Degradation, insulin secretion, and antihyperglycemic actions of two palmitate-derivitized N-terminal pyroglutamyl analogues of glucose-dependent insulinotropic polypeptide

Nigel Irwin, Brian D. Green, Victor A. Gault*, Brett Greer, Patrick Harriott, Clifford J. Bailey, Peter R. Flatt, Finbarr P.M. O'Harte

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Exploitation of glucose-dependent insulinotropic polypeptide (GIP) is hindered by its short biological half-life and rapid renal clearance. To circumvent these problems, two novel acylated N-terminally modified GIP analogues, N-pGluGIP(LysPAL16) and N-pGluGIP(LysPAL37), were evaluated. In contrast to native GIP, both analogues were completely resistant to dipeptidyl peptidase IV degradation. In GIP-receptor transfected fibroblasts, N-pGluGIP(LysPAL16) and N-pGluGIP(LysPAL37) exhibited enhanced stimulation of cAMP production. Insulinotropic responses in clonal beta-cells were similar to native GIP. When administered together with glucose to ob/ob mice, the glycemic excursions were significantly less for both analogues and insulin responses were greater than native GIP. Extended insulinotropic and antihyperglycemic actions were also evident. These data indicate that palmitate-derivitized analogues of N-terminal pyroglutamyl GIP represent a novel class of stable, long-acting, and effective GIP analogues for potential type 2 diabetes therapy.

Original languageEnglish
Pages (from-to)1244-1250
Number of pages7
JournalJournal of Medicinal Chemistry
Volume48
Issue number4
Early online date1 Feb 2005
DOIs
Publication statusPublished - 2005

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