Diabetes mellitus is characterized by the failure of insulin-secreting pancreatic β-cells (or β-cell death) due to either autoimmunity (type 1 diabetes mellitus) or failure to compensate for insulin resistance (type 2 diabetes mellitus; T2DM). In addition, mutations of critical genes cause monogenic diabetes. The endoplasmic reticulum (ER) is the primary site for proinsulin folding; therefore, ER proteostasis is crucial for both β-cell function and survival under physiological and pathophysiological challenges. Importantly, the ER is also the major intracellular Ca²⁺ storage organelle, generating Ca²⁺ signals that contribute to insulin secretion. ER stress is associated with the pathogenesis of diabetes mellitus. In this Review, we summarize the mutations in monogenic diabetes that play causal roles in promoting ER stress in β-cells. Furthermore, we discuss the possible mechanisms responsible for ER proteostasis imbalance with a focus on T2DM, in which both genetics and environment are considered important in promoting ER stress in β-cells. We also suggest that controlled insulin secretion from β-cells might reduce the progression of a key aspect of the metabolic syndrome, namely nonalcoholic fatty liver disease. Finally, we evaluate potential therapeutic approaches to treat T2DM, including the optimization and protection of functional β-cell mass in individuals with T2DM.

糖尿病的特征是由于自身免疫（1 型糖尿病）或无法代偿胰岛素抵抗（2 型糖尿病；T2DM）导致胰岛素分泌胰腺 β 细胞衰竭（或 β 细胞死亡）。此外，关键基因的突变会导致单基因糖尿病。内质网 (ER) 是胰岛素原折叠的主要部位；因此，ER 蛋白稳态对于 β 细胞功能和在生理和病理生理挑战下的存活至关重要。重要的是，ER 也是细胞内主要的 Ca ²⁺储存细胞器，产生 Ca ²⁺有助于胰岛素分泌的信号。ER应激与糖尿病的发病机制有关。在这篇综述中，我们总结了单基因糖尿病中在促进 β 细胞内质网应激中发挥因果作用的突变。此外，我们讨论了导致 ER 蛋白稳态失衡的可能机制，重点关注 T2DM，其中遗传学和环境被认为对促进 β 细胞的 ER 应激很重要。我们还建议，控制 β 细胞的胰岛素分泌可能会减少代谢综合征的一个关键方面的进展，即非酒精性脂肪性肝病。最后，我们评估了治疗 T2DM 的潜在治疗方法，包括优化和保护 T2DM 患者的功能性 β 细胞群。