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

OBJECTIVE: We showed that 17β-estradiol (E(2)) favors pancreatic β-cell survival via the estrogen receptor-α (ERα) 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 ERα 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-α (αERKO(−/−)), estrogen receptor-β (βERKO(−/−)), estrogen receptor-α and estrogen receptor-β (αβERKO(−/−)), and GPER (GPERKO(−/−)); a mouse lacking ERα binding to the ERE; and human islets. These mice and islets were studied in combination with receptor-specific pharmacological probes. RESULTS: We show that ERα protection of islet survival is ERE independent and that E(2) favors islet survival through extranuclear and membrane estrogen receptor signaling. We show that ERβ plays a minor cytoprotective role compared to ERα. Accordingly, βERKO(−/−) mice are mildly predisposed to streptozotocin-induced islet apoptosis. However, combined elimination of ERα and ERβ in mice does not synergize to provoke islet apoptosis. In αβERKO(−/−) mice and their islets, E(2) partially prevents apoptosis suggesting that an alternative pathway compensates for ERα/ERβ 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 β-cell survival through ERα and ERβ via ERE-independent, extra-nuclear mechanisms, as well as GPER-dependent mechanisms. The present study adds a novel dimension to estrogen biology in β-cells and identifies GPER as a target to protect islet survival.