Estrogen reduces endoplasmic reticulum stress to protect against glucotoxicity induced-pancreatic β-cell death

J Steroid Biochem Mol Biol. 2014 Jan;139:25-32. doi: 10.1016/j.jsbmb.2013.09.018. Epub 2013 Oct 9.


Estrogen can improve glucose homeostasis not only in diabetic rodents but also in humans. However, the molecular mechanism by which estrogen prevents pancreatic β-cell death remains unclear. To investigate this issue, INS-1 cells, a rat insulinoma cell line, were cultured in medium with either 11.1mM or 40mM glucose in the presence or the absence of estrogen. Estrogen significantly reduced apoptotic β-cell death by decreasing nitrogen-induced oxidative stress and the expression of the ER stress markers GRP 78, ATF6, P-PERK, PERK, uXBP1, sXBP1, and CHOP in INS-1 cells after prolonged culture in medium with 40mM glucose. In contrast, estrogen increased the expression of survival proteins, including sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA-2), Bcl-2, and P-p38, in INS-1 cells after prolonged culture in medium with 40mM glucose. The cytoprotective effect of estrogen was attenuated by addition of the estrogen receptor (ERα and ERβ) antagonist ICI 182,780 and the estrogen membrane receptor inhibitor G15. We showed that estrogen decreases not only oxidative stress but also ER stress to protect against 40mM glucose-induced pancreatic β-cell death.

Keywords: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide thiazolyl blue; Apoptosis; BCA; CCAAT/enhancer-binding protein homologous protein; CHOP; CREB; ELISA; ER; Endoplasmic reticulum stress; Ero 1; Estrogen; G protein-coupled estrogen receptor; GPER; GRP-78; Glucotoxicity; HRP; MTT; PI; Pancreatic β-cell; RIPA; SDS–PAGE; SERCA; UPR; bicinchoninic acid; cDNA; complementary DNA; cyclic AMP response element–binding protein; endoplasmic reticulum; endoplasmic reticulum oxidoreductin I; enzyme-linked immunosorbent assay; glucose-regulated protein 78; horseradish peroxidase; propidium iodide; radioimmunoprecipitation assay; sarco-/endoplasmic reticulum Ca(2+) ATPase; sodium dodecyl sulfate–polyacrylamide gel electrophoresis; unfolded protein response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Cell Survival
  • Cytoprotection
  • Endoplasmic Reticulum Stress*
  • Estradiol / physiology*
  • Estrogens / physiology*
  • Glucose / pharmacology
  • Glucose / physiology*
  • Insulin-Secreting Cells / physiology*
  • Oxidative Stress
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rats
  • Receptors, Estrogen / metabolism
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
  • Unfolded Protein Response
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Atp2a2 protein, rat
  • Estrogens
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Estrogen
  • Estradiol
  • p38 Mitogen-Activated Protein Kinases
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Glucose