Abnormal glucose tolerance and insulin secretion in pancreas-specific Tcf7l2-null mice

Aims/hypothesisIndividuals carrying type 2 diabetes risk alleles in TCF7L2 display decreased beta cell levels of T cell factor 7 like-2 (TCF7L2) immunoreactivity, and impaired insulin secretion and beta cell sensitivity to glucagon-like peptide 1 (GLP-1). Here, we sought to determine whether selective deletion of Tcf7l2 in mouse pancreas impairs insulin release and glucose homeostasis.MethodsPancreas-specific Tcf7l2-null (pTcf7l2) mice were generated by crossing mice carrying conditional knockout alleles of Tcf7l2 (Tcf7l2-flox) with mice expressing Cre recombinase under the control of the Pdx1 promoter (Pdx1.Cre). Gene expression was assessed by real-time quantitative PCR and beta cell mass by optical projection tomography. Glucose tolerance, insulin secretion from isolated islets, and plasma insulin, glucagon and GLP-1 content were assessed by standard protocols.ResultsFrom 12 weeks of age, pTcf7l2 mice displayed decreased oral glucose tolerance vs control littermates; from 20 weeks they had glucose intolerance upon administration of glucose by the intraperitoneal route. pTcf7l2 islets displayed impaired insulin secretion in response to 17 (vs 3.0) mmol/l glucose (54.6 ± 4.6%, p < 0.01) or to 17 mmol/l glucose plus 100 nmol/l GLP-1 (44.3 ± 4.9%, p < 0.01) compared with control islets. Glp1r (42 ± 0.08%, p < 0.01) and Ins2 (15.4 ± 4.6%, p < 0.01) expression was significantly lower in pTcf7l2 islets than in controls. Maintained on a high-fat (but not on a normal) diet, pTcf7l2 mice displayed decreased expansion of pancreatic beta cell volume vs control littermates. No differences were observed in plasma insulin, proinsulin, glucagon or GLP-1 concentrations.Conclusions/interpretationSelective deletion of Tcf7l2 in the pancreas replicates key aspects of the altered glucose homeostasis in human carriers of TCF7L2 risk alleles, indicating the direct role of this factor in controlling beta cell function.

[1]  T. Jin,et al.  TCF-4 mediates cell type-specific regulation of proglucagon gene expression by beta-catenin and glycogen synthase kinase-3beta. , 2005, The Journal of biological chemistry.

[2]  T. Hudson,et al.  A genome-wide association study identifies novel risk loci for type 2 diabetes , 2007, Nature.

[3]  Marcia M. Nizzari,et al.  Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels , 2007, Science.

[4]  M. McCarthy,et al.  Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes , 2007, Science.

[5]  R. Nusse,et al.  Wnt signaling regulates pancreatic β cell proliferation , 2007, Proceedings of the National Academy of Sciences.

[6]  An alternative polyadenylation signal in TCF7L2 generates isoforms that inhibit T cell factor/lymphoid-enhancer factor (TCF/LEF)-dependent target genes , 2011, Diabetologia.

[7]  M. Taketo,et al.  Stabilization of β-catenin impacts pancreas growth , 2006 .

[8]  Xueying Gu,et al.  Wnt signaling regulates pancreatic beta cell proliferation. , 2007, Proceedings of the National Academy of Sciences of the United States of America.

[9]  H Clevers,et al.  TCF transcription factors: molecular switches in carcinogenesis. , 1999, Biochimica et biophysica acta.

[10]  T. Jin,et al.  The Wnt signaling pathway effector TCF7L2 and type 2 diabetes mellitus. , 2008, Molecular endocrinology.

[11]  K. Maedler,et al.  Transcription Factor 7-Like 2 Regulates β-Cell Survival and Function in Human Pancreatic Islets , 2008, Diabetes.

[12]  J. B. Lopes de Faria,et al.  Diabetic Retinal Neurodegeneration Is Associated With Mitochondrial Oxidative Stress and Is Improved by an Angiotensin Receptor Blocker in a Model Combining Hypertension and Diabetes , 2009, Diabetes.

[13]  Alex Doney,et al.  Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge , 2010, Nature Genetics.

[14]  C. Mcintosh,et al.  Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell function. , 2009, Human molecular genetics.

[15]  J. Gulcher,et al.  A variant in CDKAL1 influences insulin response and risk of type 2 diabetes , 2007, Nature Genetics.

[16]  Mark I McCarthy,et al.  Genomics, type 2 diabetes, and obesity. , 2010, The New England journal of medicine.

[17]  Karen L. Mohlke,et al.  A map of open chromatin in human pancreatic islets , 2010, Nature Genetics.

[18]  M. Taketo,et al.  Stabilization of beta-catenin impacts pancreas growth. , 2006, Development.

[19]  Mark I. McCarthy,et al.  Type 2 diabetes and obesity: genomics and the clinic , 2011, Human Genetics.

[20]  Peter Almgren,et al.  Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. , 2007, The Journal of clinical investigation.

[21]  Hans Clevers,et al.  Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4 , 1998, Nature Genetics.

[22]  M. Loder,et al.  TCF7L2 Regulates Late Events in Insulin Secretion From Pancreatic Islet β-Cells , 2009, Diabetes.

