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Guy A Rutter - One of the best experts on this subject based on the ideXlab platform.
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Adipocyte-specific deletion of TCF7L2 induces dysregulated lipid metabolism and impairs glucose tolerance in mice
Diabetologia, 2020Co-Authors: Marie-sophie Nguyen-tu, Guy A Rutter, Aida Martinez-sanchez, Isabelle Leclerc, Gabriela Da Silva XavierAbstract:Aims/hypothesis Transcription factor 7-like 2 (TCF7L2) is a downstream effector of the Wnt/β-catenin signalling pathway implicated in type 2 diabetes risk through genome-wide association studies. Although its expression is critical for adipocyte development, the potential roles of changes in adipose tissue TCF7L2 levels in diabetes risk are poorly defined. Here, we investigated whether forced changes in TCF7L2 expression in adipocytes affect whole body glucose or lipid metabolism and crosstalk between disease-relevant tissues. Methods TCF7L2 was selectively ablated in mature adipocytes in C57BL/6J mice using Cre recombinase under Adipoq promoter control to recombine TCF7L2 alleles floxed at exon 1 (referred to as aTCF7L2 mice). aTCF7L2 mice were fed normal chow or a high-fat diet for 12 weeks. Glucose and insulin sensitivity, as well as beta cell function, were assessed in vivo and in vitro. Levels of circulating NEFA, selected hormones and adipokines were measured using standard assays. Results Reduced TCF7L2 expression in adipocytes altered glucose tolerance and insulin secretion in male but not in female mice. Thus, on a normal chow diet, male heterozygote knockout mice (aTCF7L2het) exhibited impaired glucose tolerance at 16 weeks ( p = 0.03) and increased fat mass (1.4 ± 0.1-fold, p = 0.007) but no changes in insulin secretion. In contrast, male homozygote knockout (aTCF7L2hom) mice displayed normal body weight but impaired oral glucose tolerance at 16 weeks ( p = 0.0001). These changes were mechanistically associated with impaired in vitro glucose-stimulated insulin secretion (decreased 0.5 ± 0.1-fold vs control mice, p = 0.02) and decreased levels of the incretins glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (0.6 ± 0.1-fold and 0.4 ± 0.1-fold vs control mice, p = 0.04 and p
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transcription factor 7 like 2 TCF7L2 gene acts downstream of the lkb1 stk11 kinase to control mtor signaling β cell growth and insulin secretion
Journal of Biological Chemistry, 2018Co-Authors: Mariesophie Nguyentu, Isabelle Leclerc, Gabriela Da Silva Xavier, Guy A RutterAbstract:Variants in the transcription factor-7-like 2 (TCF7L2/TCF4) gene, involved in Wnt signaling, are associated with type 2 diabetes. Loss of TCF7L2 selectively from the β cell in mice has previously been shown to cause glucose intolerance and to lower β cell mass. Deletion of the tumor suppressor liver kinase B1 (LKB1/STK11) leads to β cell hyperplasia and enhanced glucose-stimulated insulin secretion, providing a convenient genetic model for increased β cell growth and function. The aim of this study was to explore the possibility that TCF7L2 may be required for the effects of Lkb1 deletion on insulin secretion in the mouse β cell. Mice bearing floxed Lkb1 and/or TCF7L2 alleles were bred with knockin mice bearing Cre recombinase inserted at the Ins1 locus (Ins1Cre), allowing highly β cell-selective deletion of either or both genes. Oral glucose tolerance was unchanged by the further deletion of a single TCF7L2 allele in these cells. By contrast, mice lacking both TCF7L2 alleles on this background showed improved oral glucose tolerance and insulin secretion in vivo and in vitro compared with mice lacking a single TCF7L2 allele. Biallelic TCF7L2 deletion also enhanced β cell proliferation, increased β cell mass, and caused changes in polarity as revealed by the "rosette-like" arrangement of β cells. TCF7L2 deletion also increased signaling by mammalian target of rapamycin (mTOR), augmenting phospho-ribosomal S6 levels. We identified a novel signaling mechanism through which a modifier gene, TCF7L2, lies on a pathway through which LKB1 acts in the β cell to restrict insulin secretion.
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Pancreatic alpha cell-selective deletion of TCF7L2 impairs glucagon secretion and counter-regulatory responses to hypoglycaemia in mice.
