insulin receptor substrate proteins


Summary: A structurally-related group of signaling proteins that are phosphorylated by the INSULIN RECEPTOR PROTEIN-TYROSINE KINASE. The proteins share an N-terminal PLECKSTRIN HOMOLOGY DOMAIN, a phosphotyrosine-binding domain that interacts with the phosphorylated INSULIN RECEPTOR, and a C-terminal TYROSINE-rich domain. Upon tyrosine phosphorylation, insulin receptor substrate proteins interact with specific SH2 DOMAIN containing proteins that are involved in insulin receptor signaling.

Top Publications

  1. Pektaş M, Sadi G, Akar F. Long-Term Dietary Fructose Causes Gender-Different Metabolic and Vascular Dysfunction in Rats: Modulatory Effects of Resveratrol. Cell Physiol Biochem. 2015;37:1407-20 pubmed publisher
    ..Long-term fructose intake may differently affect metabolic and vascular function between male and female rats, which are modified by resveratrol. ..
  2. Fallucca S, Vasta M, Sciullo E, Balducci S, Fallucca F. Birth weight: genetic and intrauterine environment in normal pregnancy. Diabetes Care. 2009;32:e149 pubmed publisher
  3. Eckstein S, Weigert C, Lehmann R. Divergent Roles of IRS (Insulin Receptor Substrate) 1 and 2 in Liver and Skeletal Muscle. Curr Med Chem. 2017;24:1827-1852 pubmed publisher
    ..Dysregulated muscular or hepatic abundance and/or phosphorylation status of IRS1 and IRS2 are important factors in the pathogenesis of insulin resistance, type 2 diabetes and muscle wasting. ..
  4. Law N, Donaubauer E, Zeleznik A, Hunzicker Dunn M. How Protein Kinase A Activates Canonical Tyrosine Kinase Signaling Pathways To Promote Granulosa Cell Differentiation. Endocrinology. 2017;158:2043-2051 pubmed publisher
    ..Thus, for the two central signaling pathways that regulate gene expression in GCs, FSH via PKA intersects canonical RTK-regulated signaling by modulating the activity of PPs...
  5. Jing Y, Zhang L, Gao L, Qi C, Lv D, Song Y, et al. Autophagy plays beneficial effect on diabetic encephalopathy in type 2 diabetes: studies in vivo and in vitro. Neuro Endocrinol Lett. 2017;38:27-37 pubmed
    ..These results demonstrate that autophagy activation confers protection to neurons under aberrant metabolism and that autophagy dysfunction in the hypothalamus occurs in the chronic metabolic disorder such as T2DM. ..
  6. Ghaffar S, Afridi S, Aftab M, Murtaza M, Syed S, Begum S, et al. Attenuation of palmitate induced insulin resistance in muscle cells by harmala, clove and river red gum. Pak J Pharm Sci. 2016;29:1795-1800 pubmed
    ..As a result, these herbal extracts may be considered useful to protect from insulin resistance. ..
  7. Jing Y, Li D, Wu F, Gong L, Li R. GDF11 does not improve the palmitate induced insulin resistance in C2C12. Eur Rev Med Pharmacol Sci. 2017;21:1795-1802 pubmed
  8. Sasaki M, Sasako T, Kubota N, Sakurai Y, Takamoto I, Kubota T, et al. Dual Regulation of Gluconeogenesis by Insulin and Glucose in the Proximal Tubules of the Kidney. Diabetes. 2017;66:2339-2350 pubmed publisher
  9. Bottomley W, Soos M, Adams C, Guran T, Howlett T, Mackie A, et al. IRS2 variants and syndromes of severe insulin resistance. Diabetologia. 2009;52:1208-11 pubmed publisher

More Information


  1. Taguchi T, Kishikawa H, Motoshima H, Sakai K, Nishiyama T, Yoshizato K, et al. Involvement of bradykinin in acute exercise-induced increase of glucose uptake and GLUT-4 translocation in skeletal muscle: studies in normal and diabetic humans and rats. Metabolism. 2000;49:920-30 pubmed
  2. Mansour A, Nassan M, Saleh O, Soliman M. PROTECTIVE EFFECT OF CAMEL MILK AS ANTI-DIABETIC SUPPLEMENT: BIOCHEMICAL, MOLECULAR AND IMMUNOHISTOCHEMICAL STUDY. Afr J Tradit Complement Altern Med. 2017;14:108-119 pubmed publisher
    ..CM administration is of medical importance and helps physicians in the treatment of diabetes mellitus. ..
