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Cell Death Dis. 2017 May 25;8(5):e2821. doi: 10.1038/cddis.2016.216.

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

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Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
College of Life Sciences, Qingdao Agricultural University, Qingdao 266109, PR China.
Tulane University School of Medicine, New Orleans, LA 70118, USA.
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA.
Antagen Institute for Biomedical Research Inc., Boston, MA 02118, USA.
Department of Endocrinology, Medical University of South Carolina, Charleston, SC 29425, USA.


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.

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