Diabetes outfoxed by GLP-1?

Abstract

Foxo1, a member of the Fox0 subfamily of winged-helix forkhead transcription factors, is a target of insulin and insulin-like growth factor-1 (IGF-1) signal transduction pathways that activate protein kinase B (PKB) in pancreatic beta cells. Foxo1 is a substrate for PKB, and its phosphorylation results in nuclear exclusion with concomitant alterations in gene expression that are important to cellular growth and differentiation. Because activation of PKB can require insulin receptor substrate proteins (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase (PI3K), it is of interest to determine whether the activity of Foxo1 is also regulated by heterotrimeric G protein-coupled receptors (GPCRs) with IRS-1 or -2, PI3K, or PKB signaling potential. Indeed, studies of beta cells have demonstrated that activation of a GPCR for the blood glucose-lowering hormone GLP-1 leads to major alterations of IRS-2, PI3K, and PKB activity. By promoting nuclear exclusion of Foxo1 in a PKB-mediated manner, GLP-1 may up-regulate the expression of a homeodomain transcription factor (PDX-1) that serves as a master regulator of beta-cell growth and differentiation. This STKE Perspective summarizes signaling properties of GLP-1 that may explain its ability to increase beta-cell mass, to increase pancreatic insulin secretory capacity, and to lower levels of blood glucose in type 2 diabetic subjects.

Fig. 1

GLP-1 acts by means of the GLP-1-R to stimulate adenylyl cyclase (AC), and thereby cAMP production, and to activate the cAMP-binding proteins PKA and Epac. PKA promotes translocation of PDX-1 to the nucleus, where it binds to regulatory elements within the enhancer or promoter sequences of genes important to β-cell growth and differentiation (13, 32). PKA also acts by means of CREB to up-regulate expression of IRS-2. Actions of Epac include a stimulation of intracellular Ca²⁺ signaling (5), secretory granule exocytosis (5), and the promotion of β-cell survival (33). Binding of GLP-1 to the GLP-1-R transactivates the EGFR in a manner mediated by c-Src and the ADAM (a disintegrin and metalloproteinase)–family metalloproteinase. Liberation of the soluble EGFR ligand betacellulin (BTC) stimulates EGFR autophosphorylation and promotes formation of an EGFR-Grb2-Gab1-PI3K complex with resultant activation of PKB. The IR and IGF-1-R signaling pathways acting by means of IRS-2 and PI3K converge with the GLP-1-R signaling pathway at PKB. Activated PKB translocates to the nucleus, where it acts at Foxo1 to disinhibit Foxa2-dependent PDX-1 gene promoter activity. Phosphorylated Foxo1 (Foxo1-P) associates with 14-3-3 proteins and is exported out of the nucleus to accumulate in the cytosol.