Document Detail


Small-molecule inhibitors of the cystic fibrosis transmembrane conductance regulator increase pancreatic endocrine cell development in rat and mouse.
MedLine Citation:
PMID:  23178930     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
S Zertal-Zidani; K Busiah; A Edelman; M Polak; R Scharfmann
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-11-24
Journal Detail:
Title:  Diabetologia     Volume:  56     ISSN:  1432-0428     ISO Abbreviation:  Diabetologia     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-04     Completed Date:  2013-06-12     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  0006777     Medline TA:  Diabetologia     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  330-9     Citation Subset:  IM    
Affiliation:
INSERM U845, Research Center Growth and Signalling, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Faculty Necker, 156 Rue de Vaugirard, Paris, France. samia.zertal@gmail.com
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MeSH Terms
Descriptor/Qualifier:
Animals
Basic Helix-Loop-Helix Transcription Factors / metabolism
Cystic Fibrosis Transmembrane Conductance Regulator / antagonists & inhibitors*,  metabolism*
Female
Glyburide / pharmacology*
Glycine / analogs & derivatives*,  pharmacology
Hydrazines / pharmacology*
Immunochemistry
Mice
Nerve Tissue Proteins / metabolism
Organ Culture Techniques
Pancreas / cytology*,  drug effects,  metabolism
Pregnancy
Rats
Rats, Wistar
Real-Time Polymerase Chain Reaction
Chemical
Reg. No./Substance:
0/Basic Helix-Loop-Helix Transcription Factors; 0/Hydrazines; 0/N-(2-naphthalenyl)-((3,5-dibromo-2,4-dihydroxyphenyl)methylene)glycine hydrazide; 0/Nerve Tissue Proteins; 0/Neurog3 protein, mouse; 0/Neurog3 protein, rat; 10238-21-8/Glyburide; 126880-72-6/Cystic Fibrosis Transmembrane Conductance Regulator; 56-40-6/Glycine
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