Gault, Victor A.Irwin, NigelGreen, Brian D.McCluskey, Jane T.Greer, BrettBailey, Clifford J.Harriott, PatrickO'harte, Finbarr P. M.Flatt, Peter R.2018-06-292018-06-292005-08Gault, V.A., Irwin, N., Green, B.D., McCluskey, J.T., Greer, B., Bailey, C.J., Harriott, P., O’Harte, F.P.M. and Flatt, P.R. (2005) ‘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’, Diabetes, 54(8), pp. 2436–2446. Available at: https://doi.org/10.2337/diabetes.54.8.2436.0012-1797https://doi.org/10.2337/diabetes.54.8.2436https://eresearch.qmu.ac.uk/handle/20.500.12289/4497Glucose-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 beta-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.2436-46articlehttp://10.2337/diabetes.54.8.2436