Modulation of insulin action by vanadate: evidence of a role for phosphotyrosine phosphatase activity to alter cellular signaling

  • I. G. Fantus
  • G. Deragon
  • R. Lai
  • S. Tang
Part of the Developments in Molecular and Cellular Biochemistry book series (DMCB, volume 16)


A number of vanadium compounds (vanadate, vanadyl sulfate, metavanadate) have insulin-mimicking actions both in vitro and in vivo. They have multiple biological effects in cultured cells and interact directly with various enzymes. The inhibitory action on phosphoprotein tyrosine phosphatases (PTPs) and enhancement of cellular tyrosine phosphorylation appear to be the most relevant to explain the ability to mimic insulin. We demonstrated that in rat adipocytes both acute insulin effects, e.g. stimulation of IGF-II and transferrin binding and a chronic effect, insulin receptor downregulation, were stimulated by vanadate. Vanadate also enhanced insulin binding, particularly at very low insulin concentrations, associated with increased receptor affinity. This resulted in increased adipocyte insulin sensitivity. Finally vanadate augmented the extent of activation of the insulin receptor kinase by submaximal insulin concentrations. This was associated with a prolongation of the insulin biological response, lipogenesis, after removal of hormone.

In conclusion: in rat adipocytes vanadate promotes insulin action by three mechanisms, 1) a direct insulin-mimetic action, 2) an enhancement of insulin sensitivity and 3) a prolongation of insulin biological response. These data suggest that PTP inhibitors have potential as useful therapeutic agents in insulin-resistant and relatively insulin-deficient forms of diabetes mellitus.

Key words

insulin resistance adipocytes insulin receptor vanadate tyrosine kinase 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Tolman EL, Barris E, Burns M, Pansini A, Partridge R: Effects of vanadium on glucose metabolism in vitro. Life Sciences 25: 1159–1164, 1979PubMedCrossRefGoogle Scholar
  2. 2.
    Shechter Y, Karlish SJD: Insulin-like stimulation of glucose oxidation in rat adipocytes by vandyl (IV) ions. Nature (London) 284: 556–558, 1980CrossRefGoogle Scholar
  3. 3.
    Dubyak GR, Kleinzeller A: The insulin-mimetic effects of vanadate in isolated rat adipocytes. Dissociation from effects of vanadate as a (Na+/K+) ATPase inhibitor. J Biol Chem 255: 5306–5312, 1980PubMedGoogle Scholar
  4. 4.
    Jackson TK, Salhanick AI, Sparks JD, Sparks CE, Bolognino M, Amatruda JM: Insulin-mimetic effects of vanadate in primary cultures of rat hepatocytes. Diabetes 37: 1234–1240, 1988.PubMedCrossRefGoogle Scholar
  5. 5.
    Clark AS, Fagan JM, Mitch WE: Selectivity of the insulin-like action of vanadate on glucose and protein metabolism in skeletal muscle. Biochem J 232: 273–276, 1985PubMedGoogle Scholar
  6. 6.
    Haugaard N, Torbati A, Smithgall T, Wildey G: Stimulation of the phosphorylation of uridine in skeletal muscle by insulin and vanadate. Mol Cell Biochem 93: 13–19, 1990PubMedCrossRefGoogle Scholar
  7. 7.
    Bruck R, Prigozin H, Krepel Z, Rotenberg P, Shechter Y, Bar-Meir S: Vanadate inhibits glucose output from isolated perfused rat liver. Hepatology 14: 540–544, 1991PubMedCrossRefGoogle Scholar
  8. 8.
    Tamura S, Brown TA, Whipple JH, Fujita-Yamaguchi Y, Dubler RE, Cheng K, Larner J: A novel mechanism for the insulin-like effect of vanadate on glycogen synthase in rat adipocytes. J Biol Chem 259: 6650–6658, 1984PubMedGoogle Scholar
  9. 9.
    Kadota S, Fantus IG, Hersh B, Posner BI: Vanadate stimulation of IGF binding to rat adipocytes. Biochem Biophys Res Commun 138: 174–178, 1986PubMedCrossRefGoogle Scholar
  10. 10.
    Duckworth WC, Solomon SS, Liepnieks J, Hamel FG, Hand S, Peavy DE: Insulin-like effects of vanadate in isolated rat adipocytes. Endocrinology 122: 2285–2289, 1988PubMedCrossRefGoogle Scholar
  11. 11.
