GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress |
| |
Authors: | Yusta Bernardo Baggio Laurie L Estall Jennifer L Koehler Jackie A Holland Dianne P Li Hongyun Pipeleers Danny Ling Zhidong Drucker Daniel J |
| |
Institution: | Department of Medicine, Banting and Best Diabetes Centre, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. |
| |
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. |
| |
Keywords: | SIGNALING HUMDISEASE |
本文献已被 ScienceDirect PubMed 等数据库收录! |
|