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.
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