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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

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

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Volume 386, Issue 7 (Jul 2005)


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 Irwin
  • School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, N. Ireland, UK
/ Victor A. Gault
  • School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, N. Ireland, UK
/ Brian D. Green
  • School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, N. Ireland, UK
/ Brett Greer
  • School of Biology and Biochemistry, Queen's University of Belfast, Medical Biology Centre, Belfast, BT9 7BL, N. Ireland, UK
/ Patrick Harriott
  • Centre for Synthesis and Chemical Biology, Department of Pharmaceutical and Medicinal Chemistry, Royal College of Surgeons in Ireland,St. Stephen's Green, Dublin 2, Ireland
/ Clifford J. Bailey
  • School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET, UK
/ Peter R. Flatt
  • School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, N. Ireland, UK
/ Finbarr P.M. O'Harte
  • School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, N. Ireland, UK
Published Online: 2005-08-08 | DOI: https://doi.org/10.1515/BC.2005.079


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


About the article

Corresponding author

Received: March 9, 2005

Accepted: May 30, 2005

Published Online: 2005-08-08

Published in Print: 2005-07-01

Citation Information: Biological Chemistry, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/BC.2005.079. Export Citation

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