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;
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.
Although the GIP receptor -/- mouse exhibits only mild glucose intolerance, upregulation of the β cell responsivity to GLP-1 may contribute to maintenance of insulin secretion in this murine model. See Glucose-dependent Insulinotropic Polypeptide Receptor Null Mice (GIPR-/-) Exhibit Compensatory Changes in the Enteroinsular Axis. Am J Physiol Endocrinol Metab. 2003 Jan 21
To review the data on GIP and human diabetes, see GIP and human diabetes