(Pro3)-Gastric Inhibitory Polypeptide (human) is an analog of human glucose-dependent insulinotropic polypeptide (GIP), distinguished by the substitution of proline for glutamate at the third amino acid position. (Pro3)-Gastric Inhibitory Polypeptide acts as a potent, stable, and specific full agonist of the human GIP receptor (hGIPR), exhibiting high binding affinity (Ki/Kd=0.90nM)[1-2]. (Pro3)-Gastric Inhibitory Polypeptide is used in research related to obesity-associated diabetes and type 2 diabetes[3-4].
In vitro, using isolated human atrial preparations, simultaneous stimulation with (Pro3)-Gastric Inhibitory Polypeptide (100nM) and Tirzepatide (100nM) was performed. (Pro3)-Gastric Inhibitory Polypeptide attenuated the positive inotropic effect induced by Tirzepatide. (Pro3)-Gastric Inhibitory Polypeptide antagonized the GIP receptor-mediated enhancement of myocardial contractility[5]. COS-7 cells transiently transfected with the human GIP receptor were stimulated with (Pro3)-Gastric Inhibitory Polypeptide (4.7nM to 92nM) for 30 minutes. (Pro3)-Gastric Inhibitory Polypeptide acted as a full agonist with similar efficacy to native human GIP at the human GIP receptor[6].
In vivo, (Pro3)-Gastric Inhibitory Polypeptide (25nmol/kg) was administered via intraperitoneal injection once or twice daily to high-fat diet-induced obese diabetic mice for 48 days. (Pro3)-Gastric Inhibitory Polypeptide significantly improved glucose tolerance and insulin sensitivity, and reduced weight gain and hyperinsulinemia[7]. In fasted obese diabetic (ob/ob) mice, a single intraperitoneal injection of (Pro3)-Gastric Inhibitory Polypeptide (25nmol/kg) was administered. (Pro3)-Gastric Inhibitory Polypeptide significantly reduced the plasma insulin response 15 minutes after re-feeding, decreasing overall insulin release by 42%. In non-fasted ob/ob mice, a single intraperitoneal injection of (Pro3)-Gastric Inhibitory Polypeptide (25nmol/kg) ameliorated the basal hyperinsulinemia[8].
References:
[1] Rosenkilde MM, Lindquist P, Kizilkaya HS, et al. GIP-derived GIP receptor antagonists - a review of their role in GIP receptor pharmacology. Peptides. 2024 Jul;177:171212.
[2] McClean PL, Irwin N, Cassidy RS, et al. GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet. Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1746-55.
[3] McClean PL, Gault VA, 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. Diabetes Obes Metab. 2008 Apr;10(4):336-42.
[4] Cassidy RS, Irwin N, Flatt PR. Effects of gastric inhibitory polypeptide (GIP) and related analogues on glucagon release at normo- and hyperglycaemia in Wistar rats and isolated islets. Biol Chem. 2008 Feb;389(2):189-93.
[5] Neumann J, Hofmann B, Kirchhefer U, et al. Tirzepatide increased force of contraction in the isolated human atrium. Naunyn Schmiedebergs Arch Pharmacol. 2025 Oct;398(10):14451-14459.
[6] Sparre-Ulrich AH, Hansen LS, Svendsen B, et al. Species-specific action of (Pro3)GIP - a full agonist at human GIP receptors, but a partial agonist and competitive antagonist at rat and mouse GIP receptors. Br J Pharmacol. 2016 Jan;173(1):27-38.
[7] McClean PL, Irwin N, Hunter K, et al. (Pro(3))GIP[mPEG]: novel, long-acting, mPEGylated antagonist of gastric inhibitory polypeptide for obesity-diabetes (diabesity) therapy. Br J Pharmacol. 2008 Nov;155(5):690-701.
[8] Gault VA, O'Harte FP, 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. Diabetologia. 2003 Feb;46(2):222-30.