The WNT signalling pathway and diabetes mellitus

Abstract

The WNT signalling pathway is involved in many physiological and pathophysiological activities. WNT ligands bind to Frizzled receptors and co-receptors (LDL receptor-related protein 5/6), triggering a cascade of signalling events. The major effector of the canonical WNT signalling pathway is the bipartite transcription factor β-catenin/T cell transcription factor (β-cat/TCF), formed by free β-cat and one of the four TCFs. The WNT pathway is involved in lipid metabolism and glucose homeostasis, and mutations in LRP5 may lead to the development of diabetes and obesity. β-Cat/TCF is also involved in the production of the incretin hormone glucagon-like peptide-1 in the intestinal endocrine L cells. More recently, genome-wide association studies have identified TCF7L2 as a diabetes susceptibility gene, and individuals carrying certain TCF7L2 single nucleotide polymorphisms could be more susceptible to the development of type 2 diabetes. Furthermore, β-cat is able to interact with forkhead box transcription factor subgroup O (FOXO) proteins. Since FOXO and TCF proteins compete for a limited pool of β-cat, enhanced FOXO activity during ageing and oxidative stress may attenuate WNT-mediated activities. These observations shed new light on the pathogenesis of type 2 diabetes as an age-dependent disease.

Insulin treatment and high-fat diet feeding reduces the expression of three Tcf genes in rodent pancreas

“…This was further supported by observations in both western blotting and immunostaining. The role of nuclear b-cat and the canonical Wnt signaling pathway in the development of pancreatic islets and the function of pancreatic b cells have been documented recently in a number of transgenic mouse studies (Rulifson et al 2007, Jin 2008, Jin & Liu 2008, suggesting that pancreatic islet cells may express certain Tcf family members. We show in this study that in rodent pancreas and rat pancreatic islets, in addition to a low level of expression of Tcf7l2, mRNAs for two other Tcf family members, Tcf7 and Tcf7l1, were detectable.…”

“…After the demonstration of a very strong association between the risk of T2D and specific polymorphisms in the TCF7L2 gene (Grant et al 2006), this effector of Wnt signaling has drawn global attention (Florez et al 2006, Munoz et al 2006, Scott et al 2006, Cauchi et al 2007, Dahlgren et al 2007, Elbein 2007, Sladek et al 2007, Jin 2008, Jin & Liu 2008. How these single-nucleotide polymorphisms (SNPs) within intronic regions of the human TCF7L2 gene led to an increase in the risk of the development of T2D is unknown because it is difficult to assess whether these SNPs actually affect TCF7L2 expression levels.…”

“…The major effector of the canonical Wnt signaling pathway is the bipartite transcription factor cat/TCF, formed by free b-catenin (b-cat) and a member of the TCF protein family (TCF-1/TCF7, LEF1, TCF-3/TCF7L1, and TCF-4/TCF7L2 ;Jin 2008). This pathway exerts important physiological and pathological functions in different cell lineages and organs, including organogenesis, tumor development, and metabolic homeostasis (Kinzler & Vogelstein 1996, He et al 1998.…”

“…Grant et al (2006) identified an association between TCF7L2 polymorphisms and the risk of type 2 diabetes mellitus (T2D) among European and American populations. Since then, extensive genome-wide association studies have further confirmed their discovery globally and among ethnically diverse populations (Florez et al 2006, Munoz et al 2006, Scott et al 2006, Cauchi et al 2007, Dahlgren et al 2007, Elbein 2007, Sladek et al 2007, Jin 2008, Jin & Liu 2008. Although several investigations have indicated that individuals who carry the risk of TCF7L2 polymorphisms exhibited impaired insulin secretion and enhanced rate of hepatic glucose production (Florez et al 2006, Lyssenko et al 2007, Schafer et al 2007, Kirchhoff et al 2008, in mouse models and in humans, whether Tcf7l2 regulates the function of b cells remains controversial (Jin 2008, Liu & Habener 2008, Krutzfeldt & Stoffel 2010.…”

The involvement of beta-catenin in the inflammatory response leading to autoimmune diabetes development.

“…Components of the Wnt pathway have been found to be involved in beta cell proliferation, cholesterol metabolism, insulin secretion, and production of GLP-1 (glucagon-like peptide-1). Additionally, TCF4, a transcription factor that binds to β-catenin, has been identified as a susceptibility gene for Type II diabetes [133]. Interestingly, the human LRP5 gene, which codes for one of the Frizzled coreceptors LRP5, is associated, although not strongly, with Type I diabetes.…”