ß-cell dysfunctional ERAD/ubiquitin/proteasome system in type 2 diabetes mediated by islet amyloid polypeptide-induced UCH-L1 deficiency.
Diabetes
; 60(1): 227-38, 2011 Jan.
Article
in En
| MEDLINE
| ID: mdl-20980462
ABSTRACT
OBJECTIVE:
The islet in type 2 diabetes is characterized by ß-cell apoptosis, ß-cell endoplasmic reticulum stress, and islet amyloid deposits derived from islet amyloid polypeptide (IAPP). Toxic oligomers of IAPP form intracellularly in ß-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. RESEARCH DESIGN ANDMETHODS:
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.RESULTS:
We report accumulation of polyubiquinated proteins and UCH-L1 deficiency in ß-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 ß-cells induced endoplasmic reticulum stress leading to apoptosis.CONCLUSIONS:
Our results indicate that defective protein degradation in ß-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 ß-cell viability.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Ubiquitin
/
Ubiquitin Thiolesterase
/
Proteasome Endopeptidase Complex
/
Diabetes Mellitus, Type 2
/
Insulin-Secreting Cells
/
Islet Amyloid Polypeptide
Limits:
Animals
/
Humans
Language:
En
Journal:
Diabetes
Year:
2011
Document type:
Article
Affiliation country: