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β-cell dysfunctional ERAD/ubiquitin/proteasome system in type 2 diabetes mediated by islet amyloid polypeptide-induced UCH-L1 deficiency.
- Source :
-
Diabetes [Diabetes] 2011 Jan; Vol. 60 (1), pp. 227-38. Date of Electronic Publication: 2010 Oct 27. - Publication Year :
- 2011
-
Abstract
- Objective: The islet in type 2 diabetes is characterized by β-cell apoptosis, β-cell endoplasmic reticulum stress, and islet amyloid deposits derived from islet amyloid polypeptide (IAPP). Toxic oligomers of IAPP form intracellularly in β-cells in humans with type 2 diabetes, suggesting impaired clearance of misfolded proteins. In this study, we investigated whether human-IAPP (h-IAPP) disrupts the endoplasmic reticulum-associated degradation/ubiquitin/proteasome system.<br />Research Design and Methods: We used pancreatic tissue from humans with and without type 2 diabetes, isolated islets from h-IAPP transgenic rats, isolated human islets, and INS 832/13 cells transduced with adenoviruses expressing either h-IAPP or a comparable expression of rodent-IAPP. Immunofluorescence and Western blotting were used to detect polyubiquitinated proteins and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) protein levels. Proteasome activity was measured in isolated rat and human islets. UCH-L1 was knocked down by small-interfering RNA in INS 832/13 cells and apoptosis was evaluated.<br />Results: We report accumulation of polyubiquinated proteins and UCH-L1 deficiency in β-cells of humans with type 2 diabetes. These findings were reproduced by expression of oligomeric h-IAPP but not soluble rat-IAPP. Downregulation of UCH-L1 expression and activity to reproduce that caused by h-IAPP in β-cells induced endoplasmic reticulum stress leading to apoptosis.<br />Conclusions: Our results indicate that defective protein degradation in β-cells in type 2 diabetes can, at least in part, be attributed to misfolded h-IAPP leading to UCH-L1 deficiency, which in turn further compromises β-cell viability.
- Subjects :
- Animals
Autopsy
Diabetes Mellitus, Type 2 drug therapy
Diabetes Mellitus, Type 2 metabolism
Humans
Hypoglycemic Agents therapeutic use
Insulin therapeutic use
Insulin-Secreting Cells drug effects
Insulin-Secreting Cells pathology
Islet Amyloid Polypeptide genetics
Nuclear Proteins drug effects
Nuclear Proteins metabolism
Obesity complications
Obesity pathology
Rats
Rats, Transgenic
Ubiquitin drug effects
Ubiquitin Thiolesterase drug effects
Diabetes Mellitus, Type 2 genetics
Insulin-Secreting Cells physiology
Islet Amyloid Polypeptide pharmacology
Proteasome Endopeptidase Complex metabolism
Ubiquitin metabolism
Ubiquitin Thiolesterase deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 1939-327X
- Volume :
- 60
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 20980462
- Full Text :
- https://doi.org/10.2337/db10-0522