The Essential Role of Insulin-Like Growth Factor-1 in the Intestinal Tropic Effects of Glucagon-Like Peptide-2 in Mice

Background & Aims: Glucagon-like peptide-2 (GLP-2) is an intestinal hormone that acts through unknown pathways to induce intestinal growth. We investigated the role of the insulin-like growth factors (IGF-1 and IGF-2) as mediators of GLP-2–enhanced growth in the murine intestine. Methods: IGF-1 expression and secretion were determined in GLP-2–responsive primary intestinal cultures treated with GLP-2. Parameters of intestinal growth were assessed in wild-type (CD1, Igf1+/+ and Igf2+), heterozygous (Igf1+/−), and null (Igf1−/− and Igf2−P) mice treated chronically with saline, GLP-2, IGF-1, or R-Spondin1. Results: GLP-2 increased IGF-1 messenger RNA expression and IGF-1 secretion in intestinal cultures and increased expression of IGF-1 messenger RNA in mouse small intestine in vivo. Igf1+/+ and Igf2+ mice responded to .1 μg/g−1 per day−1 GLP-2 with increased intestinal weights, morphometric parameters, and proliferative indices. In contrast, Igf1−/− mice were unresponsive to the same dose of GLP-2, failing to demonstrate changes in intestinal weight, morphometry, or proliferation. However, a significant effect of 1 μg/g−1 per day−1 GLP-2 was observed in Igf1−/− mice, but only in terms of small intestinal weight when normalized for body weight. Furthermore, Igf2−P mice demonstrated a partially impaired response in terms of small intestinal growth. Both Igf1−/− and Igf2−P mice exhibited normal-enhanced intestinal growth in response to IGF-1 and/or R-Spondin1. Conclusions: GLP-2 enhances intestinal IGF-1 expression and secretion, and IGF-1 is required for small and large intestinal growth in response to GLP-2. These findings identify IGF-1 as an essential mediator of the intestinotropic actions of GLP-2.