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;

Okawada and colleagues examined the effects of sitagliptin in C57BL/6 mice subjected to 50% small bowel resection, a model of short bowel syndrome (SBS). Sitagliptin administration (dosed every 8 hrs for 3 days) significantly increased villus height and crypt depth and cell proliferation and reduced enterocyte apoptosis in the jejunum and ileum beyond that observed in SBS mice alone. Levels of intact plasma GLP-2 increased from ~30 to ~ 41 pmol/l with sitagliptin. Levels of Glp2r mRNA transcripts were not significantly different in jejunum or ileum in any of the experimental groups. Sitagliptin also increased mRNA levels of b-cetenin and and c-myc in the ileum. See Administration of a dipeptidyl peptidase IV inhibitor enhances the intestinal adaptation in a mouse model of short bowel syndrome Surgery. 2011 Jun 28. [Epub ahead of print]

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]