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Induction of endoplasmic reticulum stress-induced beta-cell apoptosis and accumulation of polyubiquitinated proteins by human islet amyloid polypeptide.
- Source :
-
American journal of physiology. Endocrinology and metabolism [Am J Physiol Endocrinol Metab] 2007 Dec; Vol. 293 (6), pp. E1656-62. Date of Electronic Publication: 2007 Oct 02. - Publication Year :
- 2007
-
Abstract
- The islet in type 2 diabetes is characterized by an approximately 60% beta-cell deficit, increased beta-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 beta-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 beta-cell loss. We report that by 10 wk of age hIAPP mice develop diabetes with a deficit in beta-cell mass due to increased beta-cell apoptosis. The rIAPP transgenic mice counterparts do not develop diabetes or have decreased beta-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 beta-cell toxic effects of hIAPP depend on the propensity of IAPP to aggregate, but not on the consequence of protein overexpression.
- Subjects :
- Activating Transcription Factor 4 metabolism
Amyloid genetics
Animals
Blood Glucose metabolism
Body Weight
Caspase 12 metabolism
Cell Line, Tumor
Cytosol metabolism
DNA-Binding Proteins metabolism
Endoplasmic Reticulum Chaperone BiP
Heat-Shock Proteins metabolism
Humans
Insulin metabolism
Insulin-Secreting Cells cytology
Islet Amyloid Polypeptide
Mice
Mice, Inbred Strains
Mice, Transgenic
Molecular Chaperones metabolism
Nuclear Proteins metabolism
Proteins metabolism
Rats
Regulatory Factor X Transcription Factors
Transcription Factor CHOP metabolism
Transcription Factors
Amyloid metabolism
Apoptosis physiology
Endoplasmic Reticulum physiology
Insulin-Secreting Cells metabolism
Polyubiquitin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0193-1849
- Volume :
- 293
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Endocrinology and metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 17911343
- Full Text :
- https://doi.org/10.1152/ajpendo.00318.2007