Therapeutic opportunities for pancreatic β-cell ER stress in diabetes mellitus

• Published in: Nature reviews. Endocrinology 2021-08, Vol.17 (8), p.455-467
• Main Authors: Yong, Jing, Johnson, James D., Arvan, Peter, Han, Jaeseok, Kaufman, Randal J.
• Format: Article
• Language: English
• Subjects: 631/443/319/1642/137/773; 692/163/2743/2815; Animals; Apoptosis; Autoimmunity; Beta cells; Calcium (intracellular); Calcium signalling; Cell death; Cell survival; Diabetes; Diabetes mellitus (insulin dependent); Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - physiopathology; Endocrinology; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum Stress - physiology; Fatty liver; Humans; Hypoglycemic Agents - therapeutic use; Insulin; Insulin resistance; Insulin secretion; Insulin Secretion - physiology; Insulin-Secreting Cells - physiology; Liver diseases; Medicine; Medicine & Public Health; Metabolic syndrome; Molecular Targeted Therapy - methods; Molecular Targeted Therapy - trends; Mutation; Pancreas; Proinsulin - metabolism; Review Article; Secretion
• ISSN: 1759-5029; 1759-5037
• DOI: 10.1038/s41574-021-00510-4

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 Ca 2+ storage organelle, generating Ca 2+ 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. This Review summarizes the mechanisms by which endoplasmic reticulum (ER) stress contributes to β-cell dysfunction and cell death in monogenic diabetes and type 2 diabetes mellitus (T2DM). In addition, the potential therapeutic strategies for T2DM and metabolic syndrome that target ER stress in β-cells are discussed. Key points Physiological and chronic endoplasmic reticulum (ER) ‘stress’ exists in healthy β-cells. Adaptive unfolded protein response signalling via chaperones maintains ER protein folding homeostasis in healthy β-cells. Gene mutations in maturity-onset diabetes of the young exacerbate physiological ER stress, which causes β-cell loss. Proinsulin is prone to misfolding and increased insulin production can exacerbate physiological ER stress on the path to type 2 diabetes mellitus. The therapeutic inhibition of genes that promote ER stress in β-cells (for example, CHOP ) might reduce the disease burden for patients with type 2 diabetes mellitus and is worthy of further exploration.