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Endoplasmic Reticulum Stress–Induced Apoptosis Is Partly Mediated by Reduced Insulin Signaling Through Phosphatidylinositol 3-Kinase/Akt and Increased Glycogen Synthase Kinase-3ß in Mouse Insulinoma Cells

Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri

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 ß-cell apoptosis and diabetes. Because insulin/IGF/Akt signaling has been implicated in ß-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 3ß (GSK3ß). In control cells, ER stress–induced apoptosis was associated with a reduction in phospho-Akt and phospho-GSK3ß. To further assess the role of GSK3ß in ER stress–induced apoptosis, stable cell lines were created by siRNA with up to 80% reduction in GSK3ß 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/GSK3ß pathway and that GSK3ß represents a novel target for agents to promote ß-cell survival.

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