Dipeptidyl peptidase IV inhibition enhances the intestinotrophic effect of glucagon-like peptide-2 in rats and mice.
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 s.c. injection of GLP-2 with or without the specific DPP-IV inhibitor, valine-pyrrolidide (VP). Rats were injected s.c. with 40 microg GLP-2 or 40 microg 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 microg GLP-2, 40 microg GLP-2+15 mg VP; 40 microg GLP-2 (3-33). Mice were treated for 10 days with: saline; 5 microg GLP-2; 5 microg GLP-2+1.5 mg VP; 25 microg GLP-2; 25 microg GLP-2 (3-33). In both cases, body weight, intestinal weight, length, and morphometric data were measured. After s.c. 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 microg GLP-2+VP was comparable with that of 25 microg 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.
Hartmann
B
B
Department of Medical Physiology, The Panum Institute, University of Copenhagen, Denmark.
Thulesen
J
J
Kissow
H
H
Thulesen
S
S
Orskov
C
C
Ropke
C
C
Poulsen
S S
SS
Holst
J J
JJ
D000818:Animals; D001835:Body Weight; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D053767:Glucagon-Like Peptide 2; D004763:Glucagon-Like Peptides; D006801:Humans; D007422:Intestines / Q000187:drug effects* / Q000254:growth & development*; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D014633:Valine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D053767:Glucagon-Like Peptide 2; D010455:Peptides; D011758:Pyrroles; D011994:Recombinant Proteins; C112092:valine-pyrrolidide; D004763:Glucagon-Like Peptides; D018819:Dipeptidyl Peptidase 4; D014633:Valine