High expression rates of human islet amyloid polypeptide induce endoplasmic reticulum stress–mediated β-cell apoptosis, a characteristic of humans with type 2 but …
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 β-cell apoptosis. We questioned the
following: 1) whether IAPP-induced β-cell apoptosis is mediated by ER stress and 2)
whether β-cells in type 2 diabetes are characterized by ER stress. RESEARCH DESIGN …
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 β-cell apoptosis. We questioned the
following: 1) whether IAPP-induced β-cell apoptosis is mediated by ER stress and 2)
whether β-cells in type 2 diabetes are characterized by ER stress. RESEARCH DESIGN …
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 β-cell apoptosis. We questioned the following: 1) whether IAPP-induced β-cell apoptosis is mediated by ER stress and 2) whether β-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 β-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 β-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 β-cell apoptosis and is characteristic of β-cells in humans with type 2 diabetes but not type 1 diabetes. These findings are consistent with a role of protein misfolding in β-cell apoptosis in type 2 diabetes.
Am Diabetes Assoc