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Gene Review

Insr  -  insulin receptor

Mus musculus

Synonyms: 4932439J01Rik, CD220, D630014A15Rik, IR, IR-A, ...
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Disease relevance of Insr

  • Insr ablation in approximately 80% of cells caused extreme growth retardation, lipoatrophy, and hypoglycemia, a clinical constellation that resembles the human syndrome of leprechaunism [1].
  • Insr ablation in 98% of cells, while resulting in similar growth retardation and lipoatrophy, caused diabetes without beta-cell hyperplasia [1].
  • The very pronounced hyperglycemia in Insr-/- mice could result in an increased plasma insulin level of up to approximately 300 microU/ml, as compared with approximately 25 microU/ml for normal littermates [2].
  • The Insulin Receptor (IR) is a potential oncogene for mammary epithelial cells since its content is increased in most human breast cancer specimens, and both ligand-dependent malignant transformation and ligand-dependent enhanced growth occurs in cultured breast cells overexpressing the IR [3].
  • Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles [4].

High impact information on Insr


Chemical compound and disease context of Insr

  • Subsequently, these cells were infected with adenovirus encoding cre recombinase to delete insulin receptor (beta-IR(-/-)). beta-Cells expressed insulin and Pdx-1 mRNA in response to glucose [10].

Biological context of Insr

  • Analyses of protein expression indicated that L1 mice had modestly reduced Insr content but normal insulin-stimulated Akt phosphorylation in the liver [11].
  • To examine this question, we generated mice with variable cellular mosaicism for null Insr alleles [1].
  • The IR is expressed in two isoforms (IR-A and IR-B) differing by 12 amino acids due to the alternative splicing of exon 11 [12].
  • Insulin receptor transphosphorylates several immediate substrates, resulting in modulation of a cascade of downstream signal transduction molecules [13].
  • We investigated the molecular mechanism involved and characterized two RNA-splicing events that could account for the decrease in IGF-IR [14].

Anatomical context of Insr

  • Partial restoration of insulin receptor Insr expression in brain, liver, and pancreatic beta cells is sufficient for rescuing Insr knockout mice from neonatal death, preventing diabetes ketoacidosis, and normalizing life span and reproductive function [11].
  • Conversely, L1 mice had a near complete ablation of Insr protein product in the arcuate and paraventricular nuclei of the hypothalamus, which was associated with a failure to undergo insulin-dependent Akt phosphorylation in the hypothalamus [11].
  • Earlier studies with both cultured cells and transgenic mice, however, have suggested that in the embryo the insulin receptor (IR) may also be a receptor for IGF-II [12].
  • Electron microscopy analysis detected all stages of differentiation of the adipocyte precursor in IR-/- mice, suggesting that lack of insulin receptors is not associated with selective impairment of the adipocyte differentiation process [15].
  • Histological, immunohistochemical, and ultrastructural analyses of white dermal adipose tissue were performed in newborn IR-/- mice, as well as normal (IR +/+ ) and heterozygous controls (IR+/-) [15].

Associations of Insr with chemical compounds


Physical interactions of Insr


Enzymatic interactions of Insr

  • The IR isolated from TNF-alpha-treated cells is also defective in the ability to autophosphorylate and phosphorylate IR substrate 1 in vitro [20].

Regulatory relationships of Insr

  • However, IR could replace IGF-IR if efficiently activated by IGF-II [21].
  • Only the A isoform of the insulin receptor (IR) can induce IRS-1 nuclear translocation, which is significant when the receptor is over-expressed [22].
  • The observed reduction in endogenous IGF-IR expression was sufficient to inhibit IGF-I-stimulated cell proliferation [23].
  • The partial differentialPHPTB IRS-2 protein is dependent for its effect on an activated IGF-IR, is cytoplasmic, binds to the beta-subunit of the IGF-IR, and requires for its action the presence of phosphatidylinositol 3-kinase binding sequences [24].
  • Two closely-related protein tyrosine phosphatases, PTP1B and TCPTP both showed abilities to negatively regulate insulin receptor signaling [25].