[23]  J. Gulcher,et al.  Localization of a susceptibility gene for type 2 diabetes to chromosome 5q34-q35.2. , 2003, American journal of human genetics.

[24]  D. Melton,et al.  Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. , 2002, Development.

[25]  T. Hansen,et al.  The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men , 2009, Diabetologia.

[26]  J. Holst,et al.  Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms , 2009, Diabetologia.

[27]  K. Polonsky,et al.  TCF7L2 Variant rs7903146 Affects the Risk of Type 2 Diabetes by Modulating Incretin Action , 2009, Diabetes.

[28]  G. Thomas,et al.  The human T-cell transcription factor-4 gene: structure, extensive characterization of alternative splicings, and mutational analysis in colorectal cancer cell lines. , 2000, Cancer research.

[29]  J. Habener,et al.  Glucagon-like Peptide-1 Activation of TCF7L2-dependent Wnt Signaling Enhances Pancreatic Beta Cell Proliferation* , 2008, Journal of Biological Chemistry.

[30]  G. Rutter,et al.  Acute overexpression of lactate dehydrogenase-A perturbs beta-cell mitochondrial metabolism and insulin secretion. , 2000, Diabetes.

[31]  B. Wicksteed,et al.  Conditional Gene Targeting in Mouse Pancreatic β-Cells , 2010, Diabetes.

[32]  G. A. Rutter,et al.  Ablation of AMP-activated protein kinase α1 and α2 from mouse pancreatic beta cells and RIP2.Cre neurons suppresses insulin release in vivo , 2010, Diabetologia.

[33]  Inês Barroso,et al.  TCF7L2 Polymorphisms Modulate Proinsulin Levels and β-Cell Function in a British Europid Population , 2007, Diabetes.

[34]  R. Cox,et al.  Mouse models and the interpretation of human GWAS in type 2 diabetes and obesity , 2011, Disease Models & Mechanisms.

[35]  Ayellet V. Segrè,et al.  Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis , 2010, Nature Genetics.

[36]  L. Groop,et al.  Unique splicing pattern of the TCF7L2 gene in human pancreatic islets , 2009, Diabetologia.

[37]  H. Stefánsson,et al.  Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes , 2006, Nature Genetics.

[38]  James Sharpe,et al.  Tomographic molecular imaging and 3D quantification within adult mouse organs , 2007, Nature Methods.

[39]  H. Edlund,et al.  Attenuated Wnt signaling perturbs pancreatic growth but not pancreatic function. , 2005, Diabetes.

[40]  M. King,et al.  Concordance for Type 2 (non-insulin-dependent) diabetes mellitus in male twins , 1987, Diabetologia.

[41]  D. Drucker,et al.  Mouse pancreatic beta-cells exhibit preserved glucose competence after disruption of the glucagon-like peptide-1 receptor gene. , 1998, Diabetes.

[42]  S. Leach,et al.  Wnt/β-catenin signaling is required for development of the exocrine pancreas , 2007, BMC Developmental Biology.

[43]  B. Wicksteed,et al.  Conditional Gene Targeting in Mouse Pancreatic-Cells Analysis of Ectopic Cre Transgene Expression in the Brain , 2010 .

[44]  H. Keen,et al.  Risk of Diabetes in Offspring of Parents with Non‐insulin‐dependent Diabetes , 1995, Diabetic medicine : a journal of the British Diabetic Association.

[45]  H. Clevers,et al.  Wnt signalling in stem cells and cancer , 2005, Nature.

[46]  G. Rutter,et al.  Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression. , 2003, The Biochemical journal.

[47]  D. Kufe,et al.  MUC1-C Oncoprotein Induces TCF7L2 Transcription Factor Activation and Promotes Cyclin D1 Expression in Human Breast Cancer Cells* , 2012, The Journal of Biological Chemistry.

[48]  N. Wareham,et al.  Genetics of Type 2 diabetes , 2005, Diabetic medicine : a journal of the British Diabetic Association.

[49]  Laura J. Scott,et al.  Tissue-specific alternative splicing of TCF7L2 , 2009, Human molecular genetics.

[50]  A. Joyner,et al.  Glucose intolerance but normal satiety in mice with a null mutation in the glucagon–like peptide 1 receptor gene , 1996, Nature Medicine.

[51]  G. Rutter,et al.  Nucleo-cytosolic Shuttling of FoxO1 Directly Regulates Mouse Ins2 but Not Ins1 Gene Expression in Pancreatic Beta Cells (MIN6)* , 2011, The Journal of Biological Chemistry.

[52]  B. Spencer‐Dene,et al.  The Links between Transcription, β-catenin/JNK Signaling, and Carcinogenesis , 2009, Molecular Cancer Research.

[53]  G. Abecasis,et al.  A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants , 2007, Science.

[54]  S. Grant,et al.  Genotype and Tissue-Specific Effects on Alternative Splicing of the Transcription Factor 7-Like 2 Gene in Humans , 2010 .

[55]  M. Nóbrega,et al.  Alterations in TCF7L2 expression define its role as a key regulator of glucose metabolism. , 2011, Genome research.

[56]  P. Froguel,et al.  TCF7L2 splice variants have distinct effects on beta-cell turnover and function. , 2011, Human molecular genetics.