Eizirik Décio L, Cardozo Alessandra K, Cnop Miriam
Laboratory of Experimental Medicine, Université Libre de Bruxelles, Route de Lennik, 808-CP-618, 1070 Brussels, Belgium.
Endocr Rev. 2008 Feb;29(1):42-61. doi: 10.1210/er.2007-0015. Epub 2007 Nov 29.
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.
越来越多的证据表明，内质网（ER）应激在糖尿病发病机制中起作用，导致胰腺β细胞丢失和胰岛素抵抗。未折叠蛋白反应（UPR）的组成部分在β细胞中起双重作用，在生理条件下作为有益的调节因子，而在慢性应激情况下则作为β细胞功能障碍和凋亡的触发因素。新的研究结果表明，“使β细胞成为β细胞的因素”，即其合成和分泌胰岛素的巨大能力，也是其致命弱点，使其易受慢性高血糖和脂肪酸暴露的影响，这些因素会导致2型糖尿病中的β细胞功能衰竭。在这篇综述中，我们探讨了从生理到病理的转变，即生理UPR如何以及为何演变为促凋亡的ER应激反应，以及β细胞针对这些挑战触发了哪些防御机制。ER应激也可能将肥胖与2型糖尿病中的胰岛素抵抗联系起来。高脂肪喂养和肥胖会在肝脏中诱导ER应激，通过激活c-Jun氨基末端激酶抑制胰岛素信号传导。体外数据表明，ER应激也可能导致细胞因子诱导的β细胞死亡。因此，细胞因子白细胞介素-1β和干扰素-γ是1型糖尿病中β细胞丢失的假定介质，它们分别通过NO介导的ER钙耗竭和ER伴侣抑制诱导严重的ER应激，从而阻碍β细胞防御并放大促凋亡途径。更好地理解调节β细胞中ER应激的途径可能有助于设计预防糖尿病中β细胞丢失的新疗法。