Diabetologia, 2017Co-Authors: Gabriela Da Silva Xavier, V Mourougavelou, C Cruciani-guglielmacci, J Denom, C Magnan, Angeles Mondragon, Pedro Luis Herrera, Guy A RutterAbstract:Aims/hypothesis Transcription factor 7-like 2 (TCF7L2) is a high mobility group (HMG) box-containing transcription factor and downstream effector of the Wnt signalling pathway. SNPs in the TCF7L2 gene have previously been associated with an increased risk of type 2 diabetes in genome-wide association studies. In animal studies, loss of TCF7L2 function is associated with defective islet beta cell function and survival. Here, we explore the role of TCF7L2 in the control of the counter-regulatory response to hypoglycaemia by generating mice with selective deletion of the TCF7L2 gene in pancreatic alpha cells.
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selective disruption of TCF7L2 in the pancreatic β cell impairs secretory function and lowers β cell mass
Human Molecular Genetics, 2015Co-Authors: Ryan K Mitchell, Angeles Mondragon, Lingling Chen, James Mcginty, P M W French, Jorge Ferrer, Bernard Thorens, David J Hodson, Guy A Rutter, Gabriela Da Silva XavierAbstract: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.
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abnormal glucose tolerance and insulin secretion in pancreas specific TCF7L2 null mice
Diabetologia, 2012Co-Authors: G Da Silva Xavier, Angeles Mondragon, Lingling Chen, James Mcginty, P M W French, Gao Sun, Guy A RutterAbstract:Aims/hypothesis Individuals 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.
Kathrin Maedler - One of the best experts on this subject based on the ideXlab platform.
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TCF7L2 promotes beta cell regeneration in human and mouse pancreas.
Diabetologia, 2012Co-Authors: Luan Shu, Jose Oberholzer, K. S. Zien, G. Gutjahr, François Pattou, Julie Kerr-conte, Kathrin MaedlerAbstract:Diabetes is characterised by loss and dysfunction of the beta cell. A major goal of diabetes therapy is to promote the formation of new beta cells. Polymorphisms of T cell factor 7-like 2 (TCF7L2) are associated with type 2 diabetes, negatively regulating beta cell survival and function. Here, we provide evidence for a role of TCF7L2 in beta cell proliferation and regeneration. Pancreatic sections from three mouse models (high-fat diet, exendin-4 and streptozotocin-treated mice) and from healthy individuals and patients with type 2 diabetes were used to investigate the association of beta cell regeneration and TCF7L2 levels. To analyse a direct effect of TCF7L2 on duct cell to beta cell conversion, TCF7L2 was overexpressed in isolated exocrine cells. TCF7L2 levels correlated with beta cell compensation during high-fat diet feeding. TCF7L2 was increased together with pancreatic duct cell proliferation and differentiation. Small islet-like cell clusters (ICCs) that contained TCF7L2 originated in the vicinity of the ductal epithelium. In human isolated exocrine tissue, TCF7L2 overexpression induced proliferation of pancreatic duct cells and ICC formation next to duct cells, an effect dependent on the JAK2/STAT3 pathway. The present study demonstrates that TCF7L2 overexpression fosters beta cell regeneration. Our findings imply correlation of TCF7L2 levels and new beta cell formation.
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TCF7L2 splice variants have distinct effects on β-cell turnover and function
Human molecular genetics, 2011Co-Authors: Olivier Le Bacquer, Luan Shu, François Pattou, Marion Marchand, Bernadette Neve, Federico Paroni, Julie Kerr Conte, Philippe Froguel, Kathrin MaedlerAbstract:Type 2 diabetes manifests when the β-cell fails to secrete sufficient amounts of insulin to maintain normoglycemia and undergoes apoptosis. The disease progression results from an interplay of environmental factors and genetic predisposition. Polymorphisms in T-cell factor 7-like 2 (TCF7L2) strongly correlate with type 2 diabetes mellitus (T2DM). While TCF7L2 mRNA is upregulated in islets in diabetes, protein levels are downregulated. The loss of TCF7L2 induces impaired function and apoptosis. By analyzing human isolated islets, we provide three explanations for this opposite regulation and the mechanisms of TCF7L2 on β-cell function and survival. (i) We found TCF7L2 transcripts in the human β-cell, which had opposite effects on β-cell survival, function and Wnt signaling activation. While TCF7L2 clone B1, which lacks exons 13, 14, 15 and 16 induced β-cell apoptosis, impaired function and inhibited glucagon-like peptide 1 response and downstream targets of Wnt signaling, clones B3 and B7 which both contain exon 13, improved β-cell survival and function and activated Wnt signaling. (ii) TCF7L2 mRNA is extremely unstable and is rapidly degraded under pro-diabetic conditions and (iii) TCF7L2 depletion in islets induced activation of glycogen synthase kinase 3-β, but this was independent of endoplasmic reticulum stress. We demonstrated function-specific transcripts of TCF7L2, which possessed distinct physiological and pathophysiological effects on the β-cell. The presence of deleterious TCF7L2 splice variants may be a mechanism of β-cell failure in T2DM.
