Irwin, Nigel, Gault, Victor, Green, BD, Greer, B, Harriott, P, Bailey, CJ, O'Harte, Finbarr and Flatt, Peter (2005) Antidiabetic potential of two novel fatty acid derivatised, N-terminally modified analogues of glucose-dependent insulinotropic polypeptide (GIP): N-AcGIP(LysPAL(16)) and N-AcGIP(LysPAL(37)). BIOLOGICAL CHEMISTRY, 386 (7). pp. 679-687. [Journal article]
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Fatty acid derivatisation was used to develop two novel, long-acting, N-terminally modified, glucose-dependent insulinotropic polypeptide (GIP) analogues, N-AcGIP(LysPAL(16))and N-AcGIP(LysPAL(37)). 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 NAcGIP(LysPAL(37)). The glucose-lowering action of the fatty acid-derivatised peptide was greater than that of NAcGIP. 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.
|Item Type:||Journal article|
|Faculties and Schools:||Faculty of Life and Health Sciences|
Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
|Research Institutes and Groups:||Biomedical Sciences Research Institute|
Biomedical Sciences Research Institute > Diabetes
|Deposited By:||Professor Peter Flatt|
|Deposited On:||18 Dec 2009 10:00|
|Last Modified:||19 Nov 2012 16:21|
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