The Role for Endoplasmic Reticulum Stress in Diabetes Mellitus

Abstract

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

Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis

“…As a consequence, beta cells are in a constant state of mild ER-stress, characterised by high basal expression of UPR transducers such as IRE1α, allowing them to adapt efficiently to the ever changing insulin demand [3]. In other cell types, activation of the IRE1α-XBP1s pathway increases production of ERproteins aiming to fold and/or degrade misfolded proteins.…”

“…The UPR seeks to restore normal ER function by attenuating translation, increasing folding capacity through upregulation of ER chaperones and promoting degradation of misfolded proteins via the ER-associated degradation (ERAD) pathway. If the UPR is unable to restore cell function, it eventually triggers the apoptosis cascade [3]. The UPR is mediated by the activation of three ER transmembrane sensor proteins: the activating transcription factor (ATF)6α, the PKR-like ER kinase (PERK) and the endoribonuclease inositol-requiring enzyme (IRE)1α [3].…”

“…If the UPR is unable to restore cell function, it eventually triggers the apoptosis cascade [3]. The UPR is mediated by the activation of three ER transmembrane sensor proteins: the activating transcription factor (ATF)6α, the PKR-like ER kinase (PERK) and the endoribonuclease inositol-requiring enzyme (IRE)1α [3].…”

“…Although it is well established that cytokines induce ERstress in beta cells [3], the role of ER-stress in cytokineinduced beta cell apoptosis remains controversial. Thus while some studies suggest that C/EBP homologous protein (CHOP) [7] and binding immunoglobulin protein (BIP) [8] play proand anti-apoptotic roles in this process respectively, others failed to observe any association between ER-stress markers and cytokine-induced beta cell apoptosis [9][10][11].…”

Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice

“…In addition to genetic factors, processes involving glucotoxicity and/or lipotoxicity are likely to be contributory [4]. Endoplasmic reticulum (ER) stress has also recently emerged as a candidate mechanism [5][6][7].…”