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Dipeptidyl Peptidase IV Inhibition Enhances the Intestinotrophic Effect of Glucagon-Like Peptide-2 in Rats and Mice¹

Departments of Medical Physiology (B.H., J.J.H.) and Anatomy (J.T., H.K., S.T., C.O., C.R., S.S.P.), The Panum Institute, University of Copenhagen, Copenhagen N, DK-2200 Denmark

Address all correspondence and requests for reprints to: Prof. Jens Juul Holst, Department of Medical Physiology, University of Copenhagen, The Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen, Denmark. E-mail: holst{at}mfi.ku.dk

Glucagon-like peptide-2 (GLP-2) induces intestinal growth in mice; but in normal 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 was to investigate the survival and effect of GLP-2 in rats and mice after sc injection of GLP-2 with or without the specific DPP-IV inhibitor, valine-pyrrolidide (VP). Rats were injected sc with 40 µg GLP-2 or 40 µg GLP-2+15 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; 40 µg GLP-2, 40 µg GLP-2+15 mg VP; 40 µg GLP-2 (3–33). Mice were treated for 10 days with: saline; 5 µg GLP-2; 5 µg GLP-2+1.5 mg VP; 25 µg GLP-2; 25 µg GLP-2 3–33). In both cases, body weight, intestinal weight, length, and morphometric data were measured. After sc injection, the plasma concentration of GLP-2 reached a maximum after 15 min, and elevated concentrations persisted for 4–8 h. With VP, the concentration of intact GLP-2 was about 2-fold higher for at least the initial 60 min. Rats treated with GLP-2+VP 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) and 2.94 ± 0.07% (NaCl)] and GLP-2 alone (3.52 ± 0.10%). In mice, the growth effect of 5 µg GLP-2+VP was comparable with that of 25 µg GLP-2. GLP-2 (3–33) had no effect in rats, but it had a weak effect on intestinal growth 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 considered to enhance the efficacy of GLP-2 as a therapeutic agent.

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