Chronic administration of glucagon-like peptide-2 (GLP-2) induces intestinal growth and crypt cell proliferation through an indirect mechanism requiring insulin-like growth factor-1 (IGF-1). However, the intracellular pathways through which IGF-1 mediates GLP-2-induced epithelial tropic signaling remain undefined. As -catenin and Akt are important regulators of crypt cell proliferation, we hypothesized that GLP-2 activates these signaling pathways through an IGF-1-dependent mechanism. Fasted mice were administered Gly²-GLP-2 or LR³-IGF-1 (positive control), for 0.5h to 4h. Nuclear translocation of -catenin in non-Paneth crypt cells was assessed by immunohistochemistry, and expression of its downstream proliferative marker, c-myc, by qRT-PCR. Akt phosphorylation and activation of its targets, GSK-3 and caspase-3, were determined by western blot. IGF-1 receptor (IGF-1R) and IGF-1 signaling were blocked by pre-administration of NVP-AEW541 and through the use of IGF-1 knock-out mice, respectively. GLP-2 increased -catenin nuclear translocation in non-Paneth crypt cells by 72 ± 17% (P < 0.05), and increased mucosal c-myc mRNA expression by 90 ± 20% (P < 0.05), with similar results observed with IGF-1. This effect of GLP-2 was prevented by blocking the IGF-1R, as well as by ablation of IGF-1 signaling. GLP-2 also produced a time- and dose-dependent activation of Akt in the intestinal mucosa (P < 0.01), most notably in the epithelium. This action was reduced by IGF-1R inhibition, but not by IGF-1 knockout. Acute administration of GLP-2 activates -catenin and proliferative signaling in non-Paneth murine intestinal crypt cells, as well as Akt signaling in the mucosa. However, IGF-1 is required only for the GLP-2-induced alterations in -catenin.