RGD Reference Report - Small-molecule inhibitors of the cystic fibrosis transmembrane conductance regulator increase pancreatic endocrine cell development in rat and mouse. - Rat Genome Database

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Small-molecule inhibitors of the cystic fibrosis transmembrane conductance regulator increase pancreatic endocrine cell development in rat and mouse.

Authors: Zertal-Zidani, S  Busiah, K  Edelman, A  Polak, M  Scharfmann, R 
Citation: Zertal-Zidani S, etal., Diabetologia. 2013 Feb;56(2):330-9. doi: 10.1007/s00125-012-2778-8. Epub 2012 Nov 24.
RGD ID: 11567224
Pubmed: PMID:23178930   (View Abstract at PubMed)
PMCID: PMC3536988   (View Article at PubMed Central)
DOI: DOI:10.1007/s00125-012-2778-8   (Journal Full-text)

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 mumol/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.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CftrRatnegative regulation of type B pancreatic cell development  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cftr  (CF transmembrane conductance regulator)


Additional Information