The Role for Endoplasmic Reticulum Stress in Diabetes Mellitus

This is the authors' abstract. We don't add key points for this paper.

Accumulating evidence suggests that endoplasmic reticulum (ER) stress plays a role in the pathogenesis of diabetes, contributing to pancreatic -cell loss and insulin resistance. Components of the unfolded protein response (UPR) play a dual role in -cells, acting as beneficial regulators under physiological conditions or as triggers of -cell dysfunction and apoptosis under situations of chronic stress. Novel findings suggest that "what makes a -cell a -cell", i.e., its enormous capacity to synthesize and secrete insulin, is also its Achilles heel, rendering it vulnerable to chronic high glucose and fatty acid exposure, agents that contribute to -cell failure in type 2 diabetes. In this review, we address the transition from physiology to pathology, namely how and why the physiological UPR evolves to a proapoptotic ER stress response and which defenses are triggered by -cells against these challenges. ER stress may also link obesity and insulin resistance in type 2 diabetes. High fat feeding and obesity induce ER stress in liver, which suppresses insulin signaling via c-Jun N-terminal kinase activation. In vitro data suggest that ER stress may also contribute to cytokine-induced -cell death. Thus, the cytokines IL-1 and interferon-, putative mediators of -cell loss in type 1 diabetes, induce severe ER stress through, respectively, NO-mediated depletion of ER calcium and inhibition of ER chaperones, thus hampering -cell defenses and amplifying the proapoptotic pathways. A better understanding of the pathways regulating ER stress in -cells may be instrumental for the design of novel therapies to prevent -cell loss in diabetes. (Endocrine Reviews 29: 42-61, 2008) I. Introduction II. Endoplasmic Reticulum (ER) Stress and the Unfolded Protein Response (UPR) A. The dialogue between the ER and the nucleus B. ER stress and apoptosis III. The UPR and -Cell Adaptation to Physiological Demand IV. ER Stress and -Cell Death in Monogenic and Type 2 Diabetes A. ER stress and human diabetes B. Animal models of ER stress and diabetes C. Lipotoxicity and glucotoxicity as triggers of ER stress-when physiology turns into pathology V. ER Stress and -Cell Death in Type 1 Diabetes-the Role of Cytokines and Nitric Oxide (NO) VI. -Cell Recovery from ER Stress VII. ER Stress as a Putative Link between Obesity and Insulin Resistance A. Liver B. Adipose tissue VIII.