The Role for Endoplasmic Reticulum Stress in Diabetes Mellitus
Décio L. Eizirik,
Alessandra K. Cardozo and
Miriam Cnop
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, contributingto pancreatic β-cell loss and insulin resistance. Componentsof the unfolded protein response (UPR) play a dual role in β-cells,acting as beneficial regulators under physiological conditionsor as triggers of β-cell dysfunction and apoptosis undersituations of chronic stress. Novel findings suggest that "whatmakes a β-cell a β-cell", i.e., its enormous capacityto synthesize and secrete insulin, is also its Achilles heel,rendering it vulnerable to chronic high glucose and fatty acidexposure, agents that contribute to β-cell failure in type2 diabetes. In this review, we address the transition from physiologyto pathology, namely how and why the physiological UPR evolvesto a proapoptotic ER stress response and which defenses aretriggered by β-cells against these challenges. ER stressmay also link obesity and insulin resistance in type 2 diabetes.High fat feeding and obesity induce ER stress in liver, whichsuppresses insulin signaling via c-Jun N-terminal kinase activation.In vitro data suggest that ER stress may also contribute tocytokine-induced β-cell death. Thus, the cytokines IL-1βand interferon-, putative mediators of β-cell loss in type1 diabetes, induce severe ER stress through, respectively, NO-mediateddepletion of ER calcium and inhibition of ER chaperones, thushampering β-cell defenses and amplifying the proapoptoticpathways. A better understanding of the pathways regulatingER stress in β-cells may be instrumental for the designof novel therapies to prevent β-cell loss in diabetes.
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, 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. 