Other interactions of Insr


Analytical, diagnostic and therapeutic context of Insr


  1. Mosaic analysis of insulin receptor function. Kitamura, T., Kitamura, Y., Nakae, J., Giordano, A., Cinti, S., Kahn, C.R., Efstratiadis, A., Accili, D. J. Clin. Invest. (2004) [Pubmed]
  2. Targeted disruption of the insulin receptor gene in the mouse results in neonatal lethality. Joshi, R.L., Lamothe, B., Cordonnier, N., Mesbah, K., Monthioux, E., Jami, J., Bucchini, D. EMBO J. (1996) [Pubmed]
  3. The insulin receptor content is increased in breast cancers initiated by three different oncogenes in transgenic mice. Frittitta, L., Cerrato, A., Sacco, M.G., Weidner, N., Goldfine, I.D., Vigneri, R. Breast Cancer Res. Treat. (1997) [Pubmed]
  4. Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Brüning, J.C., Winnay, J., Bonner-Weir, S., Taylor, S.I., Accili, D., Kahn, C.R. Cell (1997) [Pubmed]
  5. Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling. Withers, D.J., Burks, D.J., Towery, H.H., Altamuro, S.L., Flint, C.L., White, M.F. Nat. Genet. (1999) [Pubmed]
  6. Insulin receptor tyrosine kinase is defective in skeletal muscle of insulin-resistant obese mice. Le Marchand-Brustel, Y., Grémeaux, T., Ballotti, R., Van Obberghen, E. Nature (1985) [Pubmed]
  7. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Hotamisligil, G.S., Peraldi, P., Budavari, A., Ellis, R., White, M.F., Spiegelman, B.M. Science (1996) [Pubmed]
  8. IR gene regulation of the response to trinitrophenyl-polysaccharides. Two independent genes are required for antibody production. Hillstrom, L.M., Niederhuber, J.E. J. Exp. Med. (1983) [Pubmed]
  9. Anti I-A antibody suppresses active encephalomyelitis: treatment model for diseases linked to IR genes. Sriram, S., Steinman, L. J. Exp. Med. (1983) [Pubmed]
  10. Differential mitogenic signaling in insulin receptor-deficient fetal pancreatic beta-cells. Guillen, C., Navarro, P., Robledo, M., Valverde, A.M., Benito, M. Endocrinology (2006) [Pubmed]
  11. Restoration of liver insulin signaling in Insr knockout mice fails to normalize hepatic insulin action. Okamoto, H., Obici, S., Accili, D., Rossetti, L. J. Clin. Invest. (2005) [Pubmed]
  12. Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Frasca, F., Pandini, G., Scalia, P., Sciacca, L., Mineo, R., Costantino, A., Goldfine, I.D., Belfiore, A., Vigneri, R. Mol. Cell. Biol. (1999) [Pubmed]
  13. Discovery of a small molecule insulin receptor activator. Salituro, G.M., Pelaez, F., Zhang, B.B. Recent Prog. Horm. Res. (2001) [Pubmed]
  14. A targeted partial invalidation of the insulin-like growth factor I receptor gene in mice causes a postnatal growth deficit. Holzenberger, M., Leneuve, P., Hamard, G., Ducos, B., Perin, L., Binoux, M., Le Bouc, Y. Endocrinology (2000) [Pubmed]
  15. Lack of insulin receptors affects the formation of white adipose tissue in mice. A morphometric and ultrastructural analysis. Cinti, S., Eberbach, S., Castellucci, M., Accili, D. Diabetologia (1998) [Pubmed]
  16. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Ueki, K., Kondo, T., Kahn, C.R. Mol. Cell. Biol. (2004) [Pubmed]
  17. Metformin enhances insulin signalling in insulin-dependent and-independent pathways in insulin resistant muscle cells. Kumar, N., Dey, C.S. Br. J. Pharmacol. (2002) [Pubmed]