    Heyliger CE, Tahiliani AG, McNeill JH: Effect of vanadate on elevated blood glucose and depressed cardiac performance of diabetic rats. Science 227: 1474–1476, 1985PubMedCrossRefGoogle Scholar
  12. 12.
    Meyerovitch J, Farfel Z, Sack J, Shechter Y: Oral administration of vanadate normalizes blood glucose levels in streptozotocin-treated rats. Characterization and mode of action. J Biol Chem 262: 6658–6662, 1987PubMedGoogle Scholar
  13. 13.
    Brichard SM, Okitolonda W, Henquin JC: Long term improvement of glucose homeostasis by vanadate treatment in diabetic rats. Endocrinology 123: 2048–2053, 1988PubMedCrossRefGoogle Scholar
  14. 14.
    Rossetti L, Laughlin MR: Correction of chronic hyperglycemia with vanadate, but not with phlorizin, normalizes in vivo glycogen repletion and in vitro glycogen synthase activity in diabetic skeletal muscle. J Clin Invest 84: 892–899, 1989PubMedCrossRefGoogle Scholar
  15. 15.
    Blondel O, Bailbe D, Portha B. In vivo insulin resistance in streptozotocin-diabetic rats — evidence for reversal following oral vanadate treatment. Diabetologia 32: 185–190, 1989PubMedCrossRefGoogle Scholar
  16. 16.
    Ramanadham S, Mongold JJ, Brownsey RW, Cros GH, McNeill JH: Vanadyl sulfate in the treatment of diabetes mellitus in rats. Am J Physiol 257: H904–H911, 1989PubMedGoogle Scholar
  17. 17.
    Bendayan M, Gingras D: Effect of vanadate administration on blood glucose and insulin levels as well as on the exocrine pancreatic function in streptozotocin-diabetic rats. Diabetologia 32: 561–567, 1989PubMedCrossRefGoogle Scholar
  18. 18.
    Shechter Y: Insulin-mimetic effects of vanadate: possible implications for future treatment of diabetes. Diabetes 39: 1–5, 1990PubMedCrossRefGoogle Scholar
  19. 19.
    Brichard SM, Pottier AM, Henquin JC: Long term improvement of glucose homeostasis by vanadate in obese hyperinsulinemic fa/fa rats. Endocrinology 125: 2510–2516, 1989PubMedCrossRefGoogle Scholar
  20. 20.
    Brichard SM, Bailey CJ, Henquin JC: Marked improvement of glucose homeostasis in diabetic ob/ob mice given oral vanadate. Diabetes 39: 1326–1332, 1990PubMedCrossRefGoogle Scholar
  21. 21.
    Meyerovitch J, Rothenberg P, Shechter Y, Bonner-Weir S, Kahn CR: Vanadate normalizes hyperglycemia in two mouse models of non-insulin-dependent diabetes mellitus. J Clin Invest 87: 1286–1294, 1991PubMedCrossRefGoogle Scholar
  22. 22.
    Pugazhenti S, Angel JF, Khandelwal RL: Long term effects of vanadate treatment on glycogen metabolizing and lipogenic enzymes of liver in genetically diabetic (db/db) mice. Metabolism 40: 941–946, 1991CrossRefGoogle Scholar
  23. 23.
    Brichard SM, Ongemba LN, Henquin JC: Oral vanadate decreases muscle insulin resistance in obese fa/fa rats. Diabetologia 35: 522–527, 1992PubMedCrossRefGoogle Scholar
  24. 24.
    Eriksson JW, Lönnroth P, Smith U: Vanadate increases cell surface insulin binding and improves insulin sensitivity in both normal and insulin-resistant rat adipocytes. Diabetologia 35: 510–516, 1992PubMedCrossRefGoogle Scholar
  25. 25.
    Bhanot S, Bryer-Ash M, Cheung A, McNeill JH: Bis (maltolato) oxovanadium (IV) attenuates hyperinsulinemia and hypertension in spontaneously hypertensive rats. Diabetes 43: 857–861, 1994PubMedCrossRefGoogle Scholar
  26. 26.
    DeFronzo RA, Ferrannini E: Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia and atherosclerotic cardiovascular disease. Diabetes Care 14:173–194, 1991PubMedCrossRefGoogle Scholar
  27. 27.
