GLP-2 is related in sequence to GLP-1, glucagon, GIP and other members of the glucagon peptide superfamily. Many of these peptides exhibit an alanine at position 2, rendering them ideal substrates for degradation by the enzyme DP IV. Indeed, Analysis of circulating forms of GLP-2 in rodents and humans confirms that both GLP-21-33 and GLP-23-33 are detected in the fasting and postprandial states. See Circulating and tissue forms of the intestinal growth factor, glucagon-like peptide-2 Endocrinology 1997 Nov;138(11):4837-43 for an overview of the data.

Consistent with the importance of DP IV for GLP-2 bioactivity and degradation, a relatively larger amount of GLP-2 is required to stimulate GLP-2-dependent endpoints in rats compared to mice, as the former exhibit comparatively greater levels of circulating DP IV activity. Accordingly, analogues of GLP-2 that are resistant to DP IV-mediated degradation are more potent than the native peptide in vivo. See Regulation of the biological activity of glucagon-like peptide 2 in vivo by dipeptidyl peptidase IV Nat Biotechnol 1997 Jul;15(7):673-7.

Several studies have examined the consequences of altering the GLP-2 molecule, including N, and C-terminal deletions and extensions, position 2 substitutions, and alanine scanning of the entire molecule. For an overview of the data, see Prototypic G protein-coupled receptor for the intestinotrophic factor glucagon-like peptide 2. Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1569-73 and  Structural determinants for activity of glucagon-like peptide-2. Biochemistry. 2000 Aug 1;39(30):8888-94

DP IV-mediated cleavage of GLP-2 (1-33) to GLP-2(3-33) largely inactivates GLP-2 in vivo. Nevertheless, GLP-2 (3-33) appears to function as both a very weak partial agonist and a weak antagonist in rodent studies in vivo. 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.