  18. Pervanadate stimulation of wortmannin-sensitive and -resistant 2-deoxyglucose transport in adipocytes. Ida, M., Imai, K., Hashimoto, S., Kawashima, H. Biochem. Pharmacol. (1996) [Pubmed]
  19. Differential effects of tumor necrosis factor-alpha on protein kinase C isoforms alpha and delta mediate inhibition of insulin receptor signaling. Rosenzweig, T., Braiman, L., Bak, A., Alt, A., Kuroki, T., Sampson, S.R. Diabetes (2002) [Pubmed]
  20. Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Hotamisligil, G.S., Murray, D.L., Choy, L.N., Spiegelman, B.M. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  21. Genetic engineering in mice: impact on insulin signalling and action. Lamothe, B., Baudry, A., Desbois, P., Lamotte, L., Bucchini, D., De Meyts, P., Joshi, R.L. Biochem. J. (1998) [Pubmed]
  22. Nuclear translocation of insulin receptor substrate-1 by the insulin receptor in mouse embryo fibroblasts. Wu, A., Sciacca, L., Baserga, R. J. Cell. Physiol. (2003) [Pubmed]
  23. Transcriptional regulation of insulin-like growth factor-I receptor gene expression in prostate cancer cells. Damon, S.E., Plymate, S.R., Carroll, J.M., Sprenger, C.C., Dechsukhum, C., Ware, J.L., Roberts, C.T. Endocrinology (2001) [Pubmed]
  24. Deletion of the pleckstrin and phosphotyrosine binding domains of insulin receptor substrate-2 does not impair its ability to regulate cell proliferation in myeloid cells. Sun, H., Baserga, R. Endocrinology (2004) [Pubmed]
  25. Effects of small interference RNA against PTP1B and TCPTP on insulin signaling pathway in mouse liver: Evidence for non-synergetic cooperation. Xu, J., Li, L., Hong, J., Huang, W. Cell Biol. Int. (2007) [Pubmed]
  26. Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha. Federici, M., Hribal, M.L., Menghini, R., Kanno, H., Marchetti, V., Porzio, O., Sunnarborg, S.W., Rizza, S., Serino, M., Cunsolo, V., Lauro, D., Mauriello, A., Smookler, D.S., Sbraccia, P., Sesti, G., Lee, D.C., Khokha, R., Accili, D., Lauro, R. J. Clin. Invest. (2005) [Pubmed]
  27. Growth hormone receptor gene deficiency causes delayed insulin responsiveness in skeletal muscles without affecting compensatory islet cell overgrowth in obese mice. Robertson, K., Kopchick, J.J., Liu, J.L. Am. J. Physiol. Endocrinol. Metab. (2006) [Pubmed]
  28. IGF-I induces caveolin 1 tyrosine phosphorylation and translocation in the lipid rafts. Maggi, D., Biedi, C., Segat, D., Barbero, D., Panetta, D., Cordera, R. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  29. Insulin signaling in insulin receptor substrate (IRS)-1-deficient brown adipocytes: requirement of IRS-1 for lipid synthesis. Valverde, A.M., Kahn, C.R., Benito, M. Diabetes (1999) [Pubmed]
  30. Expression of insulin-like growth factor binding protein-4, insulin-like growth factor-I receptor, and insulin-like growth factor-I in the mouse uterus throughout the estrous cycle. Henemyre, C., Markoff, E. Mol. Reprod. Dev. (1999) [Pubmed]
  31. Loss of sensitivity to insulin at early events of the insulin signaling pathway in the liver of growth hormone-transgenic mice. Dominici, F.P., Cifone, D., Bartke, A., Turyn, D. J. Endocrinol. (1999) [Pubmed]
  32. Improved glucose homeostasis and enhanced insulin signalling in Grb14-deficient mice. Cooney, G.J., Lyons, R.J., Crew, A.J., Jensen, T.E., Molero, J.C., Mitchell, C.J., Biden, T.J., Ormandy, C.J., James, D.E., Daly, R.J. EMBO J. (2004) [Pubmed]
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