SAT-LB035 The G Protein-Coupled Estrogen Receptor GPER Plays a Dominant Role in Human Islet Cell Proliferation upon High Glucose

Estrogen exerts its effects through genomic and rapid extra-nuclear signaling pathways. The classic estrogen receptors, ERα and ERβ have demonstrated favorable effects on beta-cell function and survival but their clinical utility has been questioned owing to oncogenic potential and concerns regarding feminizing effects in men. Recent work indicates, however, that the G-protein coupled estrogen receptor (GPER), expressed in pancreatic islet cells retains the estrogenic beta-cell protective effects, without the shortcomings of the classic ERs. GPER activation enhances glucose stimulated insulin secretion, reduces islet apoptosis upon insult and has been implicated in beta-cell mass expansion during pregnancy in rodent islets. Since GPER can thus comprise an attractive treatment target in hyperglycemic states we examined the effects of the three ERs on proliferation of human pancreatic islets in the presence of hyperglycemia. Islets from eight non diabetic human donors (6 males and 2 females) were grown at glucose concentrations of either 11mM or 25mM for 24 hours and examined for DNA synthesis after treatment with E2 (at increasing concentrations) and with specific agonists for ERα, ERβ and GPER (PPT 10nM, DPN 10nM and G1 100nM, respectively). At a glucose concentration of 11mM, E2 and all three ER agonists induced a significant ~2 folds increase in 3[H]-thymidine incorporation. However, under still higher glucose conditions (HG; 25mM) only the GPER agonist G1 increased proliferation equipotently (~2.5 folds; p