title: Antidiabetic potential of two novel fatty acid derivatised, N-terminally modified analogues of glucose-dependent insulinotropic polypeptide (GIP): N-AcGIP(LysPAL16) and N-AcGIP(LysPAL37).
abstract: Fatty acid derivatisation was used to develop two novel, long-acting, N-terminally modified, glucose-dependent insulinotropic polypeptide (GIP) analogues, N-AcGIP(LysPAL16) and N-AcGIP(LysPAL37). In contrast to GIP, which was rapidly degraded by in vitro incubation with dipeptidylpeptidase IV (DPP IV) (52% intact after 2 h), the analogues remained fully intact for up to 24 h. Both fatty acid-derivatised analogues stimulated cAMP production in GIP receptor Chinese hamster lung (CHL) fibroblasts (EC50 12.1-13.0 nM) and significantly improved in vitro insulin secretion from BRIN-BD11 cells (1.1- to 2.4-fold; p < 0.05 to p < 0.001) compared to control (5.6 mM glucose). Administration of N-AcGIP(LysPAL16) and N-AcGIP(LysPAL37) together with glucose in obese diabetic (ob/ob) mice significantly reduced the glycaemic excursion (1.4- and 1.5-fold, respectively; p < 0.05 to p < 0.01) and improved the insulinotropic response (1.5- and 2.3-fold, respectively; p < 0.01 to p < 0.001) compared to native peptide. Dose-response studies with N-AcGIP(LysPAL37) revealed that even the lowest concentration (6.25 nmol/kg) induced a highly significant decrease (1.4-fold; p < 0.001) in the overall glycaemic excursion, coupled with a significant increase (2.0-fold; p < 0.01) in circulating insulin. Furthermore, basal glucose values remained significantly reduced (p < 0.05) and insulin values increased 24 h following a single injection of N-AcGIP(LysPAL37). The glucose-lowering action of the fatty acid-derivatised peptide was greater than that of N-AcGIP. These data demonstrate that novel fatty acid-derivatised analogues of N-terminally modified AcGIP function as long-acting GIP-receptor agonists, with significant antidiabetic potential.
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, N. Ireland, UK. n.irwin@ulster.ac.uk
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
authors.forename: Victor A
authors.initials: VA
authors.lastname: Gault
authors.forename: Brian D
authors.initials: BD
authors.lastname: Green
authors.forename: Brett
authors.initials: B
authors.lastname: Greer
authors.forename: Patrick
authors.initials: P
authors.lastname: Harriott
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Bailey
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
authors.forename: Finbarr P M
authors.initials: FP
authors.lastname: O'Harte
mesh_terms: D000818:Animals; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D005227:Fatty Acids / Q000737:chemistry / Q000494:pharmacology*; D005749:Gastric Inhibitory Polypeptide / Q000737:chemistry / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D005227:Fatty Acids; D007004:Hypoglycemic Agents; D005749:Gastric Inhibitory Polypeptide; D000242:Cyclic AMP