(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.
(Pro3)-Gastric Inhibitory Polypeptide (human)是一种人源葡萄糖依赖性促胰岛素多肽（GIP）的类似物，(Pro3)-Gastric Inhibitory Polypeptide可作为人GIP受体（hGIPR）的高效、稳定且特异性的完全激动剂，对人GIPR具有高结合亲和力(Ki/Kd=0.90nM)[1-2]。(Pro3)-Gastric Inhibitory Polypeptide可用于肥胖相关糖尿病和2型糖尿病的相关研究[3-4]。
在体外，在离体人心房标本中，加入(Pro3)-Gastric Inhibitory Polypeptide（100nM）和Tirzepatide（100nM）进行刺激。(Pro3)-Gastric Inhibitory Polypeptide可减弱Tirzepatide诱导的正性肌力效应，(Pro3)-Gastric Inhibitory Polypeptide能拮抗由葡萄糖依赖性促胰岛素多肽受体介导的心肌收缩力增强作用[5]。在瞬时转染了人GIP受体的COS-7细胞中，用(Pro3)-Gastric Inhibitory Polypeptide（4.7nM至92nM）刺激30分钟。(Pro3)-Gastric Inhibitory Polypeptide在人GIP受体上表现为与天然人GIP效能相似的完全激动剂[6]。
在体内，(Pro3)-Gastric Inhibitory Polypeptide（25nmol/kg）每天一次或两次腹腔注射，用于处理高脂饮食诱导的肥胖糖尿病小鼠，持续48天。(Pro3)-Gastric Inhibitory Polypeptide显著改善了葡萄糖耐量和胰岛素敏感性，并降低了体重增加和高胰岛素血症[7]。在禁食的肥胖糖尿病（ob/ob）小鼠中，单次腹腔注射(Pro3)-Gastric Inhibitory Polypeptide（25nmol/kg）。(Pro3)-Gastric Inhibitory Polypeptide显著降低了小鼠重新进食15分钟后的血浆胰岛素反应，总体胰岛素释放减少了42%。在非禁食的ob/ob小鼠中，单次腹腔注射(Pro3)-Gastric Inhibitory Polypeptide（25nmol/kg）可改善小鼠基础高胰岛素血症[8]。