  3. Yoshitomi H, Tsuru R, Li L, Zhou J, Kudo M, Liu T, et al. Cyclocarya paliurus extract activates insulin signaling via Sirtuin1 in C2C12 myotubes and decreases blood glucose level in mice with impaired insulin secretion. PLoS ONE. 2017;12:e0183988 pubmed publisher
    ..These results suggest that CPE exerts antidiabetic effects similar to those of insulin, and may be an oral therapeutic alternative for the management of diabetes...
  4. Hotamisligil G, Peraldi P, Budavari A, Ellis R, White M, Spiegelman B. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science. 1996;271:665-8 pubmed
    ..An inhibitory form of IRS-1 was observed in muscle and fat tissues from obese rats. These results indicate that TNF-alpha induces insulin resistance through an unexpected action of IRS-1 to attenuate insulin receptor signaling. ..
  5. Chibalin A, Yu M, Ryder J, Song X, Galuska D, Krook A, et al. Exercise-induced changes in expression and activity of proteins involved in insulin signal transduction in skeletal muscle: differential effects on insulin-receptor substrates 1 and 2. Proc Natl Acad Sci U S A. 2000;97:38-43 pubmed
    ..Furthermore, the differential response of IRS-1 and IRS-2 to exercise suggests that these molecules have specialized, rather than redundant, roles in insulin signaling in skeletal muscle. ..
  6. Bershtein L, Ulybina I, Pozharisskii K, Imianitov E. [Analysis of polymorphisms in genes of insulin receptor substrate-1 and enzymes involved in estrogen biosynthesis and metabolism among breast cancer patients with BRCA1 mutations]. Vopr Onkol. 2009;55:158-64 pubmed
    ..Our results warrant further large-scale cooperative studies of the problem. ..
  7. Cai D. One step from prediabetes to diabetes: hypothalamic inflammation?. Endocrinology. 2012;153:1010-3 pubmed publisher
  8. Myers M, Backer J, Sun X, Shoelson S, Hu P, Schlessinger J, et al. IRS-1 activates phosphatidylinositol 3'-kinase by associating with src homology 2 domains of p85. Proc Natl Acad Sci U S A. 1992;89:10350-4 pubmed
    ..Thus, IRS-1 likely serves to transmit the insulin signal by binding and regulating intracellular enzymes containing SH2 domains. ..
  9. Isaac R, Vinik Y, Boura Halfon S, Farack L, Streim S, Elhanany E, et al. Prolonged Elimination of Negative Feedback Control Mechanisms Along the Insulin Signaling Pathway Impairs ?-Cell Function In Vivo. Diabetes. 2017;66:1879-1889 pubmed publisher
    ..These findings suggest that elimination of inhibitory Ser phosphorylation sites of IRS2 exerts short-term beneficial effects in vivo; however, their sustained elimination leads to impaired ?-cell function. ..
  10. Stephens J, Lee J, Pilch P. Tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. J Biol Chem. 1997;272:971-6 pubmed
  11. Myers M, Sun X, Cheatham B, Jachna B, Glasheen E, Backer J, et al. IRS-1 is a common element in insulin and insulin-like growth factor-I signaling to the phosphatidylinositol 3'-kinase. Endocrinology. 1993;132:1421-30 pubmed
    ..These data demonstrate that IRS-1 is a common element for signal transmission by the IGF-I and insulin receptors. ..
