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- Title
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.
- Authors
Huang, Chang-jiang; Lin, Chia-yu; Haataja, Leena; Gurlo, Tatyana; Butler, Alexandra E.; Rizza, Robert A.; Butler, Peter C.
- Abstract
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. Diabetes 56:2016-2027, 2007
- Subjects
ISLANDS of Langerhans; AMYLOID; PEPTIDE hormones; ENDOPLASMIC reticulum; PANCREATIC beta cells; APOPTOSIS; TYPE 2 diabetes
- Publication
Diabetes, 2007, Vol 56, Issue 8, p2016
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db07-0197