Submitted on August 3, 2006
Accepted on February 6, 2007
Antagonistic effects of two novel GIP analogues, (Hyp3)GIP and (Hyp3)GIPLys16PAL on the biological actions of GIP and longer term effects in diabetic ob/ob mice
Finbarr PM O'Harte1*, Kerry Hunter1, Victor A Gault1, Nigel Irwin1, Brian D Green2, Brett Greer3, Patrick Harriott3, Clifford J Bailey4, and Peter R. Flatt1
1 School of Biomedical Sciences, University of Ulster, Coleraine, United Kingdom
2 School of Biological Sciences, The Queen's University of Belfast, Belfast, United Kingdom
3 School of Biology & Biochemistry, The Queen's University of Belfast, Belfast, United Kingdom
4 Life and Health Sciences, University of Aston, Birmingham, United Kingdom
* To whom correspondence should be addressed. E-mail: fpm.oharte{at}ulster.ac.uk.
This study examines the actions of a novel enzyme-resistant, N-terminally modified GIP analogue (Hyp3)GIP and its fatty acid derivatized analogue (Hyp3)GIPLys16PAL. Acute effects are compared with the established GIP receptor antagonist, (Pro3)GIP. All three peptides exhibited DPP-IV resistance and significantly inhibited GIP stimulated cAMP formation and insulin secretion in GIP-receptor transfected fibroblasts and in clonal pancreatic BRIN-BD11 cells, respectively. Likewise in obese diabetic ob/ob mice, intraperitoneal administration of GIP analogues significantly inhibited the acute antihyperglycemic and insulin releasing effects of native GIP. Administration of once daily injections of (Hyp3)GIP or (Hyp3)GIPLys16PAL for 14 days resulted in significantly lower plasma glucose levels (P<0.05) after (Hyp3)GIP on days 12 and 14, and enhanced glucose tolerance (P<0.05) and insulin sensitivity (P<0.05 to P<0.001) in both groups by day 14. Both (Hyp3)GIP and (Hyp3)GIPLys16PAL treatment also reduced pancreatic insulin (P<0.05 to P<0.01) without affecting islet number. These data indicate that (Hyp3)GIP and (Hyp3)GIPLys16PAL function as GIP receptor antagonists with potential for ameliorating obesity-diabetes. Acylation of (Hyp3)GIP to extend bioactivity does not appear to be of any additional benefit.
