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

Abstract

The Wnt signaling pathway was initially discovered for its role in tumorigenesis and the development of Drosophila and other eukaryotic organisms. The key effector of this pathway, the bipartite transcription factor β-cat/TCF, is formed by free β-catenin (β-cat) and a TCF protein, including TCF7L2. Extensive recent investigations have highlighted the role of the Wnt signaling pathway in metabolic homeostasis and its implication in diabetes and other metabolic diseases. Genome-wide association studies have shown that several key components of the Wnt signaling pathway are implicated in metabolic homeostasis and the development of type 2 diabetes (T2D). Despite controversial observations regarding the role of Wnt signaling in the development and function of pancreatic islets, the discovery of the association between certain single nucleotide polymorphisms of TCF7L2 and T2D susceptibility has fueled great efforts to explore the role of Wnt signaling in the function of pancreatic β-cells and glucose homeostasis. Here we have introduced our basic understanding of the canonical Wnt signaling pathway, summarized our current knowledge on its implication in metabolic homeostasis and T2D, discussed the work on TCF7L2 as a T2D susceptibility gene, and presented the controversial role of Wnt signaling and TCF7L2 in pancreatic islets as well as their potential metabolic function in other organs. We then expanded our view into the crosstalk among Wnt, insulin and FOXO signaling cascades, which further illustrates the complexity of the Wnt signaling pathway in metabolic homeostasis. Finally, we have presented our perspectives.

Figure 1

Schematic of the canonical Wnt signaling pathway. A) In the absence of Wnt ligands, β-cat is sequestered in the cytoplasm by the destruction complex consisting of APC, axin, GSK-3, and CK-1α, leading to its degradation by the proteasome. TCF and Groucho bind to the promoters of Wnt target genes and repress their expression. B) Upon binding of a Wnt ligand to the Frizzled receptor and LRP-5/6 co-receptor, the destruction complex is disrupted by Dvl. In turn, β-cat enters the nucleus where it forms the bipartite transcription factor β-cat/TCF and stimulates Wnt target gene expression. GPCR, G-protein coupled receptor. Dvl, dishevelled. APC, adenomatous polyposis coli. GSK-3, glycogen synthase kinase-3. CK-1α, casein kinase 1α. IR, insulin receptor. HDAC, histone deacetylase. CtBP-1, C-terminal binding protein-1. H/N, hormone/neurotransmitter. PKA, protein kinase A. Ins, insulin. CBP, cAMP response element-binding (CREB) binding protein.

Figure 2

TCF7L2 genetic structure, T2D risk SNP locations, and protein structure. A) The human TCF7L2 gene, located on chromosome 10q25.3, consists of 17 exons (boxes). At least five exons are alternatively spliced (white boxes). Five SNPs were originally determined to be associated with T2D risk in a variety of ethnic backgrounds, all of which are located within the large intronic regions surrounding exon 5. Two additional T2D risk SNPs (yellow) were subsequently identified in Han Chinese populations. The TCF7L2 gene undergoes a significant amount of alternative splicing that produces a large number of transcripts which give rise to a number of isoforms. The major isoforms of size 79 and 58 kDa result from alternative stop codons. A novel transcription start site (called Ex1b-e) was recently identified upstream of exon 6 which leads to the production of a dominant-negative TCF7L2 isoform of size 35–40 kDa. B) The full-length TCF7L2 protein consists of two major domains including the β-cat binding domain at the N-terminal as well as the HMG-box for binding to DNA. In addition, TCF7L2 binds to a number of other factors, depicted in this figure. SNP, single nucleotide polymorphism. HMG, high-mobility group. HBP1, HMG-box transcription factor 1.

Figure 3

Summary of the potential metabolic functions of TCF7L2. The beneficial versus deleterious role of TCF7L2 in the pancreas is controversial and under debate. GLP-1, glucagon-like peptide-1. GIP, gastric inhibitory polypeptide.

Figure 4

Crosstalk among Wnt, insulin, and FOXO signaling cascades. TCF and FOXO compete with each other for a limited pool of free β-cat. Aging and oxidative stress shift the balance in favor of FOXO signaling via JNK to activate downstream FOXO target genes. Contrastingly, insulin and growth factors shift the balance in favor of Wnt/TCF signaling by facilitating the nuclear exclusion of FOXO via PKB/SGK as well as by activating β-cat, thus resulting in the activation of downstream Wnt target genes. PKB, protein kinase B. ROS, reactive oxygen species. JNK, c-Jun N-terminal kinase. FOXO, forkhead box O. SGK, serum and glucocorticoid kinase.