    Macara IG: Vanadium—an element in search of a role. Trends Biochem Sci 5: 92–94, 1980CrossRefGoogle Scholar
  28. 28.
    Nechay BR, Nanninga LB, Nechay PSE, Post RL, Granthan JJ, Macara IG, Kubena LF, Phillips TD, Nielsen FFH: Role of vanadium in biology. Fed Proc 45: 123–132, 1986Google Scholar
  29. 29.
    Klarlund J: Transformation of cells by an inhibitor of phosphatases acting on phosphotyrosine proteins. Cell 41: 707–717, 1985PubMedCrossRefGoogle Scholar
  30. 30.
    Bernier M, Laird DM, Lane MD: Effect of vanadate on the cellular accumulation of pp15, an apparent product of insulin receptor tyrosine kinase action. J Biol Chem 263: 13626–13634, 1988PubMedGoogle Scholar
  31. 31.
    Chen Y, Chan TM: Orthovanadate and 2,3-dimethoxy-l,4-naphthoquinone augment growth factor-induced cell proliferation and C-fos gene expression in 3T3-L1 cells. Arch Biochem Biophys 305: 9–16, 1993PubMedCrossRefGoogle Scholar
  32. 32.
    Kowalski LA, Tsang SS, Davison AJ: Vanadate enhances transformation of bovine papillomavirus DNA-transfected C3H/10T1/2 cells. Cancer Lett 64: 83–90, 1992PubMedCrossRefGoogle Scholar
  33. 33.
    Torossian K, Freedman D, Fantus IG: Vanadate downregulates cell surface insulin and growth hormone receptors and inhibits insulin receptor degradation in cultured human lymphocytes. J Biol Chem 263: 9353–9359, 1988PubMedGoogle Scholar
  34. 34.
    Marshall S, Monzon R: Down-regulation of cell surface insulin receptors in primary cultured rat adipocytes by sodium vanadate. Endocrinology 121: 1116–1122, 1987PubMedCrossRefGoogle Scholar
  35. 35.
    Valera A, Rodriguez-Gil JE, Bosch F: Vanadate treatment restores the expression of genes for key enzymes in the glucose and ketone bodies metabolism in the liver of diabetic rats. J Clin Invest 92: 4–11, 1993PubMedCrossRefGoogle Scholar
  36. 36.
    Miralpeix M, Carballo E, Bartrons R, Crepin K, Hue L, Rousseau GG: Oral administration of vanadate to diabetic rats restores liver 6-phosphofructo-2-kinase content and mRNA. Diabetologia 35: 243–248, 1992PubMedCrossRefGoogle Scholar
  37. 37.
    Green A: The insulin-like effect of sodium vanadate on adipocyte glucose transport is mediated at a post-insulin-receptor level. Biochem J 238: 663–669, 1986PubMedGoogle Scholar
  38. 38.
    Foot E, Bliss T, Fernandes LC, Da Costa C, Leighton B: The effects of orthovanadate, vanadyl and peroxides of vanadate on glucose metabolism in skeletal muscle preparations in vitro. Mol Cell Biochem 109: 157–162, 1992PubMedCrossRefGoogle Scholar
  39. 39.
    Kadota S, Fantus IG, Deragon G, Guyda HJ, Posner BI: Stimulation of insulin-like growth factor II receptor binding and insulin receptor kinase activity in rat adipocytes: Effects of vanadate and H2O2. J Biol Chem 262: 8252–8256, 1987PubMedGoogle Scholar
  40. 40.
    Cordera R, Andraghetti G, DeFronzo RA, Rosetti L: Effect of in vivo vanadate treatment on insulin receptor tyrosine kinase activity in partially pancreatectomized diabetic rats. Endocrinology 126: 2177–2183, 1990PubMedCrossRefGoogle Scholar
  41. 41.
    Singh J, Nordlie RC, Jorgensen RA: Vanadate: a potent inhibitor of multifunctional glucose-6-phosphatase. Biochim Biophys Acta 678: 477–482, 1981PubMedGoogle Scholar
  42. 42.
    Schulz LO: Suppression of the hepatic glucose-6-phosphatase system in diabetic rats by vanadate. Ann Nutr Metab 32: 289–296, 1988PubMedCrossRefGoogle Scholar
  43. 43.
    Rider MH, Bartrons R, Hue L: Vanadate inhibits liver fructose-2,6-bisphosphatase. Eur J Biochem 190: 53–56, 1990PubMedCrossRefGoogle Scholar
  44. 44.
