Dipeptidyl peptidase IV inhibition enhances the intestinotrophic effect ofglucagon-like peptide-2 rats and mice

Glucagon-like peptide-2 (GLP-2) induces intestinal growth in mice; but in n ormal rats, it seems less potent, possibly because of degradation of GLP-2 by the enzyme dipeptidyl peptidase IV (DPP-IV). The purpose of this study w as to investigate the survival and effect of GLP-2 in rats and mice after s c injection of GLP-2 with or without the specific DPP-IV inhibitor, valine- pyr rolidide NP). Rats were injected sc with 40 mug GLP-2 or 40 mug GLP-2+1 5 mg VP. Plasma was collected at different time points and analyzed, by RIA , for intact GLP-2. Rats were treated for 14 days with: saline; 15 mg VP; 4 0 mug GLP-2, 40 mug GLP-2 +15 mg VP; 40 mug GLP-2 (3-33). Mice were treated for 10 days with: saline; 5 mug GLP-2; 5 mug GLP-2+1.5 mg VP; 25 mug GLP-2 ; 25 mug GLP-2 (3-33). In both cases, body weight, intestinal weight, lengt h, and morphometric data were measured. After sc injection, the plasma conc entration of GLP-2 reached a maximum after 15 min, and elevated concentrati ons persisted for 4-8 h. With VP, the concentration of intact GLP-2 was abo ut a-fold higher for at least the initial 60 min. Rats treated with GLP-2+V P had increased (P < 0.01) small-bowel weight (4.68 +/- 0.11%, relative to body weight), compared with the two control groups, [3.01 +/- 0.06% (VP) an d 2.94 +/- 0.07% (NaCl)] and GLP-2 alone (3.52 +/- 0.10%). In mice, the gro wth effect of 5 <mu>g GLP-2+VP was comparable with that of 25 mug GLP-2. GL P-2 (3-33) had no effect in rats, but it had a weak effect on intestinal gr owth in mice. The extensive GLP-2 degradation in rats can be reduced by VP, and DPP-IV inhibition markedly enhances the intestinotrophic effect of GLP -2 in both rats and mice. We propose that DPP-IV inhibition may be consider ed to enhance the efficacy of GLP-2 as a therapeutic agent.