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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.
Pubmed: (View Article at PubMed) PMID:23178930
DOI: Full-text: DOI:10.1007/s00125-012-2778-8

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.


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CRRD Object Information
CRRD ID: 11567224
Created: 2016-12-01
Species: All species
Last Modified: 2016-12-01
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.