REGULATION OF THE BIOLOGICAL-ACTIVITY OF GLUCAGON-LIKE PEPTIDE-2 IN-VIVO BY DIPEPTIDYL PEPTIDASE-IV

Species-specific differences in the enzymatic inactivation of peptides is an important consideration in the evaluation of therapeutic effica cy. We demonstrate that glucagon-like peptide 2 (GLP-2), shown to be h ighly intestinotrophic in mice, promotes an increase in intestinal vil lus height but has no trophic effect on small bowel weight in rats. Th e reduced intestinotrophic activity of GLP-5 in rats is attributable t o inactivation by the enzyme dipeptidyl peptidase IV (DPP-IV), GLP-2(1 -33) was degraded to GLP-2(3-33) following incubation with human place ntal DPP-IV or rat serum but not by serum from DPP-IV-deficient rats, Administration of rat GLP-2 to DPP-IV-deficient rats was associated wi th markedly increased bioactivity of rat GLP-2 resulting in a signific ant increase in small bowel weight. A synthetic GLP-2 analog, r[Gly(2) ]GLP-2, with an alanine to glycine substitution at position 2, was res istant to cleavage by both DPP-IV and rat serum in vitro. Treatment of wild-type rats with r[Gly(2)]GLP-2 produced a statistically significa nt increase in small bowel mass. DPP-IV-mediated inactivation of GLP-5 is a critical determinant of the growth factor-like properties of GLP -2.