Regulator of G protein signaling 2 is a key regulator of pancreatic β-cell mass and function

Pancreatic beta-cell death and dysfunction contributes to the pathogenesis of both type 1 and type 2 diabetes. We aimed to examine whether the regulator of G protein signaling protein 2 (RGS2), a multifunctional inhibitor of G protein-coupled receptor (GPCR) signaling, impacts beta-cell death and function. Metabolic phenotypes, beta-cell secretory function, and glucose and insulin tolerance were measured in RGS2 knockout (RGS2(-/-)) mice and their wild-type (RGS2(+/+)) littermate controls. beta-Cell death was evaluated in RGS2-knockdown and -overexpressing beta cells and RGS2(-/-) islets by flow cytometry, western blot, ELISA, TUNEL staining, and apoptosis RT2 profiler PCR array analysis. beta-Cell mass was evaluated in pancreases from RGS2-/- and RGS2+/+ mice at 1 day, 4 weeks, and 25 weeks of age. Our data show that RGS2(-/-) islets secreted more insulin than RGS2(+/+) islets when challenged with glucose or exendin-4. RGS2- knockdown cells are susceptible to hypoxia induced cell death while RGS2- overexpressing cells are protected from cell death. Depletion of RGS2 in islets alters expression of apoptosis-related genes and RGS2-/- islets are prone to apoptosis compared with RGS2+/+ islets. Ultimately, excessive insulin secretion and increased beta-cell apoptosis contributed to a 70% reduction in pancreatic beta-cell mass in RGS2(-/-) mice compared with RGS2(+/+) mice at 25 weeks of age. RGS2 has critical roles in maintaining pancreatic beta-cell mass via modulating-cell function and apoptosis. It may serve as a druggable target to help prevent pancreatic beta-cell loss in the treatment of diabetes.