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. 2012 Jul 12:3:273.
doi: 10.3389/fphys.2012.00273. eCollection 2012.

The role of the Wnt signaling pathway in incretin hormone production and function

Yu-Ting A Chiang  1 , Wilfred Ip, Tianru Jin
Affiliations

The role of the Wnt signaling pathway in incretin hormone production and function

Yu-Ting A Chiang et al. Front Physiol. .

Abstract

Glucose metabolism is tightly controlled by multiple hormones and neurotransmitters in response to nutritional, environmental, and emotional changes. In addition to insulin and glucagon produced by pancreatic islets, two incretin hormones, namely glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP, also known as glucose-dependent insulinotropic peptide), also play important roles in blood glucose homeostasis. The incretin hormones mainly exert their regulatory effects via their corresponding receptors, which are expressed in pancreatic islets as well as many other extra-pancreatic organs. Recent studies have shown that the genes which encode these two incretin hormones can be regulated by the effectors of the Wnt signaling pathway, including TCF7L2, a transcription factor identified recently by extensive genome wide association studies as an important type 2 diabetes risk gene. Interestingly, TCF7L2 and β-catenin (β-cat), another effector of Wnt signaling pathway, may also mediate the function of the incretin hormones as well as the expression of their receptors in pancreatic β-cells. In this review, we have introduced the incretin hormones and the Wnt signaling pathway, summarized recent findings in the field, and provided our perspectives.

Keywords: GIP; GLP-1; TCF7L2; Wnt signaling pathway; insulin; β-catenin.

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Figures

Figure 1
Figure 1
Structure of proGIP and active GIPs. The proGIP, encoded by the gip gene, is a pro-hormone with 153 amino acid residues. The main circulating active hormone GIP1–42 (aa 52–81) is generated predominantly in the intestinal K cells by the pro-hormone convertase PC3. In pancreatic α-cells and in a small portion of intestinal K cells, the cleavage by both PC2 and PC3 leads to the generation of GIP1–30 (aa 52–93). SS, signal sequence.
Figure 2
Figure 2
Proglucagon and its cleavage products (proglucagon derived peptides, PGDPs) including GLP-1. (A) Proglucagon, encoded by gcg, is a pro-hormone with 160 amino acid residues. The peptide contains both PC2 and PC3 cleavage sites. (B) A schematic presentation of the cleavage products in the pancreas (top) and in the intestine and brain (bottom). Although GLP-1 is not normally produced in the pancreas, during the embryonic stage or when islets are under stress, some pancreatic α-cell will produce GLP-1. (C) Amino acid sequences of GLP-1 and its derivatives, consisting of GLP-17–37 (aa 78–107), GLP-17–36 amide (aa 78–106), GLP-19–36 (aa 80–106), and GLP-128–36 amide (aa 98–106). GRPP, glycentin related polypeptide; IP1 and IP2, intervening peptide 1 and 2; MPGF, major proglucagon fragment; DPP-IV, dipeptidyl peptidase-4; NEP 24.11, neutral endopeptidase 24.11.
Figure 3
Figure 3
Schematic presentation of the function of GLP-1. In the pancreas, stomach, heart and brain, the effects of GLP-1 are likely to be mediated by its specific receptor GLP-1R. As GLP-19–37 was also shown to exert protective effects in the heart and improve cardiac function, whether there is a yet to be identified receptor is under debate.
Figure 4
Figure 4
Schematic presentation of GIP. Since GIPR has not been detected in hepatic cells, the effect of GIP on reducing gluconeogenesis is likely due to an indirect mechanism.
Figure 5
Figure 5
A simplified illustration of the canonical Wnt signaling pathway. (A) In the absence of Wnt ligand stimulation, β-cat is located within the “destruction complex”, phosphorylated by GSK-3 and CK-1α at Ser33 and adjacent serine positions, which leads to proteasome-mediated degradation process. (B) Following Wnt ligand stimulation, the destruction complex disassembles, resulting in free β-cat accumulation. It then enters the nucleus and forms the bipartite transcription factor β-cat/TCF, which leads to the stimulation of Wnt target gene expression. Lithium is an inhibitor of GSK-3, while cAMP signaling and insulin are able to stimulate β-cat Ser675 phosphorylation. Thus, in certain cell lineages, β-cat/TCF can also mediate the effect of lithium, cAMP, and insulin on Wnt target gene expression.
Figure 6
Figure 6
Structure and functional domains of human TCF7L2. It is currently unclear which position of the domains that interact with Groucho and CtBP1. Smad4 is the major mediator of the TGFβ signaling cascade. HBP1, HMG-box transcription factor 1, a transcriptional repressor.
Figure 7
Figure 7
Depiction of the position of seven T2D risk SNPs in the human TCF7L2 gene. Human TCF7L2 is located on chromosome 10q25.3. The two SNPs that have been more extensively studied are shown in red. Ex1b-e indicates the relative position of a novel promoter, which is active in neuronal cells during embryonic stages and leads to the generation of dominant negative TCF7L2, lacking the first 161 amino acid residues at the N terminus.
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