Inhibition of dipeptidyl-peptidase IV does not increase circulating IGF-1 concentrations in growing pigs.
The enzyme dipeptidyl peptidase-IV (DPP-IV) inactivates a variety of bioactive peptides, including glucagon-like peptide-1 (GLP-1) and growth hormone releasing hormone (GHRH). Inhibiting DPP-IV in order to increase circulating GLP-1 is of interest as a treatment for Type II diabetes. Inactivation of DPP-IV may also increase circulating GHRH, potentially enhancing growth in domestic animals. To test the hypothesis that inhibition of DPP-IV activity will influence the growth hormone/ IGF-1 axis, growing pigs (Sus scrofa domesticus, 78 kg) were treated with a DPP-IV inhibitor (Compound 1, the 2,5-difluor-ophenyl analog of the triazolopiperazine MK0431, sitagliptin), and plasma concentrations of IGF-1 were monitored. Pigs were administered either sterile saline (0.11 ml/kg followed by a continuous infusion at 2 ml/hr for 72 hrs, controls, n = 2), Compound 1 (2.78 mg/kg followed by a continuous infusion at 0.327 mg/kg x hr for 72 hrs, n = 4) or GHRH (0.11 ml/kg sterile saline, followed by a continuous infusion of GHRH at 2.5 microg/ kg x hr for 48 hrs, n = 4). Plasma concentrations of Compound 1 were maintained at 1 microM, which resulted in a 90% inhibition of circulating DPP-IV activity. Relative to the predose 24-hr period, area under the IGF-1 concentration curve (AUC) tended to be lower (P = 0.062) with Compound 1 (.79 +/- 130 ng/ml x hr) than controls (543 +/- 330 ng/ml x hr). GHRH treatment increased the IGF-1 AUC (1210 +/- 160 ng/ml x hr, P = 0.049 vs. controls and P = 0.001 vs. Compound 1). We conclude that inhibition of DPP-IV does not alter the circulating levels of IGF-1 in the growing pig.
Faidley
T D
TD
Department of Pharmacology, Merck Research Laboratories, Branchburg Farm, 203 River Road, Somerville, NJ 08876, USA. terry_faidley@merck.com
Leiting
B
B
Pryor
K D
KD
Lyons
K
K
Hickey
G J
GJ
Thompson
D R
DR
D000818:Animals; D019540:Area Under Curve; D020789:Cathepsin C / Q000037:antagonists & inhibitors* / Q000097:blood / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D013007:Growth Hormone-Releasing Hormone / Q000187:drug effects / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011719:Pyrazines / Q000494:pharmacology; D000068900:Sitagliptin Phosphate; D013552:Swine; D014230:Triazoles / Q000494:pharmacology
D004791:Enzyme Inhibitors; D011719:Pyrazines; D014230:Triazoles; D007334:Insulin-Like Growth Factor I; D013007:Growth Hormone-Releasing Hormone; D020789:Cathepsin C; D000068900:Sitagliptin Phosphate