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

SummaryPerturbation of endoplasmic reticulum (ER) homeostasis impairs insulin biosynthesis, β cell survival, and glucose homeostasis. We show that a murine model of diabetes is associated with the development of ER stress in β 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 β 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 β 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 β cell death in a PKA-dependent manner. These findings demonstrate that GLP-1R signaling directly modulates the ER stress response leading to promotion of β cell adaptation and survival.