    Rosen O: After insulin binds. Science 237: 1452–1458, 1987PubMedCrossRefGoogle Scholar
  45. 45.
    White MF, Kahn CR: The insulin signaling system. J Biol Chem 269: 1–5, 1994PubMedGoogle Scholar
  46. 46.
    Kahn CR: Insulin action, diabetogenes, and the cause of Type II diabetes. Diabetes 43: 1066–1084, 1994PubMedCrossRefGoogle Scholar
  47. 47.
    Sun XJ, Crimmins DL, Myers MG, Miralpeix M, White MF: Pleiotrope insulin signals are engaged by multisite phosphorylation of IRS-1. Mol Cell Biol 13: 7418–7428, 1993PubMedGoogle Scholar
  48. 48.
    Tonks NK, Cicirelli MF, Diltz CD, Krebs EG, Fischer EH: Effect of microinjection of a low-Mr human placenta protein tyrosine phosphatase on induction of meiotic cell division in Xenopus oocytes. Mol Cell Biol 10: 458–463, 1990PubMedGoogle Scholar
  49. 49.
    Mooney RA, Bordwell KL: Differential dephosphorylation of the insulin receptor and its 160 kDa substrate (pp 160) in rat adipocytes. J Biol Chem 267: 14054–14060, 1992PubMedGoogle Scholar
  50. 50.
    Goldstein BJ: Protein-tyrosine phosphatases and the regulation of insulin action. J Cell Biochem 48: 33–42, 1992PubMedCrossRefGoogle Scholar
  51. 51.
    Oka Y, Mottola C, Oppenheimer CL, Czech MP: Insulin activates the appearance of insulin like growth factor II receptors on the adipocyte cell surface. Proc Natl Acad Sci USA 81: 4028–4032, 1984PubMedCrossRefGoogle Scholar
  52. 52.
    Simpson IA, Cushman SW: Hormonal regulation of mammalian glucose transport. Ann Rev Biochem 55: 1059–1089, 1986PubMedCrossRefGoogle Scholar
  53. 53.
    Paquet MR, Romanek RJ, Sargeant RJ: Vanadate induces the recruitment of glut-4 glucose transporter to the plasma membrane of rat adipocytes. Mol Cell Biochem 109, 149–155, 1992PubMedCrossRefGoogle Scholar
  54. 54.
    Salter AM, Fisher SC, Brindley DN: Binding of low-density lipoprotein to monolayer cultures of rat hepatocytes is increased by insulin and decreased by dexamethasone. FEBS Lett 220: 159–162, 1987PubMedCrossRefGoogle Scholar
  55. 55.
    Davis RJ, Corvera S, Czech MP: Insulin stimulates cellular iron uptake and causes the redistribution of intracellular transferrin receptors to the plasma membrane. J Biol Chem 261: 8708–8711, 1986PubMedGoogle Scholar
  56. 56.
    Gavin JR, Roth J, Neville DM Jr, DeMeyts P, Buell DN: Insulin-dependent regulation of insulin receptor concentrations: a direct demonstration in cell culture. Proc Natl Acad Sci USA 71: 84–188, 1974PubMedCrossRefGoogle Scholar
  57. 57.
    Fantus IG, Kadota S, Deragon G, Foster B, Posner BI: Pervanadate (Peroxide(s) of vanadate) mimics insulin action in rat adipocytes via activation of the insulin receptor tyrosine kinase. Biochemistry 28: 8864–8871, 1989PubMedCrossRefGoogle Scholar
  58. 58.
    Marshall S, Monzon R: Down-regulation of cell surface insulin receptors in primary cultured rats adipocytes by sodium vanadate. Endocrinology 121: 1116–1122, 1987PubMedCrossRefGoogle Scholar
  59. 59.
    Russell DS, Gherzi R, Johnson EL, Chou CK, Rosen OM: The protein-tyrosine kinase activity of the insulin receptor is necessary for insulin-mediated receptor down-regulation. J Biol Chem 262: 11833–11840, 1987PubMedGoogle Scholar
  60. 60.
    McClain DA, Maegawa H, Lee J, Dull TJ, Ullrich A, Olefsky JM: A mutant insulin receptor with defective tyrosine kinase displays no biologic activity and does not undergo endocytosis. J Biol Chem 262: 14663–14671, 1987PubMedGoogle Scholar
  61. 61.
