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ORIGINAL RESEARCH ARTICLE

Inhibition of Dipeptidyl-Peptidase IV Does Not Increase Circulating IGF-1 Concentrations in Growing Pigs

T. D. Faidley^*,1, B. Leiting^,2, K. D. Pryor, K. Lyons, G. J. Hickey^* and D. R. Thompson^*

^* Department of Pharmacology; Department of Metabolic Disorders; and Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065

To whom requests for reprints should be addressed at ¹ Merck Research Laboratories, Branchburg Farm, 203 River Road, Somerville, NJ 08876. E-mail: terry_faidley{at}merck.com

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·hr for 72 hrs, n = 4) or GHRH (0.11 ml/kg sterile saline, followed by a continuous infusion of GHRH at 2.5 µg/ kg·hr for 48 hrs, n = 4). Plasma concentrations of Compound 1 were maintained at 1 µM, 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·hr) than controls (543 ± 330 ng/ml·hr). GHRH treatment increased the IGF-1 AUC (1210 ± 160 ng/ml·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.

Key Words: growth hormone releasing hormone • DPP-IV • sitagliptin analog

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