELL is reduced in both mouse and humans in the context of Type 2 diabetes (T2D) indicating that reduced SWELL1 signaling is associated with impaired b-cell function in T2D. The objective of the current proposal is to delineate the mechanisms by which SWELL1 signaling regulates b-cell function, under basal conditions, and in the setting of Type 2 diabetes. Our central hypothesis is that SWELL1 regulates both glucose-stimulated insulin secretion and PI3K-AKT-mTOR signaling in b-cells to maintain systemic glycaemia, and that impaired SWELL1 signaling contributes to b-cell failure in Type 2 diabetes. The contribution of this proposal is significant because it explores the innovative concept the SWELL1 utilizes dual signaling domains (channel versus LRRD) to regulate b-cell function in health and T2D. Importantly, this proposal will also define the relationship between b-cell SWELL1 and T2D and test the notion that reduced SWELL1 signaling may drive impaired b-cell function in T2D. We propose the following two AIMs: AIM#1: Delineate the mechanism(s) of SWELL1-mediated regulation of excitation-secretion coupling. AIM#2: Dissect the molecular mechanisms of SWELL1 macro-complex regulation of AKT-mTOR signaling in b-cells. The contribution of this proposal is innovative because it delineates a novel SWELL1 signaling pathway that connects glucose-mediated b-cell swelling to b-cell depolarization and insulin-release - a form of b-cell swell- activation or “swell-secretion” coupling. This proposal will enhance our understanding of b-cell biology and help direct novel therapeutic app...