Fatty acid derivatised analogues of glucose-dependent insulinotropic polypeptide with improved antihyperglycaemic and insulinotropic properties

Barry D. Kerr , Nigel Irwin , Finbarr P.M. O'Harte , Clifford J. Bailey , Peter R. Flatt , Victor A. Gault

C-terminal acylation of Lys with myristic (MYR; tetradecanoic acid), palmitic (PAL; hexadecanoic acid) and stearic (octadecanoic acid) fatty acids with or without N-terminal acetylation was employed to develop long-acting analogues of the glucoregulatory hormone, glucose-dependent insulinotropic polypeptide (GIP). All GIP analogues exhibited resistance to dipeptidylpeptidase-IV (DPP-IV) and significantly improved cAMP production and insulin secretion. Administration of GIP analogues to mice significantly lowered plasma glucose - GIP(LysMYR), -AcGIP(LysMYR) and GIP(LysPAL) increased plasma insulin concentrations. GIP(LysMYR) and -AcGIP(LysMYR) elicited protracted glucose-lowering effect when administered 24h prior to an intraperitoneal glucose load. Daily administration of GIP(LysMYR) and -AcGIP(LysMYR) to mice for 24 days decreased glucose and significantly improved plasma insulin, glucose tolerance and beta-cell glucose responsiveness. Insulin sensitivity, pancreatic insulin content and triglyceride levels were not changed. These data demonstrate that C-terminal acylation particularly with myristic acid provides a class of stable, longer-acting forms of GIP for further evaluation in diabetes therapy.

Mots clés: dipeptidylpeptidase-IV (DPP-IV); glucose-dependent insulinotropic polypeptide (GIP); GIP agonist; glucose homeostasis; insulin secretion

Barry D. Kerr, Nigel Irwin, Finbarr P.M. O'Harte, Clifford J. Bailey, Peter R. Flatt, et al.. Fatty acid derivatised analogues of glucose-dependent insulinotropic polypeptide with improved antihyperglycaemic and insulinotropic properties. Biochemical Pharmacology, 2009, 78 (8), pp.1008. ⟨10.1016/j.bcp.2009.05.037⟩. ⟨hal-00514597⟩