Year: 2007
Type: dissertation
Abstract: Glucagon-like peptide-2 (GLP-2) induces intestinal growth and crypt cell proliferation through an indirect mechanism, potentially involving intestine-derived paracrine growth factors. I hypothesised that insulin-like growth factor-1 (IGF-1) is a mediator of GLP-2-induced intestinal growth. Accordingly, GLP-2 treatment increased IGF-1 mRNA levels and secretion in primary intestinal cultures, and increased intestinal IGF-1 mRNA expression in mice in vivo. To determine if IGF-1, or the related growth factor IGF-2, are required for GLP-2-induced intestinal growth, wildtype and null (Igf1-/- and Igf2-P) mice were treated chronically with saline, long-acting GLP-2, long-acting IGF-1 or R-Spondin1. Wildtype mice responded to GLP-2 with increased intestinal weights, mucosal morphometry and crypt cell proliferative indices. GLP-2-induced small and large intestinal growth was markedly impaired in Igf1 -/- mice, and, importantly, the effects of GLP-2 on morphometry and small intestinal crypt cell proliferation were completely abrogated in these mice. In contrast, GLP-2 induced intestinal growth was only partially impaired in Igf2-P mice, and both Igf1-/- and Igf2-P mice exhibited normal-enhanced responses to IGF-1 and/or R-Spondin1. As beta-catenin and Akt are important regulators of crypt cell proliferation, I hypothesised that GLP-2 activates these pathways through an IGF-1-dependent pathway. Therefore, wildtype and Igf1-/- mice were treated acutely with GLP-2 or IGF-1 (positive control), with or without prior IGF-1 receptor (IGF-1R) inhibition, crypt cell signalling was assessed. GLP-2 activated beta-catenin signalling by enhancing its nuclear translocation in non-Paneth crypt cells, and increased mRNA levels of the beta-catenin target gene, c-myc, with similar results observed with IGF-1. This effect of GLP-2 was prevented by IGF-1R inhibition, and was abrogated in Igf1-/- mice. Additionally, GLP-2 activated Akt signalling in the intestinal crypt and villus epithelium and, although this response was reduced by IGF-1R inhibition, it was normal in Igfl-/- mice. In conclusion, my studies have established that GLP-2 enhances intestinal IGF-1 expression and secretion, and that IGF-1 is required for intestinal growth and crypt cell proliferation in response to chronic GLP-2 treatment in mice. Furthermore, these studies identify that GLP-2 modulates beta-catenin signalling in the intestinal crypt cell, which occurs through a mechanism requiring IGF-1 and the IGF-1R.
Source: TSpace (University of Toronto)
Author: Dube, Philip Evan
Institution: University of Toronto
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7132902829