Impact of Endoplasmic Reticulum Stress Pathway on Pancreatic β-Cells and Diabetes Mellitus

Abstract

Diabetes is caused by impaired insulin secretion in pancreatic β-cells and peripheral insulin resistance. Overload of pancreatic β-cells leads to β-cell exhaustion and finally to the development of diabetes. Reduced β-cell mass is evident in type 2 diabetes, and apoptosis is implicated in this process. One characteristic feature of β-cells is highly developed endoplasmic reticulum (ER) due to a heavy engagement in insulin secretion. The ER serves several important functions, including post-translational modification, folding, and assembly of newly synthesized secretory proteins, and its proper function is essential to cell survival. Various conditions can interfere with ER function and these conditions are called ER stress. Recently, we found that nitric oxide (NO)-induced apoptosis in β-cells is mediated by the ER-stress pathway. NO causes ER stress and leads to apoptosis through induction of ER stress-associated apoptosis factor CHOP. The Akita mouse with a missense mutation (Cys96Tyr) in the insulin 2 gene has hyperglycemia and a reduced β-cell mass. This mutation disrupts a disulfide bond between A and B chains of insulin and may induce its conformational change. In the development of diabetes in Akita mice, mRNAs for an ER chaperone Bip and CHOP were Induced in the pancreas. Overexpression of the mutant insulin in mouse MIN6 β-cells induced CHOP expression and led to apoptosis. Targeted disruption of the CHOP gene did not delay the onset of diabetes in the homozygous Akita mice, but it protected islet cells from apoptosis and delayed the onset of diabetes in the heterozygous Akita mice. We conclude that ER overload in β-cells causes ER stress and leads to apoptosis via CHOP induction. These results highlight the importance of chronic ER stress in β-cell apoptosis in type 2 diabetes, and suggest a new target to the management of the disease.