title: TCF7L2 controls insulin gene expression and insulin secretion in mature pancreatic beta-cells.
abstract: Genetic studies have linked the risk of Type 2 diabetes with SNPs (single nucleotide polymorphisms) in the gene encoding the Wnt signalling-associated transcription factor, TCF7L2 (T-cell factor 7-like 2). The risk alleles have been associated with reduced glucose and GLP-1 (glucagon-like peptide 1)-stimulated insulin secretion. Recent evidence has suggested that inheritance of the at-risk T allele at SNP rs7903146 may increase the expression of TCF7L2 in adult human islets. However, the cellular mechanisms by which changes in TCF7L2 levels may affect insulin secretion are unclear. In the present paper, we describe the use of RNA silencing to investigate the role of TCF7L2 on insulin secretion and gene expression in rodent islets. We find that reduced TCF7L2 expression reduces glucose-simulated insulin secretion and insulin gene expression while slightly potentiating glucose stimulated changes in intracellular free Ca(2+) concentrations.
authors.affiliation: Imperial College, Faculty of Medicine, Department of Cell Biology, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, UK. m.loder@imperial.ac.uk
authors.forename: Merewyn K
authors.initials: MK
authors.lastname: Loder
authors.forename: Gabriela
authors.initials: G
authors.lastname: da Silva Xavier
authors.forename: Angela
authors.initials: A
authors.lastname: McDonald
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000235:genetics; D005786:Gene Expression Regulation; D007328:Insulin / Q000235:genetics* / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D007328:Insulin; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin