The involvement of the wnt signaling pathway and TCF7L2 in diabetes mellitus: The current understanding, dispute, and perspective

The Wnt signaling pathway was initially recognized in breast and colon cancer research as well as in embryonic developmental studies of Drosophila, Xenopus and other organisms [1-3]. This pathway involves not only a large battery of Wnt ligands, receptors and co-receptors, but also a number of proteins that can regulate the production of the Wnt ligands, the interactions between different types of Wnt ligands and receptors on the target cells, the physiological responses of target cells to Wnt ligand binding, as well as the formation of active effector molecules. Hyper-activation of the Wnt signaling pathway, such as via the attenuation of the repressive machinery or the expression of a constitutively active effector, may lead to the development of colorectal and other types of tumors [4]. During the last decade, we have learned that Wnt signaling not only interacts with several other important signaling pathways in orchestrating organogenesis, but is also involved in regulating hormone gene expression and metabolic homeostasis [5,6]. Abnormalities in the Wnt signaling pathway may lead to the development of diseases other than tumors, including type 2 diabetes (T2D) and other disorders [7-11].The major effector of the canonical Wnt signaling pathway (defined as Wnt pathway hereafter) is known as β-cat/TCF. This bipartite transcription factor is formed by free β-catenin (β-cat) and a member of the TCF protein family, including TCF7L2, which was previously known as TCF-4 [12]. In 2006, a large scale genome-wide association study (GWAS) revealed that certain single nucleotide polymorphisms (SNPs) in TCF7L2 are strongly associated with the susceptibility of T2D [13]. This important finding was subsequently replicated numerous times globally in different ethnic groups in the last few years [14-23]. Although we are still unable to determine mechanistically how these SNPs located within intronic regions of TCF7L2 affect the risk of T2D, this association, along with the rec