Analysis of the physiological vs. pharmacological actions of GLP-2 is somewhat challenging due to the lack of high affinity specific GLP-2 receptor antagonists. Hartmann and colleagues employed immunoneutralizing antisera to GLP-2 to examine the importance of endogenous GLP-2 in the development of adaptive mucosal growth in rats with experimental diabetes. GLP-2 antisera significantly attenuated the increase mucosal area in the proximal part of the small intestine without producing effects on body weight, glucose or food intake. See Immunoneutralization of endogenous glucagon-like peptide-2 reduces adaptive intestinal growth in diabetic rats. Regul Pept. 2002 May 30;105 (3):173-9

Thulesen and colleagues employed GLP-2(3-33) as a partial antagonist to demonstrate that this peptide attenuated the exogenous of GLP-2(1-33) in cell experiments in vitro and in mice in vivo. GLP-2(3-33) also acts as a partial agonist at the GLP-2 receptor. See The truncated metabolite GLP-2 (3-33) interacts with the GLP-2 receptor as a partial agonist. Regul Pept. 2002 Jan 15;103(1):9-15.

Shin and colleagues employed GLP-2(3-33) to examine the importance of endogenous murine GLP-2 in the mucosal adaptation to fasting and re-feeding. GLP-2(3-33) significantly reduced the adaptive mucosal re-growth in re-fed mice via effects on crypt cell proliferation and apoptosis as shown in Mucosal Adaptation to Enteral Nutrients is Dependent on the Physiologic Actions of Glucagon-Like Peptide-2 in Mice. Gastroenterology. 2005 May;128(5):1340-53

The actions of GLP-2 in adaptaion to mucosal nutrients have also been determined in fasted and refed Glp2r-/- mice. Mucosal adaptation is defective in Glp2r-/- mice, and associated with abnormalities in expression and activation of ErbB family members and ErbB target genes. Moreover, exogenous EGF restores re-feeding induced mucosal adaptation in Glp2r-/- mice, whereas the pan ErbB inhibitor CI-1033 abrogates re-feeding induced mucosal adaptation in WT mice. Furthermore, defective upregulation of multiple components in the ErbB pathways was observed following re-feeding in Glp2r-/- mice. See ErbB activity links the glucagon-like peptide-2 receptor to refeeding-induced adaptation in the murine small bowel. Gastroenterology. 2010 Mar 9. [Epub ahead of print]

Lee and colleagues have characterize the phenotype of Glp2r-/- mice under basal conditions, and following induction of experimental intestinal injury. Cell lineage allocation, growth and development of the small and large bowel was normal in the Glp2r-/- mouse, however the intestinal response to GLP-2 was completely extinguished. Furthermore, the large bowel did not exhibit resistance to dextran sulfate-induced injury. However injury of the small bowel by administration of the NSAID indomethacin, or the chemotherapeutic agent irinotecan, was associated with enhanced injury and greater bacterial invasion. Moreover Glp2r-/- mice exhibit defective expression of Paneth cell gene products, increased bacterial colonization in the small bowel, and defective mucosal bactericidal activity. Hence the Glp2r is an essential component of the mucosal response to bacterial pathogens and disruption of mucosal integrity. Disruption of the Murine Glp2r Impairs Paneth Cell Function and Increases Susceptibility to Small Bowel Enteritis Endocrinology en.2011-1954; doi:10.1210/en.2011-1954

Disruption of the Glp2r selectively in the poulation of neurons that express POMC was reported by Guan and colleagues. Twelve week old POMC-Glp2r-/- mice were hyperphagic yet exhibited normal energy expenditure and body weight was comparable in control vs. POMC-Glp2r-/- mice until about 22 weeks of age, following wich these mice exhibited modest age-associated obesity. Gastric emptying was also accelerated in 12 week old POMC-Glp2r-/- mice and the inhibitory effects of exogenous 4th ventricle GLP-2 administration on food intake and gastric emptying were attenuated in MC4R-/- mice GLP-2 receptor in POMC neurons suppresses feeding behavior and gastric motility Am J Physiol Endocrinol Metab. 2012 Jul 24.