Estradiol 17-β Induces Pancreatic Beta-Cell Proliferation through Distinct Estrogen Receptors in a Glucose Dependent Manner

Background: Estradiol 17-beta (E2) enhances the function and survival of pancreatic beta-cells, but its clinical use has been questioned due to concerns regarding oncogenic potential and feminizing effects in males. The G-protein coupled estrogen receptor (GPER), expressed in pancreatic islets, exhibits estrogenic beta-cell protective effects without the feminizing effects of the nuclear ERs. Here, we examine the outcome of selective activation of the three estrogen receptors ERα, ERβ, and GPER on replication in human pancreatic islets and the INS1-E rodent β-cell line under hyperglycemic conditions, such as occur in diabetes mellitus. Methods: Pancreatic islets from nine human donors and INS1-E cells were grown at glucose concentrations of 11mM and 25mM and examined for DNA synthesis using³[H]-thymidine incorporation after 24 hour treatment with E2, specific agonists for ERα, ERβ, and GPER (10nM PPT, 10nM DPN, and 100nM G1, respectively), and antagonists for ERα and ERβ (100nM MMP and 150nM PTHPP, respectively). Expression of the three ERs was examined by qRT-PCR. Results: In human islets at 11mM glucose, agonists to ERα and GPER induced a significant approximate twofold increase in³[H]-thymidine incorporation (p < 0.01), while the ERβ agonist DPN enhanced proliferation by approximately 50%, which was not significant. However, only the GPER agonist G1 retained its proliferative effect (p < 0.001) while under still higher glucose concentrations (25mM). Concurrently, expression of ERα and ERβ but not of GPER was reduced by approximately 15% at 25mM glucose (p < 0.05). In INS1-E cells, all ER agonists enhanced³[H]-thymidine incorporation by two-to threefold under 11mM glucose, but at 25mM glucose only the ERα-specific agonist elicited a similar response (p < 0.001). Concordantly, expression of ERβ and GPER but not of ERα was reduced by approximately 50% at 25mM glucose (p < 0.001). E2 enhanced static insulin secretion by 1.2-fold in human islets and by 1.8-fold in INS1-E cells (p < 0.05). Conclusions: These findings suggest that GPER may comprise an attractive target in the therapy of human diabetes and point to the phenomenon of species specificity regarding effects of glucose on estrogen receptor subtype expression and proliferative activity.