  12. Myers M, Wang L, Sun X, Zhang Y, Yenush L, Schlessinger J, et al. Role of IRS-1-GRB-2 complexes in insulin signaling. Mol Cell Biol. 1994;14:3577-87 pubmed
  13. Matulewicz N, Stefanowicz M, Nikolajuk A, Karczewska Kupczewska M. Markers of Adipogenesis, but Not Inflammation, in Adipose Tissue Are Independently Related to Insulin Sensitivity. J Clin Endocrinol Metab. 2017;102:3040-3049 pubmed publisher
    ..Macrophages seem to be the first immune cells to infiltrate AT. Adipogenesis and ECM remodeling are the initial processes in AT that are independently associated with insulin sensitivity. ..
  14. Kubota T, Kubota N, Kadowaki T. Imbalanced Insulin Actions in Obesity and Type 2 Diabetes: Key Mouse Models of Insulin Signaling Pathway. Cell Metab. 2017;25:797-810 pubmed publisher
    ..This Review focuses on recent progress in understanding insulin signaling and insulin resistance using key mouse models for elucidating pathophysiology of human obesity and type 2 diabetes. ..
  15. Zhou Y, Du Y, Du H, Shao P. Insulin resistance in Alzheimer's disease (AD) mouse intestinal macrophages is mediated by activation of JNK. Eur Rev Med Pharmacol Sci. 2017;21:1787-1794 pubmed
    ..Activation of JNK pathway played an important role in insulin resistance of AD mice, suggesting that inhibition of JNK pathway might be a new strategy toward resolving insulin resistance related diseases, such as AD. ..
  16. Man S, Ma J, Yao J, Cui J, Wang C, Li Y, et al. Systemic Perturbations of Key Metabolites in Type 2 Diabetic Rats Treated by Polyphenol Extracts from Litchi chinensis Seeds. J Agric Food Chem. 2017;65:7698-7704 pubmed publisher
    ..All in all, LSE played a pivotal role in the treatment of T2D through regulation of broad-spectrum metabolic changes and inhibition of the glycogenesis, proteolysis, and lipogenesis in T2D rats. ..
  17. Irimia J, Meyer C, Segvich D, Surendran S, DePaoli Roach A, Morral N, et al. Lack of liver glycogen causes hepatic insulin resistance and steatosis in mice. J Biol Chem. 2017;292:10455-10464 pubmed publisher
    ..Our results suggest that loss of liver glycogen synthesis diverts glucose toward fat synthesis, correlating with impaired hepatic insulin signaling and glucose disposal. ..
  18. Bailey K, Agarwal E, Chowdhury S, Luo J, Brattain M, Black J, et al. TGF?/Smad3 regulates proliferation and apoptosis through IRS-1 inhibition in colon cancer cells. PLoS ONE. 2017;12:e0176096 pubmed publisher
    ..Given that loss of TGF? signaling occurs frequently in colon cancer, an important implication of our study is that IRS-1 could be a potential therapeutic target for colon cancer treatment. ..
  19. Eldar Finkelman H, Krebs E. Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action. Proc Natl Acad Sci U S A. 1997;94:9660-4 pubmed
    ..Taken together, our studies suggest a new role for GSK-3 in attenuating insulin signaling via its phosphorylation of IRS-1 and may provide new insight into mechanisms important in insulin resistance. ..
  20. Cui A, Jin Z, Gao Z, Jin M, Zhu L, Li L, et al. Downregulation of miR-493 promoted melanoma proliferation by suppressing IRS4 expression. Tumour Biol. 2017;39:1010428317701640 pubmed publisher
    ..In summary, these results demonstrated that miR-493 acts as a tumor suppressor and inhibits cell proliferation and cell cycle in human melanoma by directly targeting IRS4. ..