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decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of gip and glp 1 receptors and impaired beta cell function
Human Molecular Genetics, 2009Co-Authors: Luan Shu, Aleksey V Matveyenko, Kathrin Maedler, Julie Kerrconte, Jae Hyoung Cho, Christopher H S McintoshAbstract:Recent human genetics studies have revealed that common variants of the TCF7L2 (T-cell factor 7-like 2, formerly known as TCF4) gene are strongly associated with type 2 diabetes mellitus (T2DM). We have shown that TCF7L2 expression in the beta-cells is correlated with function and survival of the insulin-producing pancreatic beta-cell. In order to understand how variations in TCF7L2 influence diabetes progression, we investigated its mechanism of action in the beta-cell. We show robust differences in TCF7L2 expression between healthy controls and models of T2DM. While mRNA levels were approximately 2-fold increased in isolated islets from the diabetic db/db mouse, the Vancouver Diabetic Fatty (VDF) Zucker rat and the high fat/high sucrose diet-treated mouse compared with the non-diabetic controls, protein levels were decreased. A similar decrease was observed in pancreatic sections from patients with T2DM. In parallel, expression of the receptors for glucagon-like peptide 1 (GLP-1R) and glucose-dependent insulinotropic polypeptide (GIP-R) was decreased in islets from humans with T2DM as well as in isolated human islets treated with siRNA to TCF7L2 (siTCF7L2). Also, insulin secretion stimulated by glucose, GLP-1 and GIP, but not KCl or cyclic adenosine monophosphate (cAMP) was impaired in siTCF7L2-treated isolated human islets. Loss of TCF7L2 resulted in decreased GLP-1 and GIP-stimulated AKT phosphorylation, and AKT-mediated Foxo-1 phosphorylation and nuclear exclusion. Our findings suggest that beta-cell function and survival are regulated through an interplay between TCF7L2 and GLP-1R/GIP-R expression and signaling in T2DM.
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transcription factor 7 like 2 regulates β cell survival and function in human pancreatic islets
Diabetes, 2008Co-Authors: Nadine S Sauter, Fabienne T Schulthess, Aleksey V Matveyenko, Jose Oberholzer, Kathrin MaedlerAbstract:OBJECTIVE —Type 2 diabetes is characterized by impaired insulin secretion in response to increased metabolic demand. This defect in β-cell compensation seems to result from the interplay between environmental factors and genetic predisposition. Genome-wide association studies reveal that common variants in transcription factor 7-like 2 (TCF7L2) are associated with increased risk of type 2 diabetes. The aim of the present study was to establish whether TCF7L2 plays a role in β-cell function and/or survival. RESEARCH DESIGN AND METHODS —To investigate the effects of TCFL7L2 depletion, isolated islets were exposed to TCF7L2 small interfering RNA (siRNA) versus scrambled siRNA, and β-cell survival and function were examined. For TCF7L2 overexpression, islets were cultured in glucose concentrations of 5.5–33.3 mmol/l and the cytokine mix interleukin-1β/γ-interferon with or without overexpression of TCF7L2. Subsequently, glucose-stimulated insulin secretion (GSIS), β-cell apoptosis [by transferase-mediated dUTP nick-end labeling assay and Western blotting for poly(ADP-ribose) polymerase and Caspase-3 cleavage], and β-cell proliferation (by Ki67 immunostaining) were analyzed. RESULTS —Depleting TCF7L2 by siRNA resulted in a 5.1-fold increase in β-cell apoptosis, 2.2-fold decrease in β-cell proliferation ( P P CONCLUSIONS —TCF7L2 is required for maintaining GSIS and β-cell survival. Changes in the level of active TCF7L2 in β-cells from carriers of at-risk allele may be the reason for defective insulin secretion and progression of type 2 diabetes.
