title: Characterisation and glucoregulatory actions of a novel acylated form of the (Pro3)GIP receptor antagonist in type 2 diabetes.
abstract: In this study, we tested the biological activity of a novel acylated form of (Pro3)glucose-dependent insulinotropic polypetide [(Pro3)GIP] prepared by conjugating palmitic acid to Lys16 to enhance its efficacy in vivo by promoting binding to albumin and extending its biological actions. Like the parent molecule (Pro3)GIP, (Pro3)GIPLys16PAL 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 (Pro3)GIPLys16PAL 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 (Pro3)GIPLys16PAL (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. (Pro3)GIPLys16PAL 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 (Pro3)GIPLys16PAL-treated mice. These data demonstrate that acylation of Lys16 with palmitic acid in (Pro3)GIP does not improve its biological effectiveness as a GIP receptor antagonist.
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK. va.gault@ulster.ac.uk
authors.forename: Victor A
authors.initials: VA
authors.lastname: Gault
authors.forename: Kerry
authors.initials: K
authors.lastname: Hunter
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
authors.forename: Brett
authors.initials: B
authors.lastname: Greer
authors.forename: Brian D
authors.initials: BD
authors.lastname: Green
authors.forename: Patrick
authors.initials: P
authors.lastname: Harriott
authors.forename: Finbarr P M
authors.initials: FP
authors.lastname: O'Harte
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
mesh_terms: D000215:Acylation; D000818:Animals; D001665:Binding Sites; D000242:Cyclic AMP / Q000096:biosynthesis; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D005749:Gastric Inhibitory Polypeptide / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D005947:Glucose / Q000737:chemistry / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008239:Lysine / Q000737:chemistry; D051379:Mice; D008820:Mice, Obese; D019308:Palmitic Acid / Q000737:chemistry; D011964:Receptors, Gastrointestinal Hormone / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D007328:Insulin; D011964:Receptors, Gastrointestinal Hormone; C479120:glucose-dependent insulinotropic polypeptide, Pro(3)-; C508994:glucose-dependent insulinotropic polypeptide, epsilon-palmitoyl-Lys(16)-; D019308:Palmitic Acid; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor; D000242:Cyclic AMP; D005947:Glucose; D008239:Lysine