Abstract

Objective- We showed that 17β-estradiol (E₂) favors pancreatic β-cell survival via the estrogen receptor (ER)-α in mice. E₂ activates nuclear ERs via an estrogen response element (ERE). E₂ also activates non-genomic signals via an extranuclear form of ERα and the G protein-coupled estrogen receptor (GPER). We studied the contribution of ERs to islet survival.

Research Design and Methods- We used mice and islets deficient in ERα (αERKO^−/−), ERβ (βERKO^−/−), ERα and ERβ (αβERKO^−/−), 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 E₂ favors islet survival through extranuclear and membrane ER signaling. We show that ERβ plays a minor cytoprotective role compared to ERα. Accordingly, βERKO^−/− mice are mildly predisposed to streptozotocin (STZ)-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 STZ-induced insulin deficiency.

Conclusion- 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.