  21. Deyev I, Popova N, Serova O, Zhenilo S, Regoli M, Bertelli E, et al. Alkaline pH induces IRR-mediated phosphorylation of IRS-1 and actin cytoskeleton remodeling in a pancreatic beta cell line. Biochimie. 2017;138:62-69 pubmed publisher
  22. Lin M, Huang M, Wu M. Association of Gly972Arg variant of insulin receptor subtrate-1 and Gly1057Asp variant of insulin receptor subtrate-2 with polycystic ovary syndrome in the Chinese population. J Ovarian Res. 2014;7:92 pubmed publisher
    ..Women with IRS-2 homozygous Asp variant may be considered as a risk factor for PCOS that needs early detection to prevent further complication in the Chinese population from Taiwan. ..
  23. Ahmed Q, Manzoor S, Tariq M, Khalid M, Ashraf W, Parvaiz F, et al. Hepatitis C virus infection in vitro triggers endoplasmic reticulum stress and downregulates insulin receptor substrates 1 and 2 through upregulation of cytokine signaling suppressor 3. Acta Virol. 2014;58:238-44 pubmed
    ..Altogether these findings indicate that the HCV infection induces ER stress and IR in Huh-7 cells in vitro. ..
  24. Kim S, Yu G, Park H, Kim Y, Kim J, Baik H, et al. A polymorphism (rs4773092, Cys816Cys) of IRS2 affects auditory hallucinations in schizophrenia patients. Psychiatry Res. 2013;209:124-5 pubmed publisher
  25. Griffin M, Marcucci M, Cline G, Bell K, Barucci N, Lee D, et al. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes. 1999;48:1270-4 pubmed
    ..These changes are associated with abnormalities in the insulin signaling cascade and may be mediated by FFA activation of PKC theta. ..
  26. Ceresa B, Kao A, Santeler S, Pessin J. Inhibition of clathrin-mediated endocytosis selectively attenuates specific insulin receptor signal transduction pathways. Mol Cell Biol. 1998;18:3862-70 pubmed
    ..Together, these data demonstrate that the acute actions of insulin are largely independent of insulin receptor endocytosis and are initiated by activation of the plasma membrane-localized insulin receptor. ..
  27. Ohlsson C, Hammarstedt A, Vandenput L, Saarinen N, Ryberg H, Windahl S, et al. Increased adipose tissue aromatase activity improves insulin sensitivity and reduces adipose tissue inflammation in male mice. Am J Physiol Endocrinol Metab. 2017;313:E450-E462 pubmed publisher
    ..We propose that estrogen increases insulin sensitivity via a local effect in WAT on adiponectin expression, adipose tissue inflammation, and adipogenesis. ..
  28. Patti M, Brambilla E, Luzi L, Landaker E, Kahn C. Bidirectional modulation of insulin action by amino acids. J Clin Invest. 1998;101:1519-29 pubmed
    ..This bidirectional modulation of insulin action indicates crosstalk between hormonal and nutritional signals and demonstrates a novel mechanism by which nutritional factors contribute to insulin resistance. ..
  29. Kawada Y, Asahara S, Sugiura Y, Sato A, Furubayashi A, Kawamura M, et al. Histone deacetylase regulates insulin signaling via two pathways in pancreatic ? cells. PLoS ONE. 2017;12:e0184435 pubmed publisher
    ..The identification of the histone deacetylase isoform(s) involved in these mechanisms would be a valuable approach for the treatment of type 2 diabetes. ..
  30. Kurihara C, Tanaka T, Yamanouchi D. Hyperglycemia attenuates receptor activator of NF-?B ligand-induced macrophage activation by suppressing insulin signaling. J Surg Res. 2017;214:168-175 pubmed publisher
    ..These data suggest that HG suppressed macrophage activation, through attenuation of glucose uptake via the suppression of the membrane translocation of Glut1 and insulin signaling. ..