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

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)1008-1016
Number of pages9
JournalBiochemical Pharmacology
Volume78
Issue number8
Early online date29 May 2009
DOIs
Publication statusPublished - 15 Oct 2009

Fingerprint

Hypoglycemic Agents
Fatty Acids
Glucose
Peptides
Insulin
Acylation
Myristic Acid
Plasmas
Acetylation
Palmitic Acid
Medical problems
Insulin Resistance
Triglycerides
Hormones

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

Cite this

Kerr, Barry D ; Irwin, Nigel ; O'Harte, Finbarr P M ; Bailey, Clifford J ; Flatt, Peter R ; Gault, Victor A. / Fatty acid derivatised analogues of glucose-dependent insulinotropic polypeptide with improved antihyperglycaemic and insulinotropic properties. In: Biochemical Pharmacology. 2009 ; Vol. 78, No. 8. pp. 1008-1016.
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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; Gault, Victor A.

In: Biochemical Pharmacology, Vol. 78, No. 8, 15.10.2009, p. 1008-1016.

Research output: Contribution to journalArticle

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T1 - Fatty acid derivatised analogues of glucose-dependent insulinotropic polypeptide with improved antihyperglycaemic and insulinotropic properties

AU - Kerr, Barry D

AU - Irwin, Nigel

AU - O'Harte, Finbarr P M

AU - Bailey, Clifford J

AU - Flatt, Peter R

AU - Gault, Victor A

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KW - animals

KW - blood glucose

KW - cyclic AMP

KW - fatty acids

KW - gastric inhibitory polypeptide

KW - glucose tolerance test

KW - half-life

KW - homeostasis

KW - hypoglycemic agents

KW - inhibitory concentration 50

KW - insulin

KW - insulin-secreting cells

KW - mice

KW - obese mice

KW - time factors

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DO - 10.1016/j.bcp.2009.05.037

M3 - Article

VL - 78

SP - 1008

EP - 1016

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 8

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