Pancreatic alpha cell-selective deletion of Tcf7l2 impairs glucagon secretion and counter-regulatory responses to hypoglycaemia in mice

Xavier, Gabriela da Silva; Mondragon, Angeles; Mourougavelou, Vishnou; Cruciani-Guglielmacci, Céline; Denom, Jessica; Herrera, Pedro Luis; Magnan, Christophe; Rutter, Guy A.

doi:10.1007/s00125-017-4242-2

Cited by 18 publications

(17 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Whether impaired Tcf7l2 activity in b-cells is sufficient to drive diabetes progression remains controversial, however (12,17,47,48). Accordingly, Tcf7l2 was suggested to regulate b-cell function in a nonautonomous manner (12,17); for example, pancreatic and nonpancreatic incretin production was recently shown to depend on this transcription factor (49,50). Our findings provide additional evidence for a nonautonomous role of Tcf7l2 in b-cell function through regulation the pericyte/ b-cell axis.…”

Section: Discussionmentioning

confidence: 56%

Pancreatic Pericytes Support β-Cell Function in a Tcf7l2-Dependent Manner

et al. 2017

View full text Add to dashboard Cite

Polymorphism in , a component of the canonical Wnt signaling pathway, has a strong association with β-cell dysfunction and type 2 diabetes through a mechanism that has yet to be defined. β-Cells rely on cells in their microenvironment, including pericytes, for their proper function. Here, we show that Tcf7l2 activity in pancreatic pericytes is required for β-cell function. Transgenic mice in which Tcf7l2 was selectively inactivated in their pancreatic pericytes exhibited impaired glucose tolerance due to compromised β-cell function and glucose-stimulated insulin secretion. Inactivation of pericytic Tcf7l2 was associated with impaired expression of genes required for β-cell function and maturity in isolated islets. In addition, we identified Tcf7l2-dependent pericytic expression of secreted factors shown to promote β-cell function, including bone morphogenetic protein 4 (BMP4). Finally, we show that exogenous BMP4 is sufficient to rescue the impaired glucose-stimulated insulin secretion of transgenic mice, pointing to a potential mechanism through which pericytic Tcf7l2 activity affects β-cells. To conclude, we suggest that pancreatic pericytes produce secreted factors, including BMP4, in a Tcf7l2-dependent manner to support β-cell function. Our findings thus propose a potential cellular mechanism through which abnormal TCF7L2 activity predisposes individuals to diabetes and implicates abnormalities in the islet microenvironment in this disease.

show abstract

Section: Discussionmentioning

confidence: 56%

Pancreatic Pericytes Support β-Cell Function in a Tcf7l2-Dependent Manner

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Importantly, the function of Tcf7l2 in islets is not restricted only to β-cells. In this regard, specific deletion of Tcf7l2 in α-cells reduces glucagon secretion and α-cell mass [70]. Because TCF7L2 is one of the most relevant T2D GWAS gene, a deeper understanding of the tissue-specific functions of this TF in metabolic regulation is further required.…”

Section: Wnt Signaling During β-Cell Maturation Function and Failurementioning

confidence: 99%

Wnt signaling: implications in endoderm development and pancreas organogenesis

Scheibner

Bakhti

Bastidas-Ponce

et al. 2019

Current Opinion in Cell Biology

View full text Add to dashboard Cite

The pancreas is derived from the foregut endoderm during embryonic development. After gastrulation and endoderm germ layer formation complex morphogenetic events coupled with cell differentiation programs pattern the gut tube and induce pancreas organogenesis. This results in formation of exocrine, ductal and hormone-producing endocrine cells responsible for blood glucose homeostasis. The malfunction of the endocrine pancreas leads to diabetes mellitus, which cannot be stopped or reversed by the current standard treatments. Thus, intense efforts to regenerate or replace the lost or dysfunctional insulin-producing β-cells are on the way. This depends on identifying the factors that coordinate pancreas organogenesis. Here, we highlight the contribution of canonical and non-canonical Wnt signaling branches in orchestrating endoderm formation, pancreatic morphogenesis as well as endocrine cell formation and function.

show abstract

“…In vivo glucose-stimulated insulin secretion in aTCF7L2hom male mice was impaired by exposure to an HFD (Fig. 5h), a finding reminiscent of the impact of this regimen on TCF7L2 deletion-induced impairments in insulin secretion [2,3,41]. Surprisingly, however, high-fat feeding had only minor effects on the impact on glucose tolerance.…”

Section: Discussionmentioning

confidence: 81%

Adipocyte-specific deletion of Tcf7l2 induces dysregulated lipid metabolism and impairs glucose tolerance in mice

et al. 2020

Self Cite

View full text Add to dashboard Cite

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 < 0.0001, respectively). Circulating levels of plasma NEFA and fatty acid binding protein 4 were increased by 1.3 ± 0.1-fold and 1.8 ± 0.3-fold vs control mice (p = 0.03 and p = 0.05, respectively). Following exposure to a high-fat diet for 12 weeks, male aTCF7L2hom mice exhibited reduced in vivo glucose-stimulated insulin secretion (0.5 ± 0.1-fold vs control mice, p = 0.02). Conclusions/interpretation Loss of Tcf7l2 gene expression selectively in adipocytes leads to a sexually dimorphic phenotype, with impairments not only in adipocytes, but also in pancreatic islet and enteroendocrine cells in male mice only. Our findings suggest novel roles for adipokines and incretins in the effects of diabetes-associated variants in TCF7L2, and further illuminate the roles of TCF7L2 in glucose homeostasis and diabetes risk.

show abstract

Pancreatic alpha cell-selective deletion of Tcf7l2 impairs glucagon secretion and counter-regulatory responses to hypoglycaemia in mice

Cited by 18 publications

References 49 publications

Pancreatic Pericytes Support β-Cell Function in a Tcf7l2-Dependent Manner

Pancreatic Pericytes Support β-Cell Function in a Tcf7l2-Dependent Manner

Wnt signaling: implications in endoderm development and pancreas organogenesis

Adipocyte-specific deletion of Tcf7l2 induces dysregulated lipid metabolism and impairs glucose tolerance in mice

Contact Info

Product

Resources

About