Oral 3 - 3.2
1Zivit Fesler, 1,2Patricia L Brubaker
1 Department of Physiology, University of Toronto; 2 Department of Medicine, University of Toronto
Glucagon-like peptide-2 (GLP-2) is an intestinotrophic peptide hormone produced by the enteroendocrine L cells of the intestine. As the GLP-2 receptor is not localized to the crypt cells where the proliferative effects of GLP-2 are mediated, the trophic effects of GLP-2 are thought be exerted indirectly, through other intestinal growth factors. Of these, epidermal growth factor (EGF) and its family of ErbB receptors have been demonstrated as essential players in the crypt cell proliferative response to GLP-2. Hence, administration of a pan-ErbB inhibitor decreases the trophic effects of GLP-2 in mice, as does knockout of ErbB1 from the intestinal epithelial cells. Furthermore, rats and neonatal piglets with intestinal resection exhibit synergistic increases in intestinal growth when co-treated with GLP-2 and EGF. However, normal mice receiving a sub-threshold dose of EGF and an optimal dose of GLP-2 did not exhibit an additive or synergistic increase in small intestinal weight in response to the combination treatment. We therefore hypothesized that pre- and/or co-treatment with a sub-threshold dose of EGF will increase the intestinal growth response to a sub-threshold dose of GLP-2. C57BL/6 male mice (n=4 per group) were treated with either vehicle, 0.2 g/g/day h(Gly2)GLP-2 (a long-acting degradation-resistant human GLP-2 analog), 0.4 g/g/day murine EGF given either as a pre-treatment at -3 h and/or as a co-treatment alone or with the GLP-2, for 11 days. Mice were weighed at the beginning and end of the experiment and their small and large intestines were collected and measured for weight and length; samples were also collected for later morphometric, proliferative and gene expression analysis. Body weights were not altered by any of the treatments. Pre- and co-treatment with EGF alone and treatment with GLP-2 alone did not significantly increase small or large intestinal weight or length, although pre- plus co-treatment with EGF alone did increase large intestinal length (p<.01). In contrast, combined treatment with GLP-2 and pre-EGF, or GLP-2 with pre- plus co-EGF significantly increased small intestinal weight normalized to body weight (p<0.05-0.01), with a similar trend observed in mice treated with GLP-2 and co-EGF. No effects of these treatment combinations were observed in the large intestine. In conclusion, a sub-threshold dose of EGF, given either 3 hr before and/or concomitantly with GLP-2, was found to synergistically increase the small intestinal growth responses to a sub-threshold dose of GLP-2 in normal mice. These findings may have implications with respect to the use of GLP-2 receptor agonists in patients with short bowel syndrome.