| Small-molecule inhibitors of the cystic fibrosis transmembrane conductance regulator increase pancreatic endocrine cell development in rat and mouse. | |
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MedLine Citation:
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PMID: 23178930 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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AIMS/HYPOTHESIS: The main objective of this work was to discover new drugs that can activate the differentiation of multipotent pancreatic progenitors into endocrine cells. METHODS: In vitro experiments were performed using fetal pancreatic explants from rats and mice. In this assay, we examined the actions on pancreatic cell development of glibenclamide, a sulfonylurea derivative, and glycine hydrazide (GlyH-101), a small-molecule inhibitor of cystic fibrosis transmembrane conductance regulator (CFTR). We next tested the actions of GlyH-101 on in vivo pancreatic cell development. RESULTS: Glibenclamide (10 nmol/l-100 μmol/l) did not alter the morphology or growth of the developing pancreas and exerted no deleterious effects on exocrine cell development in the pancreas. Unexpectedly, glibenclamide at its highest concentration promoted endocrine differentiation. This glibenclamide-induced promotion of the endocrine pathway could not be reproduced when other sulfonylureas were used, suggesting that glibenclamide had an off-target action. This high concentration of glibenclamide had previously been reported to inhibit CFTR. We found that the effects of glibenclamide on the developing pancreas could be mimicked both in vitro and in vivo by GlyH-101. CONCLUSIONS/INTERPRETATION: Collectively, we demonstrate that two small-molecule inhibitors of the CFTR, glibenclamide and GlyH-101, increase the number of pancreatic endocrine cells by increasing the size of the pool of neurogenin 3-positive endocrine progenitors in the developing pancreas. |
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Authors:
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S Zertal-Zidani; K Busiah; A Edelman; M Polak; R Scharfmann |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-11-24 |
Journal Detail:
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Title: Diabetologia Volume: - ISSN: 1432-0428 ISO Abbreviation: Diabetologia Publication Date: 2012 Nov |
Date Detail:
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Created Date: 2012-11-26 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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Inserm U845, Research Center Growth and Signalling, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Faculty Necker, 156 Rue de Vaugirard, 75015, Paris, France, samia.zertal@gmail.com. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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