Chemical Ablation of Gastric Inhibitory Polypeptide Receptor Action by Daily (Pro3)GIP Administration Improves Glucose Tolerance and Ameliorates Insulin Resistance and Abnormalities of Islet Structure in Obesity-Related Diabetes

  1. Victor A. Gault1,
  2. Nigel Irwin1,
  3. Brian D. Green1,
  4. Jane T. McCluskey1,
  5. Brett Greer2,
  6. Clifford J. Bailey3,
  7. Patrick Harriott4,
  8. Finbarr P.M. O’Harte1 and
  9. Peter R. Flatt1
  1. 1School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, U.K
  2. 2School of Biology and Biochemistry, Queen’s University of Belfast, Belfast, Northern Ireland, U.K
  3. 3School of Life and Health Sciences, Aston University, Birmingham, U.K
  4. 4Department of Pharmaceutical and Medicinal Chemistry, Royal College of Surgeons in Ireland, Dublin, Ireland
  1. Address correspondence and reprint requests to Victor A. Gault, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland BT52 1SA, U.K. E-mail: va.gault{at}ulster.ac.uk

Abstract

Glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide [GIP]) is an important incretin hormone secreted by endocrine K-cells in response to nutrient ingestion. In this study, we investigated the effects of chemical ablation of GIP receptor (GIP-R) action on aspects of obesity-related diabetes using a stable and specific GIP-R antagonist, (Pro3)GIP. Young adult ob/ob mice received once-daily intraperitoneal injections of saline vehicle or (Pro3)GIP over an 11-day period. Nonfasting plasma glucose levels and the overall glycemic excursion (area under the curve) to a glucose load were significantly reduced (1.6-fold; P < 0.05) in (Pro3)GIP-treated mice compared with controls. GIP-R ablation also significantly lowered overall plasma glucose (1.4-fold; P < 0.05) and insulin (1.5-fold; P < 0.05) responses to feeding. These changes were associated with significantly enhanced (1.6-fold; P < 0.05) insulin sensitivity in the (Pro3)GIP-treated group. Daily injection of (Pro3)GIP reduced pancreatic insulin content (1.3-fold; P < 0.05) and partially corrected the obesity-related islet hypertrophy and β-cell hyperplasia of ob/ob mice. These comprehensive beneficial effects of (Pro3)GIP were reversed 9 days after cessation of treatment and were independent of food intake and body weight, which were unchanged. These studies highlight a role for GIP in obesity-related glucose intolerance and emphasize the potential of specific GIP-R antagonists as a new class of drugs for the alleviation of insulin resistance and treatment of type 2 diabetes.

Footnotes

    • Accepted April 25, 2005.
    • Received September 8, 2004.
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