Importance of Extranuclear Estrogen Receptor-α and Membrane G Protein-Coupled Estrogen Receptor in Pancreatic Islet Survival

OBJECTIVE-We showed that 17 beta-estradiol (E-2) favors pancreatic beta-cell survival via the estrogen receptor-alpha (ER alpha) in mice. E-2 activates nuclear estrogen receptors via an estrogen response element (ERE). E-2 also activates nongenomic signals via an extranuclear form of ER alpha and the G protein-coupled estrogen receptor (GPER). We studied the contribution of estrogen receptors to islet survival. RESEARCH DESIGN AND METHODS-We used mice and islets deficient in estrogen receptor-alpha (alpha ERKO-/-), estrogen receptor-beta (beta ERKO-/-), estrogen receptor-alpha and estrogen receptor-beta (alpha beta ERKO-/-), and GPER (GPERKO(-/-)); a mouse lacking ER alpha binding to the ERE; and human islets. These mice and islets were studied in combination with receptor-specific pharmacological probes. RESULTS-We show that ER alpha protection of islet survival is ERE independent and that E-2 favors islet survival through extranuclear and membrane estrogen receptor signaling. We show that ER beta plays a minor cytoprotective role compared to ER alpha. Accordingly, beta ERKO-/- mice are mildly predisposed to streptozotocin-induced islet apoptosis. However, combined elimination of ER alpha and ER beta in mice does not synergize to provoke islet apoptosis. In alpha beta ERKO-/- mice and their islets, E-2 partially prevents apoptosis suggesting that an alternative pathway compensates for ER alpha/ER beta deficiency. We find that E-2 protection of islet survival is reproduced by a membrane-impermeant E-2 formulation and a selective GPER agonist. Accordingly, GPERKO(-/-) mice are susceptible to streptozotocin-induced insulin deficiency. CONCLUSIONS-E-2 protects beta-cell survival through ER alpha and ER beta via ERE-independent, extra-nuclear mechanisms, as well as GPER-dependent mechanisms. The present study adds a novel dimension to estrogen biology in beta-cells and identifies GPER as a target to protect islet survival. Diabetes 58:2292-2302, 2009