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Type 2 diabetes (T2D) is characterized by beta 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 beta cell function. While deletion of the homologous murine Tcf7l2 gene throughout the developing pancreas leads to impaired glucose tolerance, deletion in the beta cell in adult mice reportedly has more modest effects. To inactivate Tcf7l2 highly selectively in beta cells from the earliest expression of the Ins1 gene ( approximately 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 ( approximately 20%) and Glp1r ( approximately 40%) genes were significantly reduced. Glucose- and GLP-1-induced intracellular free Ca(2+) increases, and connectivity between individual beta 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 approximately 30% decrease in beta cell mass in pancreata from Tcfl2(fl/fl)::Ins1Cre mice. These data demonstrate that Tcf7l2 plays a cell autonomous role in the control of beta 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.

Original publication

DOI

10.1093/hmg/ddu553

Type

Journal article

Journal

Hum Mol Genet

Publication Date

2015

Volume

24

Pages

1390 - 1399

Keywords

Animals Blood Glucose/metabolism Diabetes Mellitus, Type 2/genetics Diet, High-Fat/veterinary Disease Models, Animal Gene Deletion Genetic Loci Genome-Wide Association Study Glucagon/blood Glucagon-Like Peptide 1/genetics/metabolism Glucagon-Like Peptide-1 Receptor Insulin/blood/genetics/*metabolism Insulin Secretion Insulin-Secreting Cells/*metabolism/pathology Integrases/genetics/metabolism Mice Mice, Inbred C57BL Mice, Knockout Molecular Weight Pancreas/metabolism/*physiopathology Polymorphism, Single Nucleotide Receptors, Glucagon/genetics/metabolism Transcription Factor 7-Like 2 Protein/genetics/*metabolism Wnt Signaling Pathway