title: Fatty acid derivatised analogues of glucose-dependent insulinotropic polypeptide with improved antihyperglycaemic and insulinotropic properties.
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.
authors.affiliation: The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Cromore Road, Coleraine BT52 1SA, Northern Ireland, UK.
authors.forename: Barry D
authors.initials: BD
authors.lastname: Kerr
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
authors.forename: Finbarr P M
authors.initials: FP
authors.lastname: O'Harte
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Bailey
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
authors.forename: Victor A
authors.initials: VA
authors.lastname: Gault
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D000242:Cyclic AMP / Q000096:biosynthesis; D005227:Fatty Acids / Q000737:chemistry / Q000627:therapeutic use*; D005749:Gastric Inhibitory Polypeptide / Q000819:agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use*; D005951:Glucose Tolerance Test; D006207:Half-Life; D006706:Homeostasis; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000627:therapeutic use*; D020128:Inhibitory Concentration 50; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D007328:Insulin; D005749:Gastric Inhibitory Polypeptide; D000242:Cyclic AMP