The GIP receptor (GIPR) was initially cloned from a rat cerebral cortex cDNA library and was followed by the cloning of the hamster and human GIPRs. The human GIPR gene is comprised of 14 exons that span approximately 14 kb and is localized to chromosome 19, band q13.3. The GIPR gene is expressed in the pancreas, stomach, small intestine, adipose tissue, adrenal cortex, pituitary, heart, testis, endothelial cells, bone, trachea, spleen, thymus, lung, kidney, thyroid, and several regions in the CNS. Like the GLP-1R, the GIPR is a member of the seven-transmembrane spanning, heterotrimeric G-protein-coupled receptor superfamily.
Little is known about the factors responsible for regulating GIPR expression. The GIPR gene 5’-flanking region contains a cAMP response element, and binding sites for Oct-1, Sp1 and Sp3 transcription factors. In addition, cis-acting negative regulatory sequences that control cell-specific GIPR gene expression have been identified in more distal 5'-flanking regions. GIPR mRNA and protein levels are reduced in islets of diabetic rats, consistent with the observation of defective GIP action in diabetic animals and humans.
Genetic variation in the GIP receptor gene may account for differences in insulin secretion and postprandial control of glucose in non-diabetic subjects. Genome Wide Association Studies identified that the rs10423928 SNP (located within an intron) was associated with reduced insulin secretion following oral but not intravenous glucose challenge. This SNP is also in linkage disequlibrium with a missense mutation E354Q that may be associated with modest reduction of GIPR action. A preliminary analysis of Gipr expression did not reveal reduced levels of RNA transcripts in islets from individuals carrying the rs10423928 allele. See Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge Nat Genet. 2010 Jan 17. [Epub ahead of print]
Activation of GIPR signaling is coupled to increases in cAMP and intracellular Ca2+ levels, as well as activation of PI-3K, PKA, PKB, MAPK and phospholipase A2. In vitro structure/function studies indicate that the N-terminal domain and the first extracellular loop of the GIPR are essential for high-affinity GIP binding, whereas portions of the N-terminal domain and the first transmembrane domain are important for receptor activation and cAMP coupling. Although the majority of the C-terminal tail of the GIPR appears to be dispensable for intracellular signaling, a minimum receptor length of approximately 405 amino acids is required for efficient transport and plasma membrane insertion.
The GIPR undergoes very rapid and reversible homologous desensitization and site-directed mutagenesis and C-terminal deletion analyses demonstrate the importance of particular serine residues in the C-terminal tail of the GIPR. Specifically, serines 406 and 411 are important for receptor desensitization, whereas serines 426 and 427 regulate the rate of GIPR internalization. In addition, regulator of G-protein signaling-2 (RGS-2), G-protein receptor kinase 2 (GRK 2), and ß-arrestin 1 have all been implicated in GIPR desensitization.
An important issue surrounding the biology of GIP action is the mechanism underlying the diminished GIP responsivity in experimental and clinical models of type 2 diabetes. Several studies have examined the expression of the GIP receptor in experimental models of diabetes, and the available evidence suggests that hyperglycemia may be associated with reduced GIP receptor expression, possibly contributing to reduced GIP action in the setting of diabetes. See Defective glucose-dependent insulinotropic polypeptide receptor expression in diabetic fatty Zucker rats. Diabetes. 2001 May;50(5):1004-11 and Downregulation of GLP-1 and GIP receptor expression by hyperglycemia: possible contribution to impaired incretin effects in diabetes. Diabetes. 2007 Jun;56(6):1551-8 Ubiquitination may also be important for the hyperglycemia-associated downregulation of islet GIP receptor expression as outlined in Ubiquitination is involved in glucose-mediated down-regulation of GIP receptors in islets. Am J Physiol Endocrinol Metab. 2007 May 15;