Selective disruption of Tcf7l2 in the pancreatic β cell impairs secretory function and lowers β cell mass.

Détails

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Etat: Public
Version: de l'auteur
ID Serval
serval:BIB_1F4851B77D5E
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Selective disruption of Tcf7l2 in the pancreatic β cell impairs secretory function and lowers β cell mass.
Périodique
Human Molecular Genetics
Auteur(s)
Mitchell R.K., Mondragon A., Chen L., Mcginty J.A., French P.M., Ferrer J., Thorens B., Hodson D.J., Rutter G.A., Da Silva Xavier G.
ISSN
1460-2083 (Electronic)
ISSN-L
0964-6906
Statut éditorial
Publié
Date de publication
2015
Volume
24
Numéro
5
Pages
1390-1399
Langue
anglais
Résumé
Type 2 diabetes (T2D) is characterized by β cell dysfunction and loss. Single nucleotide polymorphisms in the T-cell factor 7-like 2 (TCF7L2) gene, associated with T2D by genome-wide association studies, lead to impaired β cell function. While deletion of the homologous murine Tcf7l2 gene throughout the developing pancreas leads to impaired glucose tolerance, deletion in the β cell in adult mice reportedly has more modest effects. To inactivate Tcf7l2 highly selectively in β cells from the earliest expression of the Ins1 gene (∼E11.5) we have therefore used a Cre recombinase introduced at the Ins1 locus. Tcfl2(fl/fl)::Ins1Cre mice display impaired oral and intraperitoneal glucose tolerance by 8 and 16 weeks, respectively, and defective responses to the GLP-1 analogue liraglutide at 8 weeks. Tcfl2(fl/fl)::Ins1Cre islets displayed defective glucose- and GLP-1-stimulated insulin secretion and the expression of both the Ins2 (∼20%) and Glp1r (∼40%) genes were significantly reduced. Glucose- and GLP-1-induced intracellular free Ca(2+) increases, and connectivity between individual β cells, were both lowered by Tcf7l2 deletion in islets from mice maintained on a high (60%) fat diet. Finally, analysis by optical projection tomography revealed ∼30% decrease in β cell mass in pancreata from Tcfl2(fl/fl)::Ins1Cre mice. These data demonstrate that Tcf7l2 plays a cell autonomous role in the control of β cell function and mass, serving as an important regulator of gene expression and islet cell coordination. The possible relevance of these findings for the action of TCF7L2 polymorphisms associated with Type 2 diabetes in man is discussed.
Pubmed
Web of science
Open Access
Oui
Création de la notice
02/04/2015 10:43
Dernière modification de la notice
20/08/2019 12:55
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