We showed that 17β-estradiol (E₂) favors pancreatic β-cell survival via the estrogen receptor-α (ERα) in mice. E₂ activates nuclear estrogen receptors via an estrogen response element (ERE). E₂ 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.

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.

We show that ERα protection of islet survival is ERE independent and that E₂ 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, E₂ partially prevents apoptosis suggesting that an alternative pathway compensates for ERα/ERβ deficiency. We find that E₂ protection of islet survival is reproduced by a membrane-impermeant E₂ formulation and a selective GPER agonist. Accordingly, GPERKO^−/− mice are susceptible to streptozotocin-induced insulin deficiency.

E₂ 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.