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).
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.
Irwin
Nigel
N
School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, N. Ireland, UK. n.irwin@ulster.ac.uk
Gault
Victor A
VA
Green
Brian D
BD
Greer
Brett
B
Harriott
Patrick
P
Bailey
Clifford J
CJ
Flatt
Peter R
PR
O'Harte
Finbarr P M
FP
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
D005227:Fatty Acids; D007004:Hypoglycemic Agents; D005749:Gastric Inhibitory Polypeptide; D000242:Cyclic AMP