Gabriela Da Silva Xavier - One of the best experts on this subject based on the ideXlab platform.
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Adipocyte-specific deletion of TCF7L2 induces dysregulated lipid metabolism and impairs glucose tolerance in mice
Diabetologia, 2020Co-Authors: Marie-sophie Nguyen-tu, Guy A Rutter, Aida Martinez-sanchez, Isabelle Leclerc, Gabriela Da Silva XavierAbstract:Aims/hypothesis Transcription factor 7-like 2 (TCF7L2) is a downstream effector of the Wnt/β-catenin signalling pathway implicated in type 2 diabetes risk through genome-wide association studies. Although its expression is critical for adipocyte development, the potential roles of changes in adipose tissue TCF7L2 levels in diabetes risk are poorly defined. Here, we investigated whether forced changes in TCF7L2 expression in adipocytes affect whole body glucose or lipid metabolism and crosstalk between disease-relevant tissues. Methods TCF7L2 was selectively ablated in mature adipocytes in C57BL/6J mice using Cre recombinase under Adipoq promoter control to recombine TCF7L2 alleles floxed at exon 1 (referred to as aTCF7L2 mice). aTCF7L2 mice were fed normal chow or a high-fat diet for 12 weeks. Glucose and insulin sensitivity, as well as beta cell function, were assessed in vivo and in vitro. Levels of circulating NEFA, selected hormones and adipokines were measured using standard assays. Results Reduced TCF7L2 expression in adipocytes altered glucose tolerance and insulin secretion in male but not in female mice. Thus, on a normal chow diet, male heterozygote knockout mice (aTCF7L2het) exhibited impaired glucose tolerance at 16 weeks ( p = 0.03) and increased fat mass (1.4 ± 0.1-fold, p = 0.007) but no changes in insulin secretion. In contrast, male homozygote knockout (aTCF7L2hom) mice displayed normal body weight but impaired oral glucose tolerance at 16 weeks ( p = 0.0001). These changes were mechanistically associated with impaired in vitro glucose-stimulated insulin secretion (decreased 0.5 ± 0.1-fold vs control mice, p = 0.02) and decreased levels of the incretins glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (0.6 ± 0.1-fold and 0.4 ± 0.1-fold vs control mice, p = 0.04 and p
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transcription factor 7 like 2 TCF7L2 gene acts downstream of the lkb1 stk11 kinase to control mtor signaling β cell growth and insulin secretion
Journal of Biological Chemistry, 2018Co-Authors: Mariesophie Nguyentu, Isabelle Leclerc, Gabriela Da Silva Xavier, Guy A RutterAbstract:Variants in the transcription factor-7-like 2 (TCF7L2/TCF4) gene, involved in Wnt signaling, are associated with type 2 diabetes. Loss of TCF7L2 selectively from the β cell in mice has previously been shown to cause glucose intolerance and to lower β cell mass. Deletion of the tumor suppressor liver kinase B1 (LKB1/STK11) leads to β cell hyperplasia and enhanced glucose-stimulated insulin secretion, providing a convenient genetic model for increased β cell growth and function. The aim of this study was to explore the possibility that TCF7L2 may be required for the effects of Lkb1 deletion on insulin secretion in the mouse β cell. Mice bearing floxed Lkb1 and/or TCF7L2 alleles were bred with knockin mice bearing Cre recombinase inserted at the Ins1 locus (Ins1Cre), allowing highly β cell-selective deletion of either or both genes. Oral glucose tolerance was unchanged by the further deletion of a single TCF7L2 allele in these cells. By contrast, mice lacking both TCF7L2 alleles on this background showed improved oral glucose tolerance and insulin secretion in vivo and in vitro compared with mice lacking a single TCF7L2 allele. Biallelic TCF7L2 deletion also enhanced β cell proliferation, increased β cell mass, and caused changes in polarity as revealed by the "rosette-like" arrangement of β cells. TCF7L2 deletion also increased signaling by mammalian target of rapamycin (mTOR), augmenting phospho-ribosomal S6 levels. We identified a novel signaling mechanism through which a modifier gene, TCF7L2, lies on a pathway through which LKB1 acts in the β cell to restrict insulin secretion.
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Pancreatic alpha cell-selective deletion of TCF7L2 impairs glucagon secretion and counter-regulatory responses to hypoglycaemia in mice.
