This Article Full Text Full Text (PDF) All Versions of this Article: 29/1/42    most recent Final Manuscript Author Manuscript Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Google Scholar Articles by Eizirik, D. L. Articles by Cnop, M. PubMed PubMed Citation Articles by Eizirik, D. L. Articles by Cnop, M.

The Role for Endoplasmic Reticulum Stress in Diabetes Mellitus

Laboratory of Experimental Medicine (D.L.E., A.K.C., M.C.), Université Libre de Bruxelles, Division of Endocrinology (M.C.), Erasmus Hospital, 1070 Brussels, Belgium

Correspondence: Address requests for reprints to: Dr. Décio L. Eizirik, Laboratory of Experimental Medicine, Université Libre de Bruxelles, Route de Lennik, 808-CP-618, 1070 Brussels, Belgium. E-mail: deizirik{at}ulb.ac.be

Accumulating evidence suggests that endoplasmic reticulum (ER) stress plays a role in the pathogenesis of diabetes, contributing to pancreatic β-cell loss and insulin resistance. Components of the unfolded protein response (UPR) play a dual role in β-cells, acting as beneficial regulators under physiological conditions or as triggers of β-cell dysfunction and apoptosis under situations of chronic stress. Novel findings suggest that "what makes a β-cell a β-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 β-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 β-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 β-cell death. Thus, the cytokines IL-1β and interferon-, putative mediators of β-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 β-cell defenses and amplifying the proapoptotic pathways. A better understanding of the pathways regulating ER stress in β-cells may be instrumental for the design of novel therapies to prevent β-cell loss in diabetes.

This article has been cited by other articles:

				J. A. Corbett Thioredoxin-Interacting Protein Is Killing My {beta}-cells! Diabetes, April 1, 2008; 57(4): 797 - 798. [Full Text] [PDF]