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This Article Full Text Full Text (PDF) All Versions of this Article: 292/6/E1674    most recent 00391.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by O'Harte, F. P. M. Articles by Flatt, P. R. Search for Related Content PubMed PubMed Citation Articles by O'Harte, F. P. M. Articles by Flatt, P. R.

Antagonistic effects of two novel GIP analogs, (Hyp³)GIP and (Hyp³)GIPLys¹⁶PAL, on the biological actions of GIP and longer-term effects in diabetic ob/ob mice

¹School of Biomedical Sciences, University of Ulster, Coleraine; ²School of Biology and Biochemistry, The Queen's University of Belfast, Belfast, Northern Ireland; and ³School of Life and Health Sciences, Aston University, Birmingham, United Kingdom

Submitted 3 August 2006 ; accepted in final form 6 February 2007

This study examines the actions of the novel enzyme-resistant, NH₂-terminally modified GIP analog (Hyp³)GIP and its fatty acid-derivatized analog (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 analogs 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-related diabetes. Acylation of (Hyp³)GIP to extend bioactivity does not appear to be of any additional benefit.

glucose-dependent insulinotropic polypeptide receptor antagonists; insulin secretion; antihyperglycemic activity; dipeptidyl peptidase IV; fatty acid conjugation