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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred

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Antidiabetic potential of two novel fatty acid derivatised, N-terminally modified analogues of glucose-dependent insulinotropic polypeptide (GIP): N-AcGIP(LysPAL16) and N-AcGIP(LysPAL37)

Nigel Irwin1 / Victor A. Gault2 / Brian D. Green3 / Brett Greer4 / Patrick Harriott5 / Clifford J. Bailey6 / Peter R. Flatt7 / Finbarr P.M. O'Harte8

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Citation Information: Biological Chemistry. Volume 386, Issue 7, Pages 679–687, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/BC.2005.079, August 2005

Publication History

Received:
March 9, 2005
Accepted:
May 30, 2005
Published Online:
2005-08-08

Abstract

Fatty acid derivatisation was used to develop two novel, long-acting, N-terminally modified, glucose-dependent insulinotropic polypeptide (GIP) analogues, N-AcGIP(LysPAL16) and N-AcGIP(LysPAL37). In contrast to GIP, which was rapidly degraded by in vitro incubation with dipeptidylpeptidase IV (DPP IV) (52% intact after 2 h), the analogues remained fully intact for up to 24 h. Both fatty acid-derivatised analogues stimulated cAMP production in GIP receptor Chinese hamster lung (CHL) fibroblasts (EC50 12.1–13.0 nM) and significantly improved in vitro insulin secretion from BRIN-BD11 cells (1.1- to 2.4-fold; p<0.05 to p<0.001) compared to control (5.6 mM glucose). Administration of N-AcGIP(LysPAL16) and N-AcGIP(LysPAL37) together with glucose in obese diabetic (ob/ob) mice significantly reduced the glycaemic excursion (1.4- and 1.5-fold, respectively; p<0.05 to p<0.01) and improved the insulinotropic response (1.5- and 2.3-fold, respectively; p<0.01 to p<0.001) compared to native peptide. Dose-response studies with N-AcGIP(LysPAL37) revealed that even the lowest concentration (6.25 nmol/kg) induced a highly significant decrease (1.4-fold; p<0.001) in the overall glycaemic excursion, coupled with a significant increase (2.0-fold; p<0.01) in circulating insulin. Furthermore, basal glucose values remained significantly reduced (p<0.05) and insulin values increased 24 h following a single injection of N-AcGIP(LysPAL37). The glucose-lowering action of the fatty acid-derivatised peptide was greater than that of N-AcGIP. These data demonstrate that novel fatty acid-derivatised analogues of N-terminally modified AcGIP function as long-acting GIP-receptor agonists, with significant antidiabetic potential.

Keywords: dipeptidylpeptidase IV (DPP IV); fatty acid derivatisation; GIP analogues; glucose-dependent insulinotropic polypeptide (GIP); insulin secretion; obese diabetic ob/ob mice

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