Diabetologia, 2017Co-Authors: Gabriela Da Silva Xavier, V Mourougavelou, C Cruciani-guglielmacci, J Denom, C Magnan, Angeles Mondragon, Pedro Luis Herrera, Guy A RutterAbstract:Aims/hypothesis Transcription factor 7-like 2 (TCF7L2) is a high mobility group (HMG) box-containing transcription factor and downstream effector of the Wnt signalling pathway. SNPs in the TCF7L2 gene have previously been associated with an increased risk of type 2 diabetes in genome-wide association studies. In animal studies, loss of TCF7L2 function is associated with defective islet beta cell function and survival. Here, we explore the role of TCF7L2 in the control of the counter-regulatory response to hypoglycaemia by generating mice with selective deletion of the TCF7L2 gene in pancreatic alpha cells.
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selective disruption of TCF7L2 in the pancreatic β cell impairs secretory function and lowers β cell mass
Human Molecular Genetics, 2015Co-Authors: Ryan K Mitchell, Angeles Mondragon, Lingling Chen, James Mcginty, P M W French, Jorge Ferrer, Bernard Thorens, David J Hodson, Guy A Rutter, Gabriela Da Silva XavierAbstract: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.
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TCF7L2 regulates late events in insulin secretion from pancreatic islet β cells
Diabetes, 2009Co-Authors: Gabriela Da Silva Xavier, Merewyn K Loder, Angela Mcdonald, Andrei I Tarasov, Raffaella Carzaniga, Katrin Kronenberger, Sebastian Barg, Guy A RutterAbstract:Abstract Objective: Polymorphisms in the human TCF7L2 gene are associated with reduced insulin secretion and an increased risk of type 2 diabetes. However, the mechanisms by which TCF7L2 affects insulin secretion are still unclear. Here we define the effects of TCF7L2 expression level on mature β-cell function and suggest a potential mechanism for its actions. Research Design and Methods: TCF7L2 expression in rodent islets and β-cell lines was altered using RNAi or adenoviral transduction. β-cell gene profiles were measured by quantitative real-time PCR and the effects on intracellular signalling and exocytosis by live cell imaging, electron microscopy and patch clamp electrophysiology. Results: Reducing TCF7L2 expression levels by RNAi decreased glucose-, but not KCl-induced, insulin secretion. The glucose-induced increments in both ATP/ADP ratio and cytosolic free Ca 2+ concentration ([Ca 2+ ] i ) were increased compared to controls. Over-expression of TCF7L2 exerted minor inhibitory effects on glucose-regulated changes in [Ca 2+ ] i and insulin release. Gene expression profiling in TCF7L2-silenced cells revealed increased levels of mRNA encoding syntaxin 1A, but decreased Munc18-1 and ZnT8 mRNA. Whereas the number of morphologically-docked vesicles was unchanged by TCF7L2 suppression, secretory granule movement increased and capacitance changes decreased, indicative of defective vesicle fusion. Conclusion: TCF7L2 is involved in maintaining expression of β-cell genes regulating secretory granule fusion. Defective insulin exocytosis may thus underlie increased diabetes incidence in carriers of the at risk TCF7L2 allelles.
Tianru Jin - One of the best experts on this subject based on the ideXlab platform.
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curcumin represses mouse 3t3 l1 cell adipogenic differentiation via inhibiting mir 17 5p and stimulating the wnt signalling pathway effector TCF7L2
Cell Death and Disease, 2018Co-Authors: Weijuan Shao, Lili Tian, Zhuolun Song, Lisa R Zhao, Kejing Zeng, Burton B Yang, Tianru JinAbstract:Understanding mechanisms underlying adipogenic differentiation may lead to the discovery of novel therapeutic targets for obesity. Wnt signalling pathway activation leads to repressed adipogenic differentiation while certain microRNAs may regulate pre-adipocyte proliferation and differentiation. We show here that in mouse white adipose tissue, miR-17-5p level is elevated after high fat diet consumption. miR-17-5p upregulates adipogenic differentiation, as its over-expression increased while its inhibition repressed 3T3-L1 differentiation. The TCF7L2 gene encodes a key Wnt signalling pathway effector, and its human homologue TCF7L2 is a highly regarded diabetes risk gene. We found that TCF7L2 is an miR-17-5p target and confirmed the repressive effect of TCF7L2 on 3T3-L1 adipogenic differentiation. The natural plant polyphenol compound curcumin possesses the body weight lowering effect. We observed that curcumin attenuated miR-17-5p expression and stimulated TCF7L2 expression in 3T3-L1 cells. These, along with the elevation of miR-17-5p expression in mouse epididymal fat tissue in response to high fat diet consumption, allowed us to suggest that miR-17-5p is among central switches of adipogenic differentiation. It activates adipogenesis via repressing the Wnt signalling pathway effector TCF7L2, and its own expression is likely nutritionally regulated in health and disease.
