Glucagon-like Peptide-1 Activation of TCF7L2-dependent Wnt Signaling Enhances Pancreatic Beta Cell Proliferation

Liu, Zhengyu; Habener, Joel F.

doi:10.1074/jbc.m706105200

Cited by 285 publications

(275 citation statements)

References 95 publications

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“…The proglucagon gene is transcriptionally regulated by TCF7L2 and proglucagon is processed to GLP-1 in the L-cells of the intestines. Besides its insulinotropic effect, recent studies have shown that GLP-1 induces Wnt signalling in the beta cell and that WNT signalling appears to mediate GLP-1-induced beta cell proliferation [30]. Two studies have already provided evidence of an incretin-mediated insulin secretion defect in carriers of the risk allele [11,12].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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Aims/hypothesis We studied the physiological, metabolic and hormonal mechanisms underlying the elevated risk of type 2 diabetes in carriers of TCF7L2 gene. Methods We undertook genotyping of 81 healthy young Danish men for rs7903146 of TCF7L2 and carried out various beta cell tests including: 24 h glucose, insulin and glucagon profiles; OGTT; mixed meal test; IVGTT; hyperglycaemic clamp with co-infusion of glucagon-like peptide (GLP)-1 or glucose-dependent insulinotropic polypeptide (GIP); and a euglycaemic-hyperinsulinaemic clamp combined with glucose tracer infusion to study hepatic and peripheral insulin action. Results Carriers of the T allele were characterised by reduced 24 h insulin concentrations (p<0.05) and reduced insulin secretion relative to glucose during a mixed meal test (beta index: p<0.003), but not during an IVGTT. This was further supported by reduced late-phase insulinotropic action of GLP-1 (p=0.03) and GIP (p=0.07) during a 7 mmol/l hyperglycaemic clamp. Secretion of GLP-1 and GIP during the mixed meal test was normal. Despite elevated hepatic glucose production, carriers of the T allele Diabetologia (2009) 52:1298-1307 DOI 10.1007/s00125-009-1307-x Electronic supplementary

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Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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“…Taurin et al (2006) suggested that the Ser675 residue enhances TCF/ LEF transactivation by promoting the binding of b-cat to its transcriptional coactivator, the CREB (cAMP (cyclic adenosine monophosphate) response element binding-binding protein), CBP. Recently, Liu and Habener, (2008) reported that b-cat phosphorylation at Ser675 in pancreatic b cells can be activated by the incretin hormone glucagon-like peptide-1. To our knowledge, b-cat phosphorylation at Ser675 in response to insulin or IGF-1 has not been previously documented.…”

Section: Discussionmentioning

confidence: 99%

P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine

et al. 2009

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Hyperinsulinemia and type II diabetes are associated with an increased risk of developing colorectal tumors. We found previously that in intestinal cells, insulin or insulinlike growth factor-1 stimulates c-Myc and cyclin D1 protein expression through both Akt-dependent and Aktindependent mechanisms. The effect of Akt is attributed to the stimulation of c-Myc translation by mammalian target of rapamycin. However, Akt-independent stimulation was, associated with an increase in b-catenin (b-cat) in the nucleus and an increased association between b-cat and T-cell factor binding sites on the c-Myc promoter, detected by chromatin immunoprecipitation. In this study, we show that insulin stimulated the phosphorylation/ activation of p-21-activated protein kinase-1 (PAK-1) in an Akt-independent manner in vitro and in an in vivo hyperinsulinemic mouse model. Significantly, shRNA (small hairpin RNA)-mediated PAK-1 knockdown attenuated both basal and insulin-stimulated c-Myc and cyclin D1 expression, associated with a marked reduction in extracellular signal-regulated kinase activation and b-cat phosphorylation at Ser675. Furthermore, PAK-1 silencing led to a complete blockade of insulin-stimulated b-cat binding to the c-Myc promoter and cellular growth. Finally, inhibition of MEK, a downstream target of PAK-1, blocked insulin-stimulated nuclear b-cat accumulation and c-Myc expression. Our observations suggest that PAK-1 serves as an important linker between insulin and Wnt signaling pathways.

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“…There is strong evidence that the Wnt signalling pathway regulates prenatal and postnatal beta cell development in mice as well as glucose sensing in pancreatic beta cells [27,28]. Also, the activation of Wnt signalling in beta cell lines or in isolated islets has been shown to enhance beta cell proliferation [10,[29][30][31]. Thus, increased β-catenin levels in islets caused an expansion of beta cell mass, whereas the depletion of TCF7L2 reduced proliferation in human islets [10,30].…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Sfrp5 promotes beta cell proliferation during obesity in the rat

et al. 2013

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Aims/hypothesis During obesity, the increment in beta cell mass in response to the rising demand for insulin is essential to maintain normal glucose homeostasis. However, the precise cellular and molecular mechanisms involved in beta cell mass plasticity remain poorly understood. The Wnt signalling pathway has been suggested as one possible modulator of beta cell proliferation, which represents the principal process involved in beta cell mass expansion. Here, we sought to determine the mechanisms involved in beta cell mass proliferation using diet-induced obese rats. Methods Wistar rats aged 8 weeks old were fed a standard or cafeteria diet. Global transcriptomic analysis of pancreatic rat islets was performed using microarray analysis. Genetic lossof-function approaches were performed in dispersed primary rat islets and the beta cell line INS1E. Gene expression was measured by real-time PCR, protein levels by immunoblot analysis, proliferation rates by ELISA and apoptosis by flow cytometry. Results Sfrp5, coding for secreted frizzled-related protein 5, is downregulated in the pancreatic islets of cafeteria-diet-fed rats as well as in the pancreatic islets of human obese patients. We demonstrate that silencing Sfrp5 increases beta cell proliferation, which correlates with activation of Wnt signalling and enhanced levels of proliferation markers. In addition, we show that expression of Sfrp5 in beta cells is modulated by IGF binding protein 3 (IGFBP3) secreted from visceral adipose tissue. Conclusions/interpretation Together, these findings reveal an important role for SFRP5 and Wnt signalling in the regulation of beta cell proliferation in obesity.

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Glucagon-like Peptide-1 Activation of TCF7L2-dependent Wnt Signaling Enhances Pancreatic Beta Cell Proliferation

Abstract: The insulinotropic hormone GLP-1 (glucagon-like peptide-1) is a new therapeutic agent that preserves or restores pancreatic beta cell mass. We report that GLP-1 and its agonist, exendin-4 (Exd4), induce Wnt signaling in pancreatic beta cells, both isolated islets, and in INS

Cited by 285 publications

References 95 publications

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

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

P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine

Downregulation of Sfrp5 promotes beta cell proliferation during obesity in the rat

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