Infusion of ANTGIP, a truncated GIP peptide antagonist, decreased insulin secretion in rats; Effect of GIP and GLP-1 antagonists on insulin release in the rat. Am J Physiol. 1999 Jun;276(6 Pt 1):E1049-54. Similarly, GIP Receptor antisera decreased insulin secretion and increased the glycemic excursion following oral glucose challenge in both rats Glucose-dependent insulinotropic polypeptide confers early phase insulin release to oral glucose in rats: demonstration by a receptor antagonist. Endocrinology. 2000 Oct;141(10):3710-6  and mice GLP-1 but not GIP regulates fasting glycemia and non-enteral glucose clearance in mice Endocrinology 2000 141(10):3703-9. In contrast to studies of GLP-1, blockade of GIP action did not perturb glucose homeostasis or insulin secretion in the fasting state or following intraperitoneal glucose challenge, hence the physiological role of GIP appears primarily restricted to its incretin function.

GIP antagonists may also be obtained following a (Pro3) substitution in the native GIP molecule as exemplified in Characterization of the cellular and metabolic effects of a novel enzyme-resistant antagonist of glucose-dependent insulinotropic polypeptide. Biochem Biophys Res Commun. 2002 Feb 8;290(5):1420-6.  This molecule antagonizes the action of GIP in cells in vitro, and in obese diabetic ob/ob mice in vivo, as illustrated in Effects of the novel (Pro(3))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 and in Effects of the novel (Pro(3))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

More sustained chronic daily administration of the GIP receptor antagonist Pro(3))GIP for 50 days produced reduced body weight, decreased accumulation of adipose tissue, and marked improvements in levels of glucose, glycated haemoglobin and pancreatic insulin in older high fat fed diabetic mice, together with reduced triglyceride levels in muscle and liver See 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 Sep 11;

Some of the GIP antagonists employed for studies of reduced GIP action produce results consistent with the possibility that they are also partial agonists.  In a chronic study of mice injected for 4 weeks with the agonist [D-Ala2]-GIP or the putative antagonist [Pro3]-GIP, 25 nmol/kg body weight, once daily, in the evening. Remarkably, in many of the behavioral tests, the putative antagonist, [Pro3]-GIP produced results identical to those obtained with the agonist, [D-Ala2]-GIP. The authors provide several possible interpretations for their data, including the possibility that [Pro3]-GIP is really a weak antagonist/patial agonist. Eur J Pharmacol. 2011 Nov 12. Effects of acute and chronic administration of GIP analogues on cognition, synaptic plasticity and neurogenesis in mice

GIP(3-30)amide has also been used as a GIP receptor antagonist, initially characterized in cell systems in vitro, in perfused rat pancreata, and subsequently in human studies. Notably, despite minimal amino acid changes across species, there appear to be important species-specific differences in the ability of human GIP(3-30) amide to block the rat vs. the human GIP receptor GIP(3-30)NH2 is a potent competitive antagonist of the GIP receptor and effectively inhibits GIP-mediated insulin, glucagon, and somatostatin release Biochem Pharmacol. 2017 May 1;131:78-88 In non-diabetic lean humans, acute administration of GIP(3-30) amide attenuates the insulinotropic actions of exogenous GIP, and decreases GIP-stimulated adipose tissue blood flow and triglyceride uptake The Gluco- and Liporegulatory and the Vasodilatory Effects of Glucose-Dependent Insulinotropic Polypeptide (GIP) are Abolished By an Antagonist of the Human GIP Receptor Diabetes. 2017 Jun 30. pii: db170480. doi: 10.2337/db17-0480

The findings with GIP antagonists, taken together with results observed in studies of GIP receptor-/- mice Glucose intolerance caused by a defect in the entero-insular axis: a study in gastric inhibitory polypeptide receptor knockout mice. Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14843-7 suggest that the primary role of GIP is that of an incretin. The intriguing finding that GIP receptor-/- mice are resistant to the development of obesity suggests the role of GIP in control of body weight gain and development of adiposity merits further study.

Immunoneutralization of GIP action has been achieved using GIP antisera in both acute and chronic experiments. Acute antisera administration impaired oral glucose tolerance and reduced plamsa insulin levels in ob/ob mice, whereas sustained antisera administration improved intraperitoneal glucose tolerance without changes in insulin sensitivity Active immunisation against gastric inhibitory polypeptide (GIP) improves blood glucose control in an animal model of obesity-diabetes Biol Chem. 2009 Jan;390(1):75-80. In related studies, Fulurija and colleagues vaccinated mice with GIP peptides covalently linked to virus-like particles. Vaccination attenuated weight gain in high fat fed mice, without impairing glucose tolerance. Vaccination against GIP for the treatment of obesity PLoS One. 2008 Sep 9;3(9):e3163.

Loss of GIP actions has also been studied in mice with targeted ablation of enteroendocrine K cells using the GIP promoter to express an attenuated diphtheria toxin in K cells. GIP levels are markedly reduced but still detectable in these mice, and food intake, body weight and IP glucose tolerance were normal in GIP-DT mice. However targeted ablation of glucose-dependent insulinotropic polypeptide-producing cells in transgenic mice reduces obesity and insulin resistance induced by a high fat diet, associated with increased insulin sensitivity and enhanced energy expenditure but no change in glucose homeostasis. GIP-DT mice exhibit defective insulin responses to oral glucose, although GLP-1 secretion and action appear to be preserved in these mice J Biol Chem. 2008 Jun 27;283(26):18365-76. In a subsequent study the authors noted that exogenous GIP action in the context of IP glucose administration was blunted in GIP-DT mice. As some K cells produce xenin-25, which does not modulate glycemia by itself, the authors co-administered xenin-25 plus GIP, and this combination potently reduced blood glucose during IP but not oral glucose challenge in GIP-DT mice, whereas the combination had little further effect compared to GIP alone in WT mice. Moreover, xenin-25 did not potentiate the insulinotropic actions of GLP-1, however xenin-25 plus GIP did lower glucose and stimulate insulin in a second murine model of T2DM in vivo, but xenin-25 does not directly potentiate GIP-stimulated insulin release using isolated islets or the perfused pancreas ex vivo. Peripheral muscarinic receptor blockade with atropine methylbromide attenuated the potentiating actions of xenin-25 on GIP-stimulated insulin release, whereas PACAP receptor blockade or nicotinic colinergic blockade with hexamethonium was without effect. Carbachol, an activator of cholinergic muscaranic receptors, potentiated the insulinotropic actions of GIP in the perfused pancreas ex vivo. Hence xenin-25 may represent a K cell-derived signal for amplifying GIP action through the ENS acting on muscaranic receptors in vivo. Xenin-25 potentiates GIP action via a novel cholinergic relay mechanism. J Biol Chem. 2010 Apr 26. [Epub ahead of print]