title: Selective disruption of Tcf7l2 in the pancreatic β cell impairs secretory function and lowers β cell mass.
abstract: 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.
authors.affiliation: Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine.
authors.forename: Ryan K
authors.initials: RK
authors.lastname: Mitchell
authors.affiliation: Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine.
authors.forename: Angeles
authors.initials: A
authors.lastname: Mondragon
authors.affiliation: Photonics Group, Department of Physics and.
authors.forename: Lingling
authors.initials: L
authors.lastname: Chen
authors.affiliation: Photonics Group, Department of Physics and.
authors.forename: James A
authors.initials: JA
authors.lastname: Mcginty
authors.affiliation: Photonics Group, Department of Physics and.
authors.forename: Paul M
authors.initials: PM
authors.lastname: French
authors.affiliation: Section of Genetics and Medicine, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, UK.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferrer
authors.affiliation: Center for Integrative Genomics, Physiology Department, University of Lausanne, Genopode Building, CH-1015 Lausanne, Switzerland.
authors.forename: Bernard
authors.initials: B
authors.lastname: Thorens
authors.affiliation: Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hodson
authors.affiliation: Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, g.dasilva-xavier@imperial.ac.uk g.rutter@imperial.ac.uk.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.affiliation: Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, g.dasilva-xavier@imperial.ac.uk g.rutter@imperial.ac.uk.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Da Silva Xavier
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D059305:Diet, High-Fat / Q000662:veterinary; D004195:Disease Models, Animal; D017353:Gene Deletion; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008970:Molecular Weight; D010179:Pancreas / Q000378:metabolism / Q000503:physiopathology*; D020641:Polymorphism, Single Nucleotide; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: D001786:Blood Glucose; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; C514817:Ins1 protein, mouse; C561967:Ins2 protein, mouse; D007328:Insulin; D018027:Receptors, Glucagon; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; C045073:Cre recombinase; D019426:Integrases