An imbalance between the rate of protein synthesis and folding capacity of the endoplasmic reticulum (ER) results in stress that has been increasingly implicated in pancreatic islet β-cell apoptosis and diabetes. Because insulin/IGF/Akt signaling has been implicated in β-cell survival, we sought to determine whether this pathway is involved in ER stress-induced apoptosis. Mouse insulinoma cells treated with pharmacological agents commonly used to induce ER stress exhibited apoptosis within 48 h. ER stress-induced apoptosis was inhibited by cotreatment of the cells with IGF-1. Stable cell lines were created by small-interfering RNA (siRNA) with graded reduction of insulin receptor expression, and these cells had enhanced susceptibility to ER stress-induced apoptosis and reduced levels of phospho-glycogen synthase kinase 3β (GSK3β). In control cells, ER stress-induced apoptosis was associated with a reduction in phospho-Akt and phospho-GSK3β. To further assess the role of GSK3β in ER stress-induced apoptosis, stable cell lines were created by siRNA with up to 80% reduction in GSK3β expression. These cells were found to resist ER stress-induced apoptosis. These results illustrate that ER stress-induced apoptosis is mediated at least in part by signaling through the phosphatidylinositol 3-kinase/Akt/GSK3β pathway and that GSK3β represents a novel target for agents to promote β-cell survival.
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism