Alternative titles; symbols
HGNC Approved Gene Symbol: GIPR
Cytogenetic location: 19q13.32 Genomic coordinates (GRCh38): 19:45,668,221-45,683,722 (from NCBI)
Gastric inhibitory polypeptide (GIP; 137240), also called glucose-dependent insulinotropic polypeptide, is a 42-amino acid polypeptide synthesized by K cells of the duodenum and small intestine. It was originally identified as an activity in gut extracts that inhibited gastric acid secretion and gastrin release, but subsequently was demonstrated to stimulate insulin release potently in the presence of elevated glucose. The insulinotropic effect on pancreatic islet beta-cells was then recognized to be the principal physiologic action of GIP. Together with glucagon-like peptide-1, GIP is largely responsible for the secretion of insulin after eating. It is involved in several other facets of the anabolic response (summary by Usdin et al., 1993).
Usdin et al. (1993) cloned the rat cDNA for GIPR, functionally expressed it, and mapped its tissue distribution. GIP receptor is a member of the secretin-vasoactive intestinal polypeptide family of G protein-coupled receptors. GIP receptor mRNA is present in the pancreas as well as the gut, adipose tissue, heart, pituitary, and inner layers of the adrenal cortex, whereas it is not found in kidney, spleen, or liver. It is also expressed in several brain regions. The findings suggest that GIP may have previously undescribed actions; for example, GIPR localization in the adrenal cortex suggests that GIP may have effects on glucocorticoid metabolism. Furthermore, neither GIP nor its effects have been described in the central nervous system.
Volz et al. (1995) obtained a human cDNA from an insulinoma library by screening with the rat probe. The sequence encodes a predicted 466-amino acid protein with 79% identity to the rat homolog and 41% identity to human glucagon-like peptide receptor (138032). They found that cells transfected with human recombinant GIPR bound human GIP. Northern blots showed a 5.5-kb GIPR transcript in colon, insulinoma tissue, and HGT-1 stomach carcinoma cells. Yamada et al. (1995) also isolated the human GIPR gene and cDNA. The gene contains 14 exons spanning about 14 kb of genomic DNA, which also includes 17 Alu repeats. The protein is predicted to have 7 potential transmembrane domains, as expected of members of the G protein-coupled receptor family.
Gremlich et al. (1995) isolated cDNA clones for the GIP receptor from a human pancreatic islet cDNA library. They were found to encode different forms of the receptor, which differ by a 27-amino acid insertion in the COOH-terminal cytoplasmic tail. The receptor protein sequence was 81% identical to that of the rat GIP receptor.
Stoffel et al. (1995) mapped the GIPR gene to chromosome 19q13.2-q13.3 by fluorescence in situ hybridization. By fluorescence in situ hybridization and genetic linkage analysis, Gremlich et al. (1995) mapped the GIPR gene to chromosome 19q13.3, close to the APOC2 (608083) gene.
Association with 2-Hour Glucose Levels
Plasma glucose levels 2 hours after an oral glucose tolerance test (OGTT) are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. Saxena et al. (2010) reported a metaanalysis of 9 genomewide association studies involving 15,234 nondiabetic individuals and a follow-up of 29 independent loci in up to 30,620 individuals. They identified a single-nucleotide polymorphism (SNP), the A allele of rs10423928, associated with increased 2-hour glucose level (beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, p = 2.0 x 10(-15)). GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, p = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, p = 1.3 x 10(-16)); and diminished incretin effect (n = 804; p = 4.3 x 10(-4)). Saxena et al. (2010) also identified variants in ADCY5 (PGQTL1; 613460) (rs2877716, p = 4.2 x 10(-16)) and near several other genes associated with 2-hour glucose.
Shu et al. (2009) found decreased TCF7L2 (602228) protein levels in pancreatic sections from 7 patients with T2DM (NIDDM; 125853) compared with 7 healthy controls. Expression of the receptors for glucagon-like peptide-1 (GLP1R; 138032) and GIP was decreased in human T2DM islets as well as in isolated human islets treated with siRNA to TCF7L2 (siTCF7L2). Insulin secretion stimulated by glucose, GLP1 (138030), and GIP, but not KCl or cyclic adenosine monophosphate (cAMP), was impaired in siTCF7L2-treated isolated human islets. Loss of TCF7L2 resulted in decreased GLP1 and GIP-stimulated AKT (AKT1; 164730) phosphorylation, and AKT-mediated Foxo-1 (FOXO1A; 136533) phosphorylation and nuclear exclusion. Shu et al. (2009) suggested that beta-cell function and survival may be regulated through an interplay between TCF7L2 and GLP1R/GIPR expression and signaling in T2DM.
To determine the role of GIP as a mediator of signals from the gut to pancreatic beta cells, Miyawaki et al. (1999) generated mice with a targeted mutation of the GIPR gene. GIPR -/- mice had higher blood glucose levels with impaired initial insulin response after oral glucose load. Although blood glucose levels after meal ingestion were not increased by high-fat diet (HFD) in GIPR +/+ mice because of compensatory higher insulin secretion, they were significantly increased in GIPR -/- mice because of the lack of such enhancement. Accordingly, early insulin secretion mediated by GIP determines glucose tolerance after oral glucose load in vivo, and because GIP plays an important role in the compensatory enhancement of insulin secretion produced by a high insulin demand, a defect in this enteroinsular axis may contribute to the pathogenesis of diabetes.
