Abstract
Pancreatic β-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 β-cell death and function. Metabolic phenotypes, β-cell secretory function, and glucose and insulin tolerance were measured in RGS2 knockout (RGS2−/−) mice and their wild-type (RGS2+/+) littermate controls. β-Cell death was evaluated in RGS2-knockdown and -overexpressing β cells and RGS2−/− islets by flow cytometry, western blot, ELISA, TUNEL staining, and apoptosis RT2 profiler PCR array analysis. β-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 β-cell apoptosis contributed to a 70% reduction in pancreatic β-cell mass in RGS2−/− mice compared with RGS2+/+ mice at 25 weeks of age. RGS2 has critical roles in maintaining pancreatic β-cell mass via modulating β-cell function and apoptosis. It may serve as a druggable target to help prevent pancreatic β-cell loss in the treatment of diabetes.
Highlights
Pancreatic β-cell death and dysfunction contributes to the pathogenesis of both type 1 and type 2 diabetes
Β-cell secretory function, and glucose and insulin tolerance were measured in regulator of G protein signaling protein 2 (RGS2) knockout (RGS2− / −) mice and their wild-type (RGS2+/+) littermate controls. β-Cell death was evaluated in RGS2-knockdown and -overexpressing β cells and RGS2− / − islets by flow cytometry, western blot, ELISA, TUNEL staining, and apoptosis RT2 profiler PCR array analysis. β-Cell mass was evaluated in pancreases from RGS2− / − and RGS2+/+ mice at 1 day, 4 weeks, and 25 weeks of age
We show that RGS2 is a negative regulator of glucose and exendin-4-induced insulin secretion
Summary
Pancreatic β-cell death and dysfunction contributes to the pathogenesis of both type 1 and type 2 diabetes. Regulator of G protein signaling protein 2 (RGS2) is a multifunctional regulator of G protein signaling pathways It interacts directly with G protein α subunits and accelerates GTP hydrolysis, leading to a more rapid termination of G protein signaling.[8] RGS2 regulates vascular smooth muscle cell tone,[9] impairs T-cell mediated immunity,[10,11] inhibits gastric inhibitory polypeptide (GIP)-stimulated cAMP production in embryonic kidney cells, and inhibits GIP-mediated insulin release in βTC3 insulinoma cells.[10] RGS2− / − mice manifest reduced T-cell proliferation and IL-2 production, increased anxiety response, decreased male aggression, exaggerated Angiotensin II-dependent hypertension, and reduced growth.[11,12] In addition to its function as a regulator of G protein-coupled receptor (GPCR) signaling, RGS2 has been shown to function as a stress adaptive protein by controlling ion channel currents, microtubule polymerization, and protein synthesis.[13]
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