GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress.
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.
Yusta
Bernardo
B
Department of Medicine, Banting and Best Diabetes Centre, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
Baggio
Laurie L
LL
Estall
Jennifer L
JL
Koehler
Jackie A
JA
Holland
Dianne P
DP
Li
Hongyun
H
Pipeleers
Danny
D
Ling
Zhidong
Z
Drucker
Daniel J
DJ
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*
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