Lytrivi Maria, Tong Yue, Virgilio Enrico, Yi Xiaoyan, Cnop Miriam
ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium.
Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium.
Nat Rev Endocrinol. 2025 Jun 4. doi: 10.1038/s41574-025-01129-5.
Insufficient insulin secretion by pancreatic β cells is central to the pathogenesis of diabetes mellitus. As insulin is synthesized in the endoplasmic reticulum (ER), perturbations in ER homeostasis lead to ER stress and activate the ER stress response. Over the past two decades, considerable data have accumulated on the role of β cell ER stress in diabetes mellitus. Several monogenic forms of diabetes mellitus are caused by excessive ER stress, perturbed ER stress response signalling or impaired ER-Golgi protein trafficking. These pathways are now recognized to contribute to β cell failure in both type 1 and type 2 diabetes mellitus. This Review considers the role of β cell ER stress in common forms of diabetes mellitus and examines whether it is a cause or a consequence of these diseases. The strong genetic evidence for a causal role of ER stress in 15 monogenic forms of diabetes mellitus is summarized, and the effects of ER stress on human β cell differentiation, function and survival are described. Although definitive proof is lacking that ER stress responses can be therapeutically targeted to improve β cell function in diabetes mellitus, existing and novel treatments that aim to restore ER homeostasis are also outlined.
胰腺β细胞胰岛素分泌不足是糖尿病发病机制的核心。由于胰岛素在内质网（ER）中合成，内质网稳态的扰动会导致内质网应激并激活内质网应激反应。在过去二十年中，关于β细胞内质网应激在糖尿病中的作用已积累了大量数据。几种单基因形式的糖尿病是由过度的内质网应激、内质网应激反应信号传导紊乱或内质网-高尔基体蛋白转运受损引起的。现在人们认识到，这些途径在1型和2型糖尿病中均导致β细胞功能衰竭。本综述探讨了β细胞内质网应激在常见糖尿病形式中的作用，并研究它是这些疾病的原因还是结果。总结了内质网应激在15种单基因形式糖尿病中起因果作用的有力遗传学证据，并描述了内质网应激对人β细胞分化、功能和存活的影响。尽管缺乏确凿证据表明内质网应激反应可作为治疗靶点来改善糖尿病患者的β细胞功能，但本文也概述了旨在恢复内质网稳态的现有和新型治疗方法。
