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

This study examines the actions of the novel enzyme-resistant, NH ₂-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 (Hyp ³)GIP or (Hyp³)GIPLys¹⁶PAL for 14 days resulted in significantly lower plasma glucose levels (P < 0.05) after (Hyp ³)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 (Hyp ³)GIPLys¹⁶PAL function as GIP receptor antagonists with potential for ameliorating obesity-related diabetes. Acylation of (Hyp ³)GIP to extend bioactivity does not appear to be of any additional benefit. Copyright © 2007 the American Physiological Society.