Secretion of GIP, a duodenal hormone, is primarily induced by absorption of ingested fat. Miyawaki et al. (2002) described a novel pathway of obesity promotion via GIP. Wildtype mice fed an HFD exhibited both hypersecretion of GIP and extreme visceral and subcutaneous fat deposition with insulin resistance. In contrast, mice lacking the GIP receptor (Gipr -/-) by targeted disruption fed a high-fat diet were clearly protected from both the obesity and the insulin resistance. Moreover, double-homozygous mice generated by crossbreeding Gipr -/- mice with homozygous 'obese' mice (see leptin, 164160) gained less weight and had lower adiposity than did homozygous 'obese' mice. The Gipr -/- mice had a lower respiratory quotient and used fat as the preferred energy substrate, and were thus resistant to obesity. Therefore, Miyawaki et al. (2002) concluded that GIP directly links overnutrition to obesity and is a potential target for antiobesity drugs.
Kaneko et al. (2019) found that activation of Gipr in brain drove neuronal leptin resistance in HFD-induced obesity, as acute inhibition of brain Gipr resulted in leptin-dependent reductions in body weight, food intake, and fat mass in HFD-induced obese mice. Inhibition of brain Gipr also lowered blood glucose and serum levels of leptin and insulin in HFD-induced obese mice. Increased circulating Gip from intestine, as a consequence of overnutrition, acted in brain through Gipr and inhibited neural leptin action by activating Rap1 (RAP1A; 179520), resulting in increased food intake and obesity in mice.
Gremlich, S., Porret, A., Hani, E. H., Cherif, D., Vionnet, N., Froguel, P., Thorens, B. Cloning, functional expression, and chromosomal localization of the human pancreatic islet glucose-dependent insulinotropic polypeptide receptor. Diabetes 44: 1202-1208, 1995. [PubMed: 7556958] [Full Text: https://doi.org/10.2337/diab.44.10.1202]
Kaneko, K., Fu, Y., Lin, H.-Y., Cordoneir, E. L., Mo, Q., Gao, Y., Yao, T., Naylor, J., Howard, V., Saito, K., Xu, P., Chen, S. S., Chen, M.-H., Xu, Y., Williams, K. W., Ravn, P., Fukuda, M. Gut-derived GIP activates central Rap1 to impair neural leptin sensitivity during overnutrition. J. Clin. Invest. 129: 3786-3791, 2019. [PubMed: 31403469] [Full Text: https://doi.org/10.1172/JCI126107]
Miyawaki, K., Yamada, Y., Ban, N., Ihara, Y., Tsukiyama, K., Zhou, H., Fujimoto, S., Oku, A., Tsuda, K., Toyokuni, S., Hiai, H., Mizunoya, W., and 9 others. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nature Med. 8: 738-742, 2002. [PubMed: 12068290] [Full Text: https://doi.org/10.1038/nm727]
Miyawaki, K., Yamada, Y., Yano, H., Niwa, H., Ban, N., Ihara,Y., Kubota, A., Fujimoto, S., Kajikawa, M., Kuroe, A., Tsuda, K., Hashimoto, H., Yamashita, T., Jomori, T., Tashiro, F., Miyazaki, J., Seino, Y. Glucose intolerance caused by a defect in the entero-insular axis: a study in gastric inhibitory polypeptide receptor knockout mice. Proc. Nat. Acad. Sci. 96: 14843-14847, 1999. [PubMed: 10611300] [Full Text: https://doi.org/10.1073/pnas.96.26.14843]
Saxena, R., Hivert, M.-F., Langenberg, C., Tanaka, T., Pankow, J. S., Vollenweider, P., Lyssenko, V., Bouatia-Naji, N., Dupuis, J., Jackson, A. U., Kao, W. H. L., Li, M., and 143 others. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nature Genet. 42: 142-148, 2010. [PubMed: 20081857] [Full Text: https://doi.org/10.1038/ng.521]
Shu, L., Matveyenko, A. V., Kerr-Conte, J., Cho, J.-H., McIntosh, C. H. S., Maedler, K. Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell function. Hum. Molec. Genet. 18: 2388-2399, 2009. Note: Erratum: Hum. Molec. Genet. 24: 3004 only, 2015. [PubMed: 19386626] [Full Text: https://doi.org/10.1093/hmg/ddp178]
Stoffel, M., Fernald, A. A., Le Beau, M. M., Bell, G. I. Assignment of the gastric inhibitory polypeptide receptor gene (GIPR) to chromosome bands 19q13.2-q13.3 by fluorescence in situ hybridization. Genomics 28: 607-609, 1995. [PubMed: 7490109] [Full Text: https://doi.org/10.1006/geno.1995.1203]
Usdin, T. B., Mezey, E., Button, D. C., Brownstein, M. J., Bonner, T. I. Gastric inhibitory polypeptide receptor, a member of the secretin-vasoactive intestinal peptide receptor family, is widely distributed in peripheral organs and the brain. Endocrinology 133: 2861-2870, 1993. [PubMed: 8243312] [Full Text: https://doi.org/10.1210/endo.133.6.8243312]
Volz, A., Goke, R., Lankat-Buttgereit, B., Fehmann, H.-C., Bode, H. P., Goke, B. Molecular cloning, functional expression, and signal transduction of the GIP-receptor cloned from a human insulinoma. FEBS Lett. 373: 23-29, 1995. Note: Erratum: FEBS Lett. 381: 271 only, 1996. [PubMed: 7589426] [Full Text: https://doi.org/10.1016/0014-5793(95)01006-z]
Yamada, Y., Hayami, T., Nakamura, K., Kaisaki, P. J., Someya, Y., Wang, C.-Z., Seino, S., Seino, Y. Human gastric inhibitory polypeptide receptor: cloning of the gene (GIPR) and cDNA. Genomics 29: 773-776, 1995. [PubMed: 8575774] [Full Text: https://doi.org/10.1006/geno.1995.9937]