Induction of endoplasmic reticulum stress-induced β-cell apoptosis and accumulation of polyubiquitinated proteins by human islet amyloid polypeptide
- 1 December 2007
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Endocrinology and Metabolism
- Vol. 293 (6), E1656-E1662
- https://doi.org/10.1152/ajpendo.00318.2007
Abstract
The islet in type 2 diabetes is characterized by an ∼60% β-cell deficit, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). Human IAPP (hIAPP) but not rodent IAPP (rIAPP) forms toxic oligomers and amyloid fibrils in an aqueous environment. We previously reported that overexpression of hIAPP in transgenic rats triggered endoplasmic reticulum (ER) stress-induced apoptosis in β-cells. In the present study, we sought to establish whether the cytotoxic effects of hIAPP depend on its propensity to oligomerize, rather than as a consequence of protein overexpression. To accomplish this, we established a novel homozygous mouse model overexpressing rIAPP at a comparable expression rate and, on the same background, as a homozygous transgenic hIAPP mouse model previously reported to develop diabetes associated with β-cell loss. We report that by 10 wk of age hIAPP mice develop diabetes with a deficit in β-cell mass due to increased β-cell apoptosis. The rIAPP transgenic mice counterparts do not develop diabetes or have decreased β-cell mass. Both rIAPP and hIAPP transgenic mice have increased expression of BiP, but only hIAPP transgenic mice have elevated ER stress markers (X-box-binding protein-1, nuclear localized CCAAT/enhancer binding-protein homologous protein, active caspase-12, and accumulation of ubiquitinated proteins). These findings indicate that the β-cell toxic effects of hIAPP depend on the propensity of IAPP to aggregate, but not on the consequence of protein overexpression.Keywords
This publication has 38 references indexed in Scilit:
- Impairment of the Ubiquitin-Proteasome Pathway Is a Downstream Endoplasmic Reticulum Stress Response Induced by Extracellular Human Islet Amyloid Polypeptide and Contributes to Pancreatic β-Cell ApoptosisDiabetes, 2007
- Caspase-12 and Caspase-4 Are Not Required for Caspase-dependent Endoplasmic Reticulum Stress-induced ApoptosisOnline Journal of Public Health Informatics, 2005
- Atomic Force Microscopy Reveals Defects Within Mica Supported Lipid Bilayers Induced by the Amyloidogenic Human Amylin PeptideJournal of Molecular Biology, 2004
- Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of PathogenesisScience, 2003
- Induction of apoptosis by human amylin in RINm5F islet β‐cells is associated with enhanced expression of p53 and p21WAF1/CIP1FEBS Letters, 1999
- Pore Formation by the Cytotoxic Islet Amyloid Peptide AmylinOnline Journal of Public Health Informatics, 1996
- Islet Amyloid Polypeptide: A Review of Its Biology and Potential Roles in the Pathogenesis of Diabetes MellitusVeterinary Pathology, 1993
- Diabetes and tolerance in transgenic mice expressing class II MHC molecules in pancreatic beta cellsCell, 1988
- Ubiquitin Is a Component of Paired Helical Filaments in Alzheimer's DiseaseScience, 1987
- Islet Pathology and the Pathogenesis of Type 1 and Type 2 Diabetes mellitus RevisitedPathology and Immunopathology Research, 1985