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GLP-2 is a potent intestinotrophic peptide that can increase mucosal growth, intestinal blood flow, and nutrient absorption when administered exogenously. We aimed to delineate the effects of endogenous GLP-2R signalling in conditions of nutrient deprivation and excess. Using a mouse with a targeted genetic deletion of the Glp2r gene (Glp2r-/-), we addressed the hypothesis that the known GLP-2R is required for intestinal adaptation to nutrient deprivation and excess. In Chapter 2, we demonstrate that Glp2r−/− mice fasted for 24 hours and re-fed for 24 hours failed to increase intestinal growth and jejunal crypt cell proliferation compared to littermate Glp2r+/+ mice. Administration of EGF to Glp2r−/− during the re-feeding period rescued this re-feeding defect. Wildtype mice re-fed for 30, 90, and 180 minutes following a 24 hour fast displayed increased jejunal mRNA levels of the ErbB ligands amphiregulin, epiregulin and HB-EGF. Treatment with the pan ErbB inhibitor CI-1033 inhibited induction of these ErbB ligands in jejunum of mice in association with prevention of crypt cell proliferation. Re-feeding also caused an increase in jejunal p-Akt levels and treatment with CI-1033 prevented increased p-Akt levels. Moreover, re-fed Glp2r−/− mice failed to increase ErbB ligands or p-Akt levels 90 minutes following re-feeding when compared to Glp2r+/+ littermates. Therefore, the GLP-2R is essential for re-feeding induced intestinal adaptation by activating the ErbB network and p-Akt to increase crypt cell proliferation. In Chapter 3, we show that the known GLP-2R is not required for intestinal adaptation to a perceived nutrient deprivation challenge (STZ-induced diabetes) or chronic nutrient excess (high-fat diet induced glucose intolerance). Although exogenous GLP-2 administration has been previously shown to stimulate glucagon secretion, glucose homeostasis was normal in STZ-diabetic and high fat fed Glp2r−/− mice. We also developed a third model of diabetes and glucose intolerance: ob/ob: Glp2r−/−. In the absence of GLP-2R signalling, ob/ob mice display improved oral but impaired intraperitoneal glucose tolerance, elevated fed and fasted glucose levels, increased circulating glucagon, decreased beta cell and increased alpha cell mass. Taken together, these results suggest that endogenous GLP-2R signalling is essential for intestinal and islet adaptation to conditions of nutrient deprivation and excess.

Postnatal growth of the small intestine can be divided into two separate but complementary mechanisms; mucosal growth and organ (cylindrical) growth. Mucosal growth, observed by increasing villus area and crypt length, is upregulated during weaning, compared to pre or post-weaned time frames. The dynamics of organ growth, mediated by the process of crypt fission, is unknown during this period of postnatal development. Keratinocyte Growth Factor (KGF) and Hepatocyte Growth Factor (HGF) are mesenchymally derived ligands which have been demonstrated to have trophic effects on the epithelium of the gastrointestinal tract in vitro and in vivo during embryonic development, repair/restitution and tumour progression. This study explores the hypothesis that small intestine organ growth occurs independently to that of mucosal growth and the mechanisms of growth are mediated by differential expression of either HGF or KGF within the pericryptal mesenchyme derived cells (fibroblasts). / Thesis (MApSc(BiomedicalScience))--University of South Australia, 2004.

Postnatal growth of the small intestine can be divided into two separate but complementary mechanisms; mucosal growth and organ (cylindrical) growth. Mucosal growth, observed by increasing villus area and crypt length, is upregulated during weaning, compared to pre or post-weaned time frames. The dynamics of organ growth, mediated by the process of crypt fission, is unknown during this period of postnatal development. Keratinocyte Growth Factor (KGF) and Hepatocyte Growth Factor (HGF) are mesenchymally derived ligands which have been demonstrated to have trophic effects on the epithelium of the gastrointestinal tract in vitro and in vivo during embryonic development, repair/restitution and tumour progression. This study explores the hypothesis that small intestine organ growth occurs independently to that of mucosal growth and the mechanisms of growth are mediated by differential expression of either HGF or KGF within the pericryptal mesenchyme derived cells (fibroblasts). Alternatively, the corresponding receptors for these ligands, c-met and bek, may exhibit differential expression within the proliferative compartment of the crypts. The indices of mucosal and organ growth were compared at various ages during early postnatal life (suckling), then early, middle and late weaning through to adult animals. Microdissection techniques utilising whole tissue samples enabled microscopic evaluation of growth. The assessment of KGF, bek, HGF and c-met was also undertaken using immunohistochemistry on formalin fixed, paraffin processed sections of rat jejunum. The highest rate of organ growth occurred during weaning and was immediately preceded at day 14 (of age) by a peak in the incidence of branching crypts. KGF immunolabelling was observed within the mesenchymal cells at the tips of the villus from mid-weaning onwards but at no stage within pericryptal fibroblasts. Both KGF and bek were demonstrated within the crypt epithelium, with highest levels observed during weaning. Immunolabelling for HGF demonstrated an ubiquitous distribution within both epithelial and mesenchymal tissues at all ages, whilst the expression of c-met was in the crypt cell compartment was limited to the time of weaning. The use of an in vivo blockade technique utilising an anti-HGF (D9) antibody from age 7 to 14 days did not demonstrate any reduction of the indices of organ or mucosal growth. These results suggest that rate of organ and mucosal growth increase concurrently during weaning. The demonstration of both bek and c-met in the crypt cell population during this period suggests that KGF and HGF are potential mediators of organ or mucosal growth, despite only HGF being demonstrated in the pericryptal mesenchymal derived cells. Further, the expression of KGF and HGF at sites beyond the crypts suggest these ligands play a greater role in the development of the rat small intestine during postnatal growth. / thesis (MApSc(BiomedicalScience))--University of South Australia, 2005.

Thesis (Ph. D.)--University of Chicago, 1910. / [Reprinted from the American Journal of Phisiology. Vol. XXV, no. VI (Feb. 1, 1910]. Includes bibliographical references.

Thesis (M.S.)--University of Hong Kong, 1999. / Includes bibliographical references (leaves 92-125).

Thesis (Ph. D.)--University of Chicago, [1910] / [Reprinted from the American Journal of Phisiology. Vol. XXV, no. VI (Feb. 1, 1910] Includes bibliographical references. Also available on the Internet.

Thesis (M.S.)--University of Hong Kong, 1999. / Includes bibliographical references (leaves 92-125) Also available in print.