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beta-cell dysfunctional ERAD/ubiquitin/proteasome system in type 2 diabetes mediated by islet amyloid polypeptide-induced UCH-L1 deficiency Costes S; Huang CJ; Gurlo T; Daval M; Matveyenko AV; Rizza RA; Butler AE; Butler PCDiabetes 2011[Jan]; 60 (1): 227-38OBJECTIVE: The islet in type 2 diabetes is characterized by beta-cell apoptosis, beta-cell endoplasmic reticulum stress, and islet amyloid deposits derived from islet amyloid polypeptide (IAPP). Toxic oligomers of IAPP form intracellularly in beta-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 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. RESULTS: We report accumulation of polyubiquinated proteins and UCH-L1 deficiency in beta-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 beta-cells induced endoplasmic reticulum stress leading to apoptosis. CONCLUSIONS: Our results indicate that defective protein degradation in beta-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 beta-cell viability.|Animals[MESH]|Autopsy[MESH]|Diabetes Mellitus, Type 2/drug therapy/*genetics/metabolism[MESH]|Humans[MESH]|Hypoglycemic Agents/therapeutic use[MESH]|Insulin-Secreting Cells/drug effects/pathology/*physiology[MESH]|Insulin/therapeutic use[MESH]|Islet Amyloid Polypeptide/genetics/*pharmacology[MESH]|Nuclear Proteins/drug effects/metabolism[MESH]|Obesity/complications/pathology[MESH]|Proteasome Endopeptidase Complex/*metabolism[MESH]|Rats[MESH]|Rats, Transgenic[MESH]|Ubiquitin Thiolesterase/*deficiency/drug effects[MESH]|Ubiquitin/drug effects/*metabolism[MESH] |