    Torossian K, Nower P, Schwartz T, Fantus IG: Phorbol esters inhibit insulin-induced receptor downregulation in cultured human lymphocytes: association with diminished insulin receptor autophosphorylation. Biochem J 290: 151–158, 1993PubMedGoogle Scholar
  62. 62.
    Carpentier J-L, Paccaud J-P, Backer J, Gilbert A, Orci LM, Kahn CR: Two steps of insulin receptor internalization depend on different domains of the B-subunit. J Cell Biol 122: 1243–1252, 1993PubMedCrossRefGoogle Scholar
  63. 63.
    Fantus IG, Ahmad F, Deragon G: Vanadate augments insulin binding and prolongs insulin action in rat adipocytes. Endocrinology 127: 2716–2725, 1990PubMedCrossRefGoogle Scholar
  64. 64.
    Fantus IG, Ahmad F, Deragon G: Vanadate augments insulin-stimulated insulin receptor kinase activity and prolongs insulin action in rat adipocytes. Evidence for transduction of amplitude of signaling into duration of response. Diabetes 43: 375–383, 1994PubMedCrossRefGoogle Scholar
  65. 65.
    Mooney RA, Anderson DL: Phosphorylation of the insulin receptor in permeabilized adipocytes in coupled to a rapid dephosphorylation reaction. J Biol Chem 264: 6850–6857, 1989PubMedGoogle Scholar
  66. 66.
    Roth J, Grunfeld C: Mechanism of action of peptide hormones and catecholamines. In: J.D. Wilson, D.W. Foster (eds). Williams Textbook of Endocrinology. Philadelphia, Saunders, pp 76–122, 1985Google Scholar
  67. 67.
    Kahn CR: Insulin resistance, insulin insensitivity, and insulin unresponsiveness: a necessary distinction. Metabolism 27: 1893–1902, 1978PubMedCrossRefGoogle Scholar
  68. 68.
    Feng G-S, Hui C-C, PawsonT: SH2-containing phosphotyrosine phosphatase as a target of protein-tyrosine kinases. Science 259: 1607–1611, 1993PubMedCrossRefGoogle Scholar
  69. 69.
    Kuhne MR, Zhao Z, Rowles J, Lavan BE, Shen S-H, Fischer EH, Lienhard GE: Dephosphorylation of insulin receptor substrate 1 by the tyrosine phosphatase PTP2C. J Biol Chem 269: 15833–15837, 1994PubMedGoogle Scholar
  70. 70.
    Kwak SP, Hakes DJ, Martell KJ, Dixon JE: Isolation and characterization of a human dual specificity protein-tyrosine phosphatasegene. J Biol Chem 269: 3596–3604, 1994PubMedGoogle Scholar
  71. 71.
    Nishida E, Gotoh Y: The MAP kinase cascade is essential for diverse signal transduction pathways. Trends Biochem Sci 18: 128–131, 1993PubMedCrossRefGoogle Scholar
  72. 72.
    Nebreda AR: Inactivation of MAP kinases. Trends Biochem Sci 19: 1–2, 1994PubMedCrossRefGoogle Scholar
  73. 73.
    Chen R-H, Sarnecki C, Blenis J: Nuclear localization and regulation of erk- and rsk-encoded protein kinases. Mol Cell Biol 12: 915–927, 1992PubMedGoogle Scholar
  74. 74.
    Norbury C, Nurse P: Animal cell cycles and their control. Ann Rev Biochem 61: 441–470, 1992Google Scholar
  75. 75.
    Cruz TF, Morgan A, Min W: In vitro and in vivo anti-neoplastic effect of orthovanadate. Mol Cell Biochem (In press)Google Scholar
  76. 76.
    Shisheva A, Shechter Y: Role of cytosolic tyrosine kinase in mediating insulin-like actions of vanadate in rat adipocytes. J Biol Chem 268: 6463–6469, 1993PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1995

Authors and Affiliations

  • I. G. Fantus
    • 1
    • 2
  • G. Deragon
    • 1
    • 2
  • R. Lai
    • 1
    • 2
  • S. Tang
    • 1
    • 2
  1. 1.Department of MedicineMount Sinai HospitalTorontoCanada
  2. 2.Banting and Best Diabetes Centre and Department of PhysiologyUniversity of TorontoCanada

Personalised recommendations