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The Wnt signaling pathway effector TCF7L2 is upregulated by insulin and represses hepatic gluconeogenesis
American Journal of Physiology-Heart and Circulatory Physiology, 2012Co-Authors: Weijuan Shao, Yu-ting Alex Chiang, Tianru JinAbstract:Certain single nucleotide polymorphisms (SNPs) in transcription factor 7-like 2 (TCF7L2) are strongly associated with the risk of type 2 diabetes. TCF7L2 and β-catenin (β-cat) form the bipartite transcription factor cat/TCF in stimulating Wnt target gene expression. cat/TCF may also mediate the effect of other signaling cascades, including that of cAMP and insulin in cell-type specific manners. As carriers of TCF7L2 type 2 diabetes risk SNPs demonstrated increased hepatic glucose production, we aimed to determine whether TCF7L2 expression is regulated by nutrient availability and whether TCF7L2 and Wnt regulate hepatic gluconeogenesis. We examined hepatic Wnt activity in the TOPGAL transgenic mouse, assessed hepatic TCF7L2 expression in mice upon feeding, determined the effect of insulin on TCF7L2 expression and β-cat Ser675 phosphorylation, and investigated the effect of Wnt activation and TCF7L2 knockdown on gluconeogenic gene expression and glucose production in hepatocytes. Wnt activity was observed in pericentral hepatocytes in the TOPGAL mouse, whereas TCF7L2 expression was detected in human and mouse hepatocytes. Insulin and feeding stimulated hepatic TCF7L2 expression in vitro and in vivo, respectively. In addition, insulin activated β-cat Ser675 phosphorylation. Wnt activation by intraperitoneal lithium injection repressed hepatic gluconeogenic gene expression in vivo, whereas lithium or Wnt-3a reduced gluconeogenic gene expression and glucose production in hepatic cells in vitro. Small interfering RNA-mediated TCF7L2 knockdown increased glucose production and gluconeogenic gene expression in cultured hepatocytes. These observations suggest that Wnt signaling and TCF7L2 are negative regulators of hepatic gluconeogenesis, and TCF7L2 is among the downstream effectors of insulin in hepatocytes.
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minireview the wnt signaling pathway effector TCF7L2 and type 2 diabetes mellitus
Molecular Endocrinology, 2008Co-Authors: Tianru Jin, Ling LiuAbstract:Since the relationship between TCF7L2 (also known as TCF-4) polymorphisms and type 2 diabetes mellitus was identified in 2006, extensive genome-wide association examinations in different ethnic groups have further confirmed this relationship. As a component of the bipartite transcription factor β-catenin/TCF, TCF7L2 is important in conveying Wnt signaling during embryonic development and in regulating gene expression during adulthood. Although we still do not know mechanistically how the polymorphisms within the intron regions of TCF7L2 affect the risk of type 2 diabetes, this transcriptional regulator was shown to be involved in stimulating the proliferation of pancreatic β-cells and the production of the incretin hormone glucagon-like peptide-1 in intestinal endocrine L cells. In this review, we introduce background knowledge of TCF7L2 as a component of the Wnt signaling pathway, summarize recent findings demonstrating the association between TCF7L2 polymorphisms and the risk of type 2 diabetes, outline...
François Pattou - One of the best experts on this subject based on the ideXlab platform.
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alternative human liver transcripts of TCF7L2 bind to the gluconeogenesis regulator hnf4α at the protein level
Diabetologia, 2014Co-Authors: Bernadette Neve, François Pattou, Olivier Le Bacquer, Sandrine Caron, Marlene Huyvaert, Audrey Leloire, Odile Poulaingodefroy, Cecile LecoeurAbstract:Aims/hypothesis Gene polymorphisms of TCF7L2 are associated with increased risk of type 2 diabetes and transcription factor 7-like 2 (TCF7L2) plays a role in hepatic glucose metabolism. We therefore addressed the impact of TCF7L2 isoforms on hepatocyte nuclear factor 4α (HNF4α) and the regulation of gluconeogenesis genes.
