GLP-2 and GLP-1, along with GIP, contain an alanine at position 2
Following cleavage of GLP-2 by DPP-4, GLP-2 (3-33) is rapidly liberated and circulates in vivo. Hence
radioimmunoassays that do not distinguish between full length bioactive GLP-2 (1-33) versus N-terminally truncated bioinactive GLP-2 (3-33) will lead to an overestimation of GLP-2 (3-33) activity.
The importance of DPP-4 for regulation of GLP-2 bioactivity is illustrated by comparisons of GLP-2 bioactivity in mice versus rats. Administration of 0.1 mg/kg rat or human GLP-2 to mice for 7-10 days produces a highly significant increase in small bowel weight and villus height; see Biological determinants of intestinotrophic properties of GLP-2 in vivoAm J Physiol. 1997 Mar;272(3 Pt 1):G662-8.
In contrast, the same dose of GLP-2 administered to rats increases villus height but has no significant trophic effect on small bowel weight . As rats have comparatively greater DPP-4 activity, higher doses of wildtype GLP-2 or DPP-4-resistant GLP-2 analogues are required to achieve the same degree of GLP-2 bioactivity in rats, compared to mice. Regulation of the biological activity of glucagon-like peptide 2 in vivo by dipeptidyl peptidase IV Nat Biotechnol. 1997 Jul;15(7):673-7
Analysis of the relative amounts of intact versus DPP-4-cleaved forms of GLP-2 in rats and mice demonstrate that a substantial proportion of GLP-2 circulates, in both the fasting and postprandial states, as bioinactive N-terminally truncated GLP-2 (3-33), as illustrated in Circulating and tissue forms of the intestinal growth factor, glucagon-like peptide-2. Endocrinology. 1997 Nov;138(11):4837-43
These findings predict that GLP-2, like GLP-1, will exhibit a short t1/2 in vivo, in large measure due to rapid inactivation by DPP-4. Furthermore, it is also apparent that DPP-4 inhibitors will also potentiate the action of exogenous and endogenous GLP-2, and not only GLP-1 and GIP.
Indeed, studies using the DPP-4 inhibitor valine pyrrolidide (val-pyr), co-administered with native GLP-2, in rats and mice, demonstrate potentiation of the biological actions of exogenous GLP-2, and enhanced plasma levels of circulating intact biologically active GLP-2, in the presence of the DPP-4 inhibitor. In contrast, treatment with DPP-4 inhibitors alone did not potentiate GLP-2 actions as assessed by measurements of bowel growth. See Endocrinology 2000 141: 4013-4020. Dipeptidyl peptidase IV inhibition enhances the intestinotrophic effect of glucagon-like peptide-2 in rats and mice.
Analysis of CD26 mice following induction of DS-induced experimental colitis revealed no difference in the extent of bowel injury, mucosal cell proliferation, or weight loss. Intriguingly, there was no difference in the levels of DPP-4 activity in control vs CD26-/- mice, and it is not clear whether there were differences in the levels of intact GLP-2(1-33) vs. cleaved GLP-2(3-33) in these different mice. See Development and resolution of experimental colitis in mice with targeted deletion of dipeptidyl peptidase IV. J Cell Physiol. 2005 Mar 7;
Studies using the colon cancer cell lines SW480 and HT29 demonstrate that the combination of GLP-2 and DPP-4 inhibitors reduced the doubling time of cell lines in vitro, although the specific receptor mediating the actions of GLP-2 in these cells remains unclear as outlined in DPPIV inhibitors extend GLP-2 mediated tumour promoting effects on intestinal cancer cells. Regul Pept. 2006 Aug 11; [Epub ahead of print]