title: GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress.
abstract: 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.
authors.affiliation: Department of Medicine, Banting and Best Diabetes Centre, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Yusta
authors.forename: Laurie L
authors.initials: LL
authors.lastname: Baggio
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Estall
authors.forename: Jackie A
authors.initials: JA
authors.lastname: Koehler
authors.forename: Dianne P
authors.initials: DP
authors.lastname: Holland
authors.forename: Hongyun
authors.initials: H
authors.lastname: Li
authors.forename: Danny
authors.initials: D
authors.lastname: Pipeleers
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Ling
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
mesh_terms: D051701:Activating Transcription Factor 4 / Q000494:pharmacology*; D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology*; D000077270:Exenatide; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D007004:Hypoglycemic Agents / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000378:metabolism* / Q000502:physiology; D013312:Stress, Physiological; D015854:Up-Regulation; D014688:Venoms / Q000494:pharmacology*; D019892:eIF-2 Kinase / Q000502:physiology*
chemical_list: D051701:Activating Transcription Factor 4; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose; D007004:Hypoglycemic Agents; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D019892:eIF-2 Kinase; C497109:ATF4 protein, human; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat