High Expression Rates of Human Islet Amyloid Polypeptide Induce Endoplasmic Reticulum Stress–Mediated β-Cell Apoptosis, a Characteristic of Humans With Type 2 but Not Type 1 Diabetes

OBJECTIVE: Endoplasmic reticulum (ER) stress-induced apoptosis may be a common cause of cell attrition in diseases characterized by misfolding and oligomerisation of amyloidogenic proteins. The islet in type 2 diabetes is characterized by islet amyloid derived from islet amyloid polypeptide (IAPP) and increased beta-cell apoptosis. We questioned the following: 1) whether IAPP-induced beta-cell apoptosis is mediated by ER stress and 2) whether beta-cells in type 2 diabetes are characterized by ER stress. RESEARCH DESIGN AND METHODS: The mechanism of IAPP-induced apoptosis was investigated in INS-1 cells and human IAPP (HIP) transgenic rats. ER stress in humans was investigated by beta-cell C/EBP homologous protein (CHOP) expression in 7 lean nondiabetic, 12 obese nondiabetic, and 14 obese type 2 diabetic human pancreata obtained at autopsy. To assure specificity for type 2 diabetes, we also examined pancreata from eight cases of type 1 diabetes. RESULTS: IAPP induces beta-cell apoptosis by ER stress in INS-1 cells and HIP rats. Perinuclear CHOP was rare in lean nondiabetic (2.6 +/- 2.0%) and more frequent in obese nondiabetic (14.6 +/- 3.0%) and obese diabetic (18.5 +/- 3.6%) pancreata. Nuclear CHOP was not detected in lean nondiabetic and rare in obese nondiabetic (0.08 +/- 0.04%) but six times higher (P < 0.01) in obese diabetic (0.49 +/- 0.17%) pancreata. In type 1 diabetic pancreata, perinuclear CHOP was rare (2.5 +/- 2.3%) and nuclear CHOP not detected. CONCLUSIONS: ER stress is a mechanism by which IAPP induces beta-cell apoptosis and is characteristic of beta-cells in humans with type 2 diabetes but not type 1 diabetes. These findings are consistent with a role of protein misfolding in beta-cell apoptosis in type 2 diabetes.