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

Kerr, Barry D, Irwin, Nigel, O'Harte, Finbarr P M, Bailey, Clifford J, Flatt, Peter R and Gault, Victor A (2009). Fatty acid derivatised analogues of glucose-dependent insulinotropic polypeptide with improved antihyperglycaemic and insulinotropic properties. Biochemical Pharmacology, 78 (8), pp. 1008-1016.

Abstract

C-terminal acylation of Lys(37) 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 in vitro cAMP production and insulin secretion. Administration of GIP analogues to ob/ob mice significantly lowered plasma glucose-GIP(Lys(37)MYR), N-AcGIP(Lys(37)MYR) and GIP(Lys(37)PAL) increased plasma insulin concentrations. GIP(Lys(37)MYR) and N-AcGIP(Lys(37)MYR) elicited protracted glucose-lowering effects when administered 24h prior to an intraperitoneal glucose load. Daily administration of GIP(Lys(37)MYR) and N-AcGIP(Lys(37)MYR) to ob/ob 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.

Publication DOI: https://doi.org/10.1016/j.bcp.2009.05.037
Divisions: Life & Health Sciences > Biosciences
Life & Health Sciences
Uncontrolled Keywords: animals,blood glucose,cyclic AMP,fatty acids,gastric inhibitory polypeptide,glucose tolerance test,half-life,homeostasis,hypoglycemic agents,inhibitory concentration 50,insulin,insulin-secreting cells,mice,obese mice,time factors,Biochemistry,Pharmacology
Full Text Link: https://hal.arc ... 514597/document
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
Published Date: 2009-10-15
Authors: Kerr, Barry D
Irwin, Nigel
O'Harte, Finbarr P M
Bailey, Clifford J ( 0000-0002-6998-6811)
Flatt, Peter R
Gault, Victor A

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