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

Abstract

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.