| Loss of Nix in Pdx1-deficient mice prevents apoptotic and necrotic β cell death and diabetes. | |
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MedLine Citation:
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PMID: 20978346 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Mutations in pancreatic duodenal homeobox (PDX1) are linked to human type 2 diabetes and maturity-onset diabetes of the young type 4. Consistent with this, Pdx1-haploinsufficient mice develop diabetes. Both apoptosis and necrosis of β cells are mechanistically implicated in diabetes in these mice, but a molecular link between Pdx1 and these 2 forms of cell death has not been defined. In this study, we introduced an shRNA into mouse insulinoma MIN6 cells to deplete Pdx1 and found that expression of proapoptotic genes, including NIP3-like protein X (Nix), was increased. Forced Nix expression in MIN6 and pancreatic islet β cells induced programmed cell death by simultaneously activating apoptotic and mitochondrial permeability transition-dependent necrotic pathways. Preventing Nix upregulation during Pdx1 suppression abrogated apoptotic and necrotic β cell death in vitro. In Pdx1-haploinsufficient mice, Nix ablation normalized pancreatic islet architecture, β cell mass, and insulin secretion and eliminated reactive hyperglycemia after glucose challenge. These results establish Nix as a critical mediator of β cell apoptosis and programmed necrosis in Pdx1-deficient diabetes. |
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Authors:
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Kei Fujimoto; Eric L Ford; Hung Tran; Burton M Wice; Seth D Crosby; Gerald W Dorn; Kenneth S Polonsky |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-10-11 |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 120 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-11-02 Completed Date: 2010-12-07 Revised Date: 2012-04-10 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 4031-9 Citation Subset: AIM; IM |
Affiliation:
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Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / physiology* Cell Line, Tumor Diabetes Mellitus, Type 2 / metabolism* Gene Expression Profiling Glucose / metabolism Homeodomain Proteins / genetics, metabolism* Humans Insulin-Secreting Cells / cytology, metabolism*, pathology* Membrane Proteins / genetics, metabolism* Mice Mice, Knockout Microarray Analysis Mitochondrial Proteins / genetics, metabolism* Necrosis* Trans-Activators / genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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P30 DK052574/DK/NIDDK NIH HHS; P60 DK-20579/DK/NIDDK NIH HHS; R01 DK031842/DK/NIDDK NIH HHS; R01 HL059888/HL/NHLBI NIH HHS; R01 HL059888-12/HL/NHLBI NIH HHS; R01 HL059888-13/HL/NHLBI NIH HHS; UL1 RR024992/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Homeodomain Proteins; 0/Membrane Proteins; 0/Mitochondrial Proteins; 0/Nix protein, mouse; 0/Trans-Activators; 0/pancreatic and duodenal homeobox 1 protein; 50-99-7/Glucose |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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