GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress

Cell Metab. 2006 Nov;4(5):391-406. doi: 10.1016/j.cmet.2006.10.001.


Perturbation of endoplasmic reticulum (ER) homeostasis impairs insulin biosynthesis, beta cell survival, and glucose homeostasis. We show that a murine model of diabetes is associated with the development of ER stress in beta cells and that treatment with the GLP-1R agonist exendin-4 significantly reduced biochemical markers of islet ER stress in vivo. Exendin-4 attenuated translational downregulation of insulin and improved cell survival in purified rat beta cells and in INS-1 cells following induction of ER stress in vitro. GLP-1R agonists significantly potentiated the induction of ATF-4 by ER stress and accelerated recovery from ER stress-mediated translational repression in INS-1 beta cells in a PKA-dependent manner. The effects of exendin-4 on the induction of ATF-4 were mediated via enhancement of ER stress-stimulated ATF-4 translation. Moreover, exendin-4 reduced ER stress-associated beta cell death in a PKA-dependent manner. These findings demonstrate that GLP-1R signaling directly modulates the ER stress response leading to promotion of beta cell adaptation and survival.

Publication types

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

MeSH terms

  • Activating Transcription Factor 4 / pharmacology*
  • Animals
  • Cell Survival
  • Cells, Cultured
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / physiology*
  • Exenatide
  • Female
  • Glucagon-Like Peptide-1 Receptor
  • Glucose / metabolism
  • Homeostasis
  • Hypoglycemic Agents / pharmacology
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / physiology*
  • Mice
  • Peptides / pharmacology*
  • Rats
  • Rats, Wistar
  • Receptors, Glucagon / metabolism*
  • Receptors, Glucagon / physiology
  • Stress, Physiological*
  • Up-Regulation
  • Venoms / pharmacology*
  • eIF-2 Kinase / physiology*


  • ATF4 protein, human
  • GLP1R protein, human
  • Glp1r protein, mouse
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Peptides
  • Receptors, Glucagon
  • Venoms
  • Activating Transcription Factor 4
  • Exenatide
  • PERK kinase
  • eIF-2 Kinase
  • Glucose