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
2007/07/27 by Chang-jiang Huang, Chia-yu Lin, Chia‐Yu Lin +5 · 27 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Endoplasmic Reticulum Stress and Disease #Pancreatic function and diabetes #Diabetes and associated disorders
paper · pdf · doi:10.2337/db07-0197
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. 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.
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- Islet Amyloid Polypeptide, Islet Amyloid, and Diabetes Mellitus
- The Unfolded Protein Response: A Pathway That Links Insulin Demand with β-Cell Failure and Diabetes
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- Chop deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes. [europepmc]
- Beta-cell failure as a complication of diabetes. [europepmc]
- Relationship between beta-cell mass and diabetes onset. [europepmc]
- Glucolipotoxicity of the pancreatic beta cell. [europepmc]
- Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy. [europepmc]
- Endoplasmic reticulum stress and pancreatic β-cell death. [europepmc]
- Disruption of circadian rhythms accelerates development of diabetes through pancreatic beta-cell loss and dysfunction. [europepmc]
- The impact of the unfolded protein response on human disease. [europepmc]
- Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors. [europepmc]
- Aggregation of islet amyloid polypeptide: from physical chemistry to cell biology. [europepmc]
- Mechanisms of islet amyloidosis toxicity in type 2 diabetes. [europepmc]
- Islet β cell mass in diabetes and how it relates to function, birth, and death. [europepmc]
- Metabolic syndrome and insulin resistance: underlying causes and modification by exercise training. [europepmc]
- Signaling pathways from the endoplasmic reticulum and their roles in disease. [europepmc]
- Autophagy defends pancreatic β cells from human islet amyloid polypeptide-induced toxicity. [europepmc]
- Natural history of β-cell adaptation and failure in type 2 diabetes. [europepmc]
- Proinsulin misfolding and endoplasmic reticulum stress during the development and progression of diabetes. [europepmc]
- Type 2 diabetes as a protein misfolding disease. [europepmc]
- Protein Folding and Mechanisms of Proteostasis. [europepmc]
- Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics. [europepmc]
- Pancreatic Beta Cell Death: Novel Potential Mechanisms in Diabetes Therapy. [europepmc]
- Endoplasmic reticulum stress, degeneration of pancreatic islet β-cells, and therapeutic modulation of the unfolded protein response in diabetes. [europepmc]
- Pathological β-Cell Endoplasmic Reticulum Stress in Type 2 Diabetes: Current Evidence. [europepmc]
- Type 2 diabetes mellitus in adults: pathogenesis, prevention and therapy. [europepmc]
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