Insulin reduces endoplasmic reticulum stress‐induced apoptosis by decreasing mitochondrial hyperpolarization and caspase‐12 in INS‐1 pancreatic β‐cells

Abstract

Abstract Pancreatic β‐cell mass is a critical determinant of insulin secretion. Severe endoplasmic reticulum (ER) stress causes β‐cell apoptosis; however, the mechanisms of progression and suppression are not yet fully understood. Here, we report that the autocrine/paracrine function of insulin reduces ER stress‐induced β‐cell apoptosis. Insulin reduced the ER‐stress inducer tunicamycin‐ and thapsigargin‐induced cell viability loss due to apoptosis in INS‐1 β‐cells. Moreover, the effect of insulin was greater than that of insulin‐like growth factor‐1 at physiologically relevant concentrations. Insulin did not attenuate the ER stress‐induced increase in unfolded protein response genes. ER stress did not induce cytochrome c release from mitochondria. Mitochondrial hyperpolarization was induced by ER stress and prevented by insulin. The protonophore/mitochondrial oxidative phosphorylation uncoupler, but not the antioxidants N‐acetylcysteine and α‐tocopherol, exhibited potential cytoprotection during ER stress. Both procaspase‐12 and cleaved caspase‐12 levels increased under ER stress. The caspase‐12 inhibitor Z‐ATAD‐FMK decreased ER stress‐induced apoptosis. Caspase‐12 overexpression reduced cell viability, which was diminished in the presence of insulin. Insulin decreased caspase‐12 levels at the post‐translational stages. These results demonstrate that insulin protects against ER stress‐induced β‐cell apoptosis in this cell line. Furthermore, mitochondrial hyperpolarization and increased caspase‐12 levels are involved in ER stress‐induced and insulin‐suppressed β‐cell apoptosis.

Keywords

• autocrine and paracrine actions of insulin
• caspase‐12
• cytochrome c
• endoplasmic reticulum (ER) stress
• mitochondrial hyperactivation
• pancreatic β‐cells