Journal Article

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

Yong, Jing, Johnson, James D, Han Jaeseok, Kaufman, Randal J, Arvan, Peter

2021

Overview

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.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.

• Publisher: Nature Publishing Group
• Subject: Apoptosis / Autoimmunity / Beta cells / Calcium (intracellular) / Calcium signalling / Cell death / Cell survival / Diabetes / Diabetes mellitus (insulin dependent) / Diabetes mellitus (non-insulin dependent) / Endoplasmic reticulum / Fatty liver / Insulin / Insulin resistance / Insulin secretion / Liver diseases / Metabolic syndrome / Mutation / Pancreas / Secretion