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

Finbarr P.M. O'Harte, Kerry Hunter, Victor A. Gault, Nigel Irwin, Brian D. Green, Brett Greer, Patrick Harriott, Clifford J. Bailey, Peter R. Flatt

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)E1674-E1682
Number of pages9
JournalAmerican Journal of Physiology
Volume292
Issue number6
DOIs
Publication statusPublished - 1 Jun 2007

Fingerprint

Insulin
Glucose
Acylation
Fibroblasts
Medical problems
Bioactivity
Hypoglycemic Agents
Insulin Resistance
Fatty Acids
Obesity
Hyp(3)-glucose-dependent insulinotropic polypeptide
Plasmas
Peptides
Injections
Enzymes
gastric inhibitory polypeptide receptor
Therapeutics
Pro(3)-glucose-dependent insulinotropic polypeptide

Keywords

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

Cite this

O'Harte, Finbarr P.M. ; Hunter, Kerry ; Gault, Victor A. ; Irwin, Nigel ; Green, Brian D. ; Greer, Brett ; Harriott, Patrick ; Bailey, Clifford J. ; Flatt, Peter 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. In: American Journal of Physiology. 2007 ; Vol. 292, No. 6. pp. E1674-E1682.
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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. / O'Harte, Finbarr P.M.; Hunter, Kerry; Gault, Victor A.; Irwin, Nigel; Green, Brian D.; Greer, Brett; Harriott, Patrick; Bailey, Clifford J.; Flatt, Peter R.

In: American Journal of Physiology, Vol. 292, No. 6, 01.06.2007, p. E1674-E1682.

Research output: Contribution to journalArticle

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AU - O'Harte, Finbarr P.M.

AU - Hunter, Kerry

AU - Gault, Victor A.

AU - Irwin, Nigel

AU - Green, Brian D.

AU - Greer, Brett

AU - Harriott, Patrick

AU - Bailey, Clifford J.

AU - Flatt, Peter R.

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AB - 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.

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KW - dipeptidyl peptidase IV

KW - fatty acid conjugation

KW - glucose-dependent insulinotropic polypeptide receptor antagonists

KW - insulin secretion

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