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High expression rates of human islet amyloid polypeptide induce endoplasmic reticulum stress mediated beta-cell apoptosis, a characteristic of humans with type 2 but not type 1 diabetes.
- Source :
-
Diabetes [Diabetes] 2007 Aug; Vol. 56 (8), pp. 2016-27. Date of Electronic Publication: 2007 May 02. - Publication Year :
- 2007
-
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 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.<br />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.<br />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.<br />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.
- Subjects :
- Aged, 80 and over
Amyloid genetics
Animals
Animals, Genetically Modified
Biomarkers metabolism
Caspase 12 metabolism
Cell Line
Cell Nucleus metabolism
Diabetes Mellitus, Type 1 genetics
Diabetes Mellitus, Type 1 pathology
Diabetes Mellitus, Type 2 genetics
Diabetes Mellitus, Type 2 pathology
Gene Expression Regulation
Humans
Insulin metabolism
Islet Amyloid Polypeptide
Male
Rats
Transcription Factor CHOP metabolism
Amyloid metabolism
Apoptosis
Diabetes Mellitus, Type 1 metabolism
Diabetes Mellitus, Type 2 metabolism
Endoplasmic Reticulum metabolism
Insulin-Secreting Cells cytology
Insulin-Secreting Cells metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1939-327X
- Volume :
- 56
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 17475933
- Full Text :
- https://doi.org/10.2337/db07-0197