GIP is a 42-aminoacid peptide secreted from the intestinal K-cells (located mainly in the duodenum and proximal jejunum) and released in response to nutrients, especially fats. The aminoacid sequence is not identical among mammalian species but there is 90% homology. Only the first 30 aminoacids are necessary for ligand binding, receptor activation and biological activity. Short time after release (half-life of 7.3 min) the active peptide is inactivated to GIP 3-42 due to cleavage of the first two N-terminal aminoacids by the enzyme dipeptidyl-peptidase IV (DPP IV), the same enzyme that degrades GLP-1. The GIP receptor, identified in pancreas, stomach, intestine and other organs, is a seven transmembrane G-protein coupled receptor, from the same family as the GLP-1 receptor.
In pancreatic beta-cells, binding of GIP to the GIP receptor increases exocytosis of the insulin granules via a protein kinase A (PKA) mediated mechanism. In vivo, infusion of GIP has been shown to increase insulin secretion in rats, dogs and humans. The role of GIP in postprandial insulin secretion has been further emphasized by studies using GIP receptor antagonists. In rats, infusion of a GIP receptor antibody produced lower plasma insulin levels and a delayed insulin response compared with controls. Similarly, GIP receptor knockout mice have normal fasting glucose levels but higher than normal glycemia post glucose challenge. Studies attempted at determining the relative importance of GIP and GLP-1 to the incretin effect have found that the rise in GIP following oral glucose is higher than the increase in GLP-1 determined by the same load. While on a molar to molar basis GLP-1 might be more potent than GIP in stimulating insulin secretion, it appears that during a physiological, postprandial situation the proportion of incretin effect attributable to GIP is between 50% and 75 %; this finding led some authors to suggest that the main role for GLP-1 in a postprandial context is inhibition of gastrointestinal motility and secretion, leaving GIP as the more physiologically relevant incretin. In diabetes the insulinotropic ability of GIP is reduced, while the peptide amount is decreased by only 20%. It is not known, however, if the alterations in GIP physiology are a cause or a consequence of diabetes.
Unlike GLP-1, GIP plays only a minor role in regulating gastric emptying and gastric acid secretion. However, GIP is much more involved than GLP-1 in lipid metabolism. Incubation of preadipocytes with GIP stimulates lipoprotein lipase activity. GIP also stimulates fatty acid incorporation into adipose tissue by stimulating fatty acid synthase; the lipolytic effect of glucagon can be inhibited by incubation with GIP. Study of GIP receptor knockout mice (GIPR-/-), with a general disruption of GIP signaling, provided further interesting information regarding the role of GIP as a mediator of signals between gut and other organs. GIPR -/- mice exhibit higher glucose levels and lower insulin post oral glucose challenge, indicating a disruption of the entero-insular axis. On the other hand, they have normal fasting glucose and the response to intraperitoneal glucose tolerance tests is no different from the wild type. This may lead to the conclusion that GIP plays no role in maintaining normal fasting glucose or that in the GIPR-/- mouse GLP-1, the other incretin, plays a compensatory role. Measurement of serum total levels of GLP-1 showed they were unaltered. However, the insulin responses to GLP-1 of the pancreatic islets of GIPR -/- mice were higher than the wild type, and the GLP-1 induced cAMP production was elevated as well, indicating a higher sensitivity to GLP-1. Interestingly, the GIPR -/- mice also exhibited normal food and water intake and normal body weight; their total triglycerides, cholesterol and free fatty acid plasma concentration were normal as well. However, GIPR -/- mice appeared to be protected form the obesity and insulin resistance induced by a high fat diet.
Ionut, V. (2006). Role of intestinal hormone glucagon-like peptide-1 (GLP-1) in glycemic regulation.