The catabolism of glucagon-like peptide 2, a novel intestinal growth factor

grantor: University of TorontoThe intestinal peptide glucagon-like peptide 2 (GLP-2) is a potent intestinotropic hormone. Previous studies have shown that peptides with sequence homology to the N-terminus of GLP-2 (His$\sb1$-Ala$\sb2$), are cleaved and inactivated by dipeptidyl-peptidase IV (DP IV). We therefore hypothesized that DP IV would also target GLP-2. GLP-2$\sp{1-33}$ was degraded to GLP-2$\sp{3-33}$ in serum from normal and DP IV negative rats, by 69 $\pm$ 104% and 39 $\pm$ 26, respectively, while the bioactive analog Gly$\sb2$-GLP-2 was degraded by only 22 $\pm$ 10% (n = 5, P $<$ 0.01 vs controls). In vivo, GLP-2$\sp{1-33}$ was progressively degraded to GLP-2$\sp{3-33}$ over time in control rats, while DP IV negative rats and normal rats injected with GLP-2$\sp{1-33}$ and Gly2-GLP-2, respectively, showed significantly less degradation (n = 3-6, P $<$ 0.01 and P $<$ 0.001, respectively). Pro-boropro, an in vivo inhibitor of DP IV, also significantly decreased degradation of GLP-2 (n = 3, P $<$ 0.05), confirming that DP IV cleaves GLP-2. In contrast, studies using GLP-2 analogs designed to withstand cleavage by neutral endopeptidase, suggested this protease might not cleave GLP-2. Finally a role for the kidney in clearance of GLP-2$\sp{1-33}$ and GLP-2$\sp{3-33}$ from the circulation was demonstrated by analysis of the half-life of immunoreactive GLP-2 in nephrectomized and non-nephrectomized rats (4.76 $\pm$ 0.45 and 2.62 $\pm$ 0.31 min, respectively, n = 3-6, P $<$ 0.001). In conclusion, the results of this study show that the biological effectiveness of GLP-2 is determined by the actions of DP IV, which degrades GLP-2$\sp{1-33}$ to its inactive form, GLP-2$\sp{3-33}$ and the kidney, which clears GLP-2 and its metabolite from the circulation.M.Sc