Importance of extranuclear estrogen receptor-alpha and membrane G protein-coupled estrogen receptor in pancreatic islet survival

Diabetes. 2009 Oct;58(10):2292-302. doi: 10.2337/db09-0257. Epub 2009 Jul 8.


Objective: We showed that 17beta-estradiol (E(2)) favors pancreatic beta-cell survival via the estrogen receptor-alpha (ERalpha) 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 ERalpha 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 (alphaERKO(-/-)), estrogen receptor-beta (betaERKO(-/-)), estrogen receptor-alpha and estrogen receptor-beta (alphabetaERKO(-/-)), and GPER (GPERKO(-/-)); a mouse lacking ERalpha binding to the ERE; and human islets. These mice and islets were studied in combination with receptor-specific pharmacological probes.

Results: We show that ERalpha protection of islet survival is ERE independent and that E(2) favors islet survival through extranuclear and membrane estrogen receptor signaling. We show that ERbeta plays a minor cytoprotective role compared to ERalpha. Accordingly, betaERKO(-/-) mice are mildly predisposed to streptozotocin-induced islet apoptosis. However, combined elimination of ERalpha and ERbeta in mice does not synergize to provoke islet apoptosis. In alphabetaERKO(-/-) mice and their islets, E(2) partially prevents apoptosis suggesting that an alternative pathway compensates for ERalpha/ERbeta 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 ERalpha and ERbeta 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Survival
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / genetics
  • Estradiol / pharmacology
  • Estrogen Receptor alpha / deficiency
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / physiology*
  • Estrogen Receptor beta / deficiency
  • Estrogen Receptor beta / genetics
  • Gene Knockout Techniques
  • Humans
  • Immunohistochemistry
  • Insulin / analysis
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / drug effects
  • Islets of Langerhans / cytology*
  • Mice
  • Mice, Knockout
  • Pancreas / chemistry
  • Pancreas / cytology
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled / deficiency
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / physiology*
  • Streptozocin / pharmacology


  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • GPER1 protein, human
  • Insulin
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled
  • Estradiol
  • Streptozocin