title: 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.
abstract: This study examines the actions of the novel enzyme-resistant, NH2-terminally modified GIP analog (Hyp(3))GIP and its fatty acid-derivatized analog (Hyp(3))GIPLys(16)PAL. Acute effects are compared with the established GIP receptor antagonist (Pro(3))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 (Hyp(3))GIPLys(16)PAL 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 (Hyp(3))GIP and (Hyp(3))GIPLys(16)PAL treatment also reduced pancreatic insulin (P < 0.05 to P < 0.01) without affecting islet number. These data indicate that (Hyp(3))GIP and (Hyp(3))GIPLys(16)PAL 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.
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, Northern Ireland. fpm.oharte@ulster.ac.uk
authors.forename: Finbarr P M
authors.initials: FP
authors.lastname: O'Harte
authors.forename: Kerry
authors.initials: K
authors.lastname: Hunter
authors.forename: Victor A
authors.initials: VA
authors.lastname: Gault
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
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
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000037:antagonists & inhibitors; D003920:Diabetes Mellitus / Q000097:blood / Q000209:etiology* / Q000503:physiopathology*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism / Q000494:pharmacology; D004351:Drug Resistance; D005347:Fibroblasts / Q000378:metabolism; D005749:Gastric Inhibitory Polypeptide / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D005951:Glucose Tolerance Test; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000378:metabolism; D007329:Insulin Antagonists / Q000494:pharmacology; D007333:Insulin Resistance; D000078790:Insulin Secretion; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000150:complications*; D010179:Pancreas / Q000378:metabolism; D011964:Receptors, Gastrointestinal Hormone / Q000037:antagonists & inhibitors* / Q000235:genetics; D013997:Time Factors; D014162:Transfection
chemical_list: D001786:Blood Glucose; D007328:Insulin; D007329:Insulin Antagonists; D011964:Receptors, Gastrointestinal Hormone; C521299:glucose-dependent insulinotropic polypeptide, Hyp(3)-; C521300:glucose-dependent insulinotropic polypeptide, Hyp(3)-palmitoylLys(16)-; C479120:glucose-dependent insulinotropic polypeptide, Pro(3)-; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor; D000242:Cyclic AMP; D018819:Dipeptidyl Peptidase 4