| Cyclosporin and tacrolimus impair insulin secretion and transcriptional regulation in INS-1E beta-cells. | |
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MedLine Citation:
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PMID: 20825407 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND AND PURPOSE: Introducing the calcineurin inhibitors cyclosporin (CsA) and tacrolimus (Tac) has improved the outcome of organ transplants, but complications such as new onset diabetes mellitus after transplantation (NODAT) decrease survival rates. EXPERIMENTAL APPROACH: We sought, in a beta-cell culture model, to elucidate the pathogenic mechanisms behind NODAT and the relative contribution of the calcineurin inhibitors. INS-1E cells were incubated at basal and stimulatory glucose concentrations, while exposed to pharmacologically relevant doses of CsA, Tac and vehicle for 6 or 24 h. RESULTS: Tac inhibited basal (P < 0.05), but not glucose-stimulated insulin secretion (GSIS) after 6 h of exposure. After 24 h, both agents inhibited basal and GSIS (P < 0.05). Calcineurin phosphatase activity was decreased by both drugs during all conditions. Apoptosis was only seen with CsA treatment, which also induced a slight suppression of calcineurin and insulin mRNA, as well as increased levels of the sterol receptor element binding protein (SREBP)-1c, a transcription factor thought to suppress genes essential for beta-cell function and induce insulin resistance. Expression levels of nuclear factor of activated T-cells (NFAT)-c1, -c2, -c3 and -c4 were not decreased notably by either drug. CONCLUSIONS AND IMPLICATIONS: Tac had acute inhibitory effects on basal insulin secretion, but prolonged exposure (24 h) to Tac or CsA revealed similar suppression of insulin secretion. These prolonged effects were mirrored by a total inhibition of calcineurin activity in beta-cells. CsA showed greater inhibition of beta-cell survival and transcriptional markers, essential for beta-cell function. |
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Authors:
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L A Øzbay; K Smidt; D M Mortensen; J Carstens; K A Jørgensen; J Rungby |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: British journal of pharmacology Volume: 162 ISSN: 1476-5381 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2010-12-07 Completed Date: 2011-04-05 Revised Date: 2012-01-02 |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 136-46 Citation Subset: IM |
Copyright Information:
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© 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society. |
Affiliation:
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Department of Nephrology, Aarhus University Hospital, Skejby, Aarhus, Denmark. doc.aygen@gmail.com |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Base Sequence Calcineurin / antagonists & inhibitors, metabolism Cell Line Cyclosporine / pharmacology* DNA Primers Enzyme-Linked Immunosorbent Assay Immunosuppressive Agents / pharmacology* Insulin / genetics, secretion* Insulin Resistance Islets of Langerhans / drug effects*, secretion NFATC Transcription Factors / metabolism Polymerase Chain Reaction RNA, Messenger / genetics Rats Signal Transduction / drug effects Tacrolimus / pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/DNA Primers; 0/Immunosuppressive Agents; 0/Insulin; 0/NFATC Transcription Factors; 0/RNA, Messenger; 109581-93-3/Tacrolimus; 59865-13-3/Cyclosporine; EC 3.1.3.16/Calcineurin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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