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TCF7L2 promotes beta cell regeneration in human and mouse pancreas.
Diabetologia, 2012Co-Authors: Luan Shu, Jose Oberholzer, K. S. Zien, G. Gutjahr, François Pattou, Julie Kerr-conte, Kathrin MaedlerAbstract:Diabetes is characterised by loss and dysfunction of the beta cell. A major goal of diabetes therapy is to promote the formation of new beta cells. Polymorphisms of T cell factor 7-like 2 (TCF7L2) are associated with type 2 diabetes, negatively regulating beta cell survival and function. Here, we provide evidence for a role of TCF7L2 in beta cell proliferation and regeneration. Pancreatic sections from three mouse models (high-fat diet, exendin-4 and streptozotocin-treated mice) and from healthy individuals and patients with type 2 diabetes were used to investigate the association of beta cell regeneration and TCF7L2 levels. To analyse a direct effect of TCF7L2 on duct cell to beta cell conversion, TCF7L2 was overexpressed in isolated exocrine cells. TCF7L2 levels correlated with beta cell compensation during high-fat diet feeding. TCF7L2 was increased together with pancreatic duct cell proliferation and differentiation. Small islet-like cell clusters (ICCs) that contained TCF7L2 originated in the vicinity of the ductal epithelium. In human isolated exocrine tissue, TCF7L2 overexpression induced proliferation of pancreatic duct cells and ICC formation next to duct cells, an effect dependent on the JAK2/STAT3 pathway. The present study demonstrates that TCF7L2 overexpression fosters beta cell regeneration. Our findings imply correlation of TCF7L2 levels and new beta cell formation.
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TCF7L2 rs7903146 impairs islet function and morphology in non-diabetic individuals.
Diabetologia, 2012Co-Authors: O Le Bacquer, Julie Kerr-conte, Bernadette Neve, Philippe Froguel, Marlene Huyvaert, Sofia Gargani, N. Delalleau, Valery Gmyr, François PattouAbstract:Aims/hypothesis Transcription factor 7-like 2 (TCF7L2) is a Wnt-signalling-associated transcription factor. Genetic studies have clearly demonstrated that DNA polymorphisms within TCF7L2 confer the strongest known association with increased risk of type 2 diabetes. However, the impact of the TCF7L2 type-2-diabetes-associated rs7903146 T allele on biological function and morphology of human pancreatic islets is unknown.
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TCF7L2 splice variants have distinct effects on β-cell turnover and function
Human molecular genetics, 2011Co-Authors: Olivier Le Bacquer, Luan Shu, François Pattou, Marion Marchand, Bernadette Neve, Federico Paroni, Julie Kerr Conte, Philippe Froguel, Kathrin MaedlerAbstract:Type 2 diabetes manifests when the β-cell fails to secrete sufficient amounts of insulin to maintain normoglycemia and undergoes apoptosis. The disease progression results from an interplay of environmental factors and genetic predisposition. Polymorphisms in T-cell factor 7-like 2 (TCF7L2) strongly correlate with type 2 diabetes mellitus (T2DM). While TCF7L2 mRNA is upregulated in islets in diabetes, protein levels are downregulated. The loss of TCF7L2 induces impaired function and apoptosis. By analyzing human isolated islets, we provide three explanations for this opposite regulation and the mechanisms of TCF7L2 on β-cell function and survival. (i) We found TCF7L2 transcripts in the human β-cell, which had opposite effects on β-cell survival, function and Wnt signaling activation. While TCF7L2 clone B1, which lacks exons 13, 14, 15 and 16 induced β-cell apoptosis, impaired function and inhibited glucagon-like peptide 1 response and downstream targets of Wnt signaling, clones B3 and B7 which both contain exon 13, improved β-cell survival and function and activated Wnt signaling. (ii) TCF7L2 mRNA is extremely unstable and is rapidly degraded under pro-diabetic conditions and (iii) TCF7L2 depletion in islets induced activation of glycogen synthase kinase 3-β, but this was independent of endoplasmic reticulum stress. We demonstrated function-specific transcripts of TCF7L2, which possessed distinct physiological and pathophysiological effects on the β-cell. The presence of deleterious TCF7L2 splice variants may be a mechanism of β-cell failure in T2DM.
