New insight into the mechanisms underlying the function of the incretin hormone glucagon-like peptide-1 in pancreatic β-cells: the involvement of the Wnt signaling pathway effector β-catenin

Abstract

During the past two decades, the exploration of function of two incretin hormones, namely glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), has led to the development of two categories of novel therapeutic agents for diabetes and its complications, known as GLP-1 receptor (GLP-1R) agonists and DPP-IV inhibitors. Mechanisms underlying the function of GLP-1, however, still need to be further explored. GLP-1 not only functions as an incretin hormone in stimulating insulin secretion in response to nutritional, hormonal and neuronal stimulations, but also acts as an "insulin-like" factor in β-cell and extra-pancreatic organs. In addition to these insulinotropic and insulinomimetic effects, GLP-1 was shown to exert its protective effect in β-cell by repressing the expression of TxNIP, a mediator of glucolipotoxicity. A number of recent studies have shown that the Wnt signaling pathway effector, the bipartite transcription factor β-catenin/TCF, controls not only the production of GLP-1, but also the function of GLP-1. Furthermore, previously assumed "degradation" products of GLP-1(7-36)amide, including GLP-1(9-36)amide and GLP-1(28-36)amide, have been shown to exert beneficial effect in pancreas and extra-pancreatic tissues or cell lineages. Here we summarized our current knowledge on the metabolic, proliferative and protective effects of GLP-1(7-36)amide and its cleavage fragments, mainly focusing on pancreatic β-cells and the involvement of the Wnt signaling pathway effector β-catenin.

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

Figure 1. Proglucagon and its cleavage products. (A) The gcg gene encode proglucagon, a pro-hormone with 160 amino acid residues (top panel). This pro-hormone contains three PC2 and four PC1/3 cleavage sites. A schematic presentation of the cleavage products of proglucagon in the pancreas (middle panel) and in the intestine and brain (bottom panel). (B) Amino acid sequences of GLP-1(7–36)amide, GLP-1(9–36)amide and GLP-1(28–36)amide. The cleavage sites for DPP-IV and NEP24.11 are indicated with arrows. 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 2. An illustration of the Wnt signaling pathway. Without Wnt ligand stimulation, β-cat is trapped within the “destruction complex,” phosphorylated by the protein kinase GSK-3 and CK-1α at Ser33 and adjacent Ser positions, and subsequently degraded by proteasome (left). Following Wnt ligand stimulation and Dishvelled (Dvl) activation, β-cat escapes the trapping, enters the nucleus and forms the bipartite transcription factor cat/TCF, which leads to the stimulation of Wnt target gene expression (middle). GLP-1 was shown to activate cAMP-dependent protein kinase A (PKA), and stimulate β-cat Ser675 phosphorylation, which is positively associated with its nuclear translocation and Wnt target gene expression (right).

Figure 3. Summary of insulinotropic and insulinomimetic effects of GLP-1 and its cleavage products in pancreatic β-cells. The cleavage of GLP-1(7–36)amide (defined as 7–36amide) by DPP-IV leads to the production of GLP-1(9–36)amide (defined as 9–36amide). The cleavage by NEP 24.11 leads to the production of GLP-1 (28–36)amide (defined as 28–36amide). GLP-1R mediates the insulinotropic effect of 7–36amide and GLP-1R agonists, such as exendin-4, involving both cAMP/PKA and cAMP/Epac. PKA can activate β-cat via increasing its Ser675 phosphorylation, which is at least partially responsible for the insulinomimetic effect of GLP-1. Whether 28–36amide exerts its insulinomimetic effect in pancreatic β-cells via a yet to be identified receptor, or a receptor independent mechanism remain to be further investigated. Whether or not 28–36amide exerts its insulinomimetic effect via stimulating β-cat Ser675 phosphorylation is also worth to be further examined.