Characterisation and glucoregulatory actions of a novel acylated form of the (Pro(3))GIP receptor antagonist in type 2 diabetes

V.A. Gault, K. Hunter, N. Irwin, Brett Greer, Brian Green, Patrick Harriott, F.P.M. O'Harte, P.R. Flatt

Research output: Contribution to journalArticle

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Abstract

In this study, we tested the biological activity of a novel acylated form of (Pro(3))glucose-dependent insulinotropic polypetide [(Pro3)GIP] prepared by conjugating palmitic acid to Lys(16) to enhance its efficacy in vivo by promoting binding to albumin and extending its biological actions. Like the parent molecule (Pro(3))GIP, (Pro(3))GIPLys(16)PAL was completely stable to the actions of DPP-IV and significantly (p <0.01 to p <0.001) inhibited GIP-stimulated cAMP production and cellular insulin secretion. Furthermore, acute administration of (Pro(3))GIPLys(16)PAL also significantly (p <0.05 to p <0.001) countered the glucose-lowering and insulin-releasing actions of GIP in ob/ob mice. Daily injection of (Pro(3))GIPLys(16)PAL (25 nmol/kg bw) in 14-18-week-old ob/ob mice over 14 days had no effect on body weight, food intake or non-fasting plasma glucose and insulin concentrations. (Pro(3))GIPLys(16)PAL treatment also failed to significantly alter the glycaemic response to an i.p. glucose load or test meal, but insulin concentrations were significantly reduced (1.5-fold; p <0.05) after the glucose load. Insulin sensitivity was enhanced (1.3-fold; p <0.05) and pancreatic insulin was significantly reduced (p <0.05) in the (Pro(3))GIPLys(16)PAL-treated mice. These data demonstrate that acylation of Lys(16) with palmitic acid in (Pro(3))GIP does not improve its biological effectiveness as a GIP receptor antagonist.
Original languageEnglish
Pages (from-to)173-179
Number of pages7
JournalBiological Chemistry
Volume388
Issue number2
DOIs
Publication statusPublished - 01 Feb 2007

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Medical problems
Type 2 Diabetes Mellitus
Insulin
Glucose
Palmitic Acid
Acylation
Meals
Insulin Resistance
Albumins
Bioactivity
Eating
Body Weight
Pro(3)-glucose-dependent insulinotropic polypeptide
gastric inhibitory polypeptide receptor
Injections
Plasmas
Molecules
Therapeutics

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Gault, V.A. ; Hunter, K. ; Irwin, N. ; Greer, Brett ; Green, Brian ; Harriott, Patrick ; O'Harte, F.P.M. ; Flatt, P.R. / Characterisation and glucoregulatory actions of a novel acylated form of the (Pro(3))GIP receptor antagonist in type 2 diabetes. In: Biological Chemistry. 2007 ; Vol. 388, No. 2. pp. 173-179.
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Characterisation and glucoregulatory actions of a novel acylated form of the (Pro(3))GIP receptor antagonist in type 2 diabetes. / Gault, V.A.; Hunter, K.; Irwin, N.; Greer, Brett; Green, Brian; Harriott, Patrick; O'Harte, F.P.M.; Flatt, P.R.

In: Biological Chemistry, Vol. 388, No. 2, 01.02.2007, p. 173-179.

Research output: Contribution to journalArticle

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