| Involvement of thioredoxin-interacting protein (TXNIP) in glucocorticoid-mediated beta cell death. | |
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MedLine Citation:
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PMID: 22246375 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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AIM/HYPOTHESIS: Glucocorticoid hormones (GCs) are widely used to treat a variety of inflammatory and immune diseases. However, their long-term administration is associated with adverse metabolic effects, including glucose intolerance and diabetes. Our objective was to elucidate the mechanisms by which GCs affect beta cell survival with a specific emphasis on the role of the thioredoxin-interacting protein (TXNIP) in beta cell apoptosis. METHODS: Human and mouse islets, together with MIN6 beta cells, were exposed to dexamethasone (Dex) and apoptosis was assessed by measuring the percentage of sub-G1 cells, the appearance of cleaved caspase-3 or by using a TUNEL assay. Dex-upregulated expression of Txnip mRNA was analysed by real-time PCR, and GC-modulated production and modification of proteins were determined by western blotting. RESULTS: We provide evidence that TXNIP, a negative regulator of the antioxidant thioredoxin (TRX), is strongly induced in beta cells by GCs and that its induction is dependent on p38 mitogen-activated protein kinase (MAPK) activation. TXNIP downregulation by RNA interference, overexpression of the radical scavenger TRX1 or elevation of intracellular cAMP levels attenuated the Dex-mediated apoptosis. Dex-induced Txnip expression and beta cell apoptosis are mediated by the glucocorticoid receptor (GR), as the GR antagonist RU486 fully abolishes these effects. CONCLUSIONS/INTERPRETATION: Altogether, our data suggest TXNIP as a novel mediator of GC-induced apoptosis in beta cells and further contribute to our understanding of beta cell death pathways. |
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Authors:
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E Reich; A Tamary; R Vogt Sionov; D Melloul |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-14 |
Journal Detail:
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Title: Diabetologia Volume: - ISSN: 1432-0428 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-16 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0006777 Medline TA: Diabetologia Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Endocrinology, Hadassah University Hospital, PO Box 12 000, 91120, Jerusalem, Israel. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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