[Pro3]-GIP (Mouse) is potent enzyme-resistant gastric inhibitory polypeptide (GIP) receptor antagonist, with an IC50 value of 2.6μM[1]. [Pro3]-GIP can block the ability of native GIP to increase cAMP and stimulate insulin secretion[2]. [Pro3]-GIP has been widely used in diabetes mouse and obesity mouse models to improve the obesity phenotype and β-cell function[3].
In vitro, [Pro3]-GIP treatment at 1μM for 10min significantly inhibited cAMP generation in GIP receptor-transfected CHL cells[4]. Treatment of BRIN-BD11 cells with 1μM [Pro3]-GIP for 20 minutes significantly inhibited the release of insulin induced by natural GIP (0.1μM)[5].
In vivo, [Pro3]-GIP treatment via intraperitoneally injection at a dose of 25nmol/kg/day for 60 days significantly improved non-fasting glucose and insulin sensitivity in ob/ob mice[6]. Continuous intraperitoneal injection of 25nmol/kg/day dose of [Pro3]-GIP for 20 consecutive days aggravated hyperglycemia and glycosylated hemoglobin in the streptozotocin-induced diabetic mouse model, reduced glucose tolerance, and impaired insulin sensitivity[7]. [Pro3]-GIP (25nmol/kg/day) combined with AM251 (6mg/kg/day) was administered intraperitoneally for 22 consecutive days, which reduced the blood glucose levels and glucose tolerance in high-fat-fed mice and decreased the body weight[8].
References:
[1] Gault V A, O'Harte F P M, Harriott P, et al. Characterization of the cellular and metabolic effects of a novel enzyme-resistant antagonist of glucose-dependent insulinotropic polypeptide[J]. Biochemical and biophysical research communications, 2002, 290(5): 1420-1426.
[2] Koefoed-Hansen F, Helsted M M, Kizilkaya H S, et al. The evolution of the therapeutic concept ‘GIP receptor antagonism’[J]. Frontiers in Endocrinology, 2025, 16: 1570603.
[3] Gault V A, Irwin N, Green B D, et al. 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[J]. Diabetes, 2005, 54(8): 2436-2446.
[4] Gault V A, O'harte F P M, Harriott P, et al. Effects of the novel (Pro3) GIP antagonist and exendin (9–39) amide on GIP-and GLP-1-induced cyclic AMP generation, insulin secretion and postprandial insulin release in obese diabetic (ob/ob) mice: evidence that GIP is the major physiological incretin[J]. Diabetologia, 2003, 46(2): 222-230.
[5] McClean P L, Irwin N, Hunter K, et al. (Pro3) GIP [mPEG]: novel, long‐acting, mPEGylated antagonist of gastric inhibitory polypeptide for obesity‐diabetes (diabesity) therapy[J]. British journal of pharmacology, 2008, 155(5): 690-701.
[6] Irwin N, McClean P L, O’harte F P M, et al. Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro3) GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice[J]. Diabetologia, 2007, 50(7): 1532-1540.
[7] McClean P L, Gault V A, Irwin N, et al. Daily administration of the GIP‐R antagonist (Pro3) GIP in streptozotocin‐induced diabetes suggests that insulin‐dependent mechanisms are critical to anti–obesity‐diabetes actions of (Pro3) GIP[J]. Diabetes, Obesity and Metabolism, 2008, 10(4): 336-342.
[8] Irwin N, Hunter K, Flatt P R. Comparison of independent and combined chronic metabolic effects of GIP and CB1 receptor blockade in high-fat fed mice[J]. Peptides, 2008, 29(6): 1036-1041.