The Apoptosis Inhibitor ARC Alleviates the ER Stress Response to Promote beta-cell Survival in Diabetes

Abstract

Type 2 diabetes (T2D) is a disease of both insulin resistance and failure of the insulin secreting pancreatic beta-cell. This failure includes dysfunction, but is also due to increases in beta-cell apoptosis. ARC (apoptosis repressor with CARD) is an inhibitor of cell death that prevents death at multiple distinct points in the apoptotic pathway. ARC is expressed in terminally differentiated cells including cardiac and skeletal myocytes. We demonstrate that ARC is also abundant in >70% of human and >99% of mouse pancreatic beta-cells. Moreover, deletion of ARC in ob/ob mice, a genetic model of diabetes, exacerbates hyperglycemia and further impairs glucose tolerance. This is accompanied by marked islet disorganization and increases in beta-cell apoptosis. ER stress is an important initiator of beta-cell death in T2D. Using gain- and loss-of-function studies, we show ARC inhibits apoptosis triggered by ER stressors and the physiologic stressor palmitate in MIN6 cells and in isolated islets. Further, ARC inhibits cell death proximal to upregulation of the transcription factor CHOP, but distal to PERK and IRE1alpha, early sensors of ER stress. Taken together, we have uncovered a new function of ARC as a suppressor of ER stress pathways and indentify this protein as a critical survival factor for beta-cells during T2D.