Molecular and Cellular Biochemistry

, Volume 188, Issue 1–2, pp 73–80 | Cite as

Vanadium and diabetes

  • Patrick Poucheret
  • Subodh Verma
  • Marc D. Grynpas
  • John H. McNeill

Abstract

We demonstrated in 1985 that vanadium administered in the drinking water to streptozotocin (STZ) diabetic rats restored elevated blood glucose to normal. Subsequent studies have shown that vanadyl sulfate can lower elevated blood glucose, cholesterol and triglycerides in a variety of diabetic models including the STZ diabetic rat, the Zucker fatty rat and the Zucker diabetic fatty rat. Long-term studies of up to one year did not show toxicity in control or STZ rats administered vanadyl sulfate in doses that lowered elevated blood glucose. In the BB diabetic rat, a model of insulin-dependent diabetes, vanadyl sulfate lowered the insulin requirement by up to 75%. Vanadyl sulfate is effective orally when administered by either single dose or chronic doses. It is also effective by the intraperitoneal route. We have also been able to demonstrate marked long-terrn effects of vanadyl sulfate in diabetic animals following treatment and withdrawal of vanadyl sulfate. Because vanadyl sulfate is not well absorbed we have synthesized and tested a number of organic vanaditun compounds. One of these, bismaltolato-oxovanadiurn IV (BMOV), has shown promise as a therapeutic agent. BMOV is 2-3x more potent than vanadyl sulfate and has shown less toxicity. Recent studies from our laboratory have shown that the effects of vanadium are not due to a decrease in food intake and that while vanadium is deposited in bone it does not appear to affect bone strength or architecture. The mechanism of action of vanadium is currently under investigation. Several studies indicate that vanadiun is a phosphatase inhibitor and that vanadium can activate serine/threonine kineses distal to tbe insulin receptor presumably by preventing dephosphorylation due to inhibition of phosphatases Short-term clinical trials using inorganic vanadium compounds in diabetic patients have been promising.

vanadium diabetes glucose lowering insulin-mimetic 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Heyliger CE, Tahiliani AG, McNeill JH: Effect of vanadate on elevated blood glucose and depressed cardiac performance of diabetic rats. Science 227: 1474–1477, 1985Google Scholar
  2. 2.
    Nechay BR: Mechanism of action of vanadium. Ann Rev Pharmacol Toxicol 24: 501–524, 1984Google Scholar
  3. 3.
    Talvite NA, Wagner WD: Studies in vanadium toxicology. Arch Ind Hyg Occup Med 9: 414–422, 1954Google Scholar
  4. 4.
    Byrne AR, Kosta L: Vanadium in food and human body fluids and tissues. Sci Total Environ 10: 17–30, 1993Google Scholar
  5. 5.
    Nakai M, Watanabe H, Fujiwara C, Kakegawa H, Satoh T, Takeda J, Matsushita R, Sakurai H: Mechanism of insulin-like action of vanadyl sulfate: studies on interaction between rat adipocytes and vanadium compounds. J Pharm Soc Jap 18: 119–125, 1995Google Scholar
  6. 6.
    Duckworth WC, Solomon SS, Liepneks J, Hamel FG, Hand S, Peavy DE: Insulin like effects of vanadate in isolated rat adipocytes. Endocrinology 122: 2285–2289, 1988PubMedGoogle Scholar
  7. 7.
    Schechter Y, Karlish SJD: Insulin-like stimulation of glucose oxidation in rat adipocytes by vanadyl (IV) ions. Nature 284: 556–558, 1980Google Scholar
  8. 8.
    Tamura S, Brown TA, Whipple JH, Fujita-Yamaguchi Y, Dubler RE, Cheng K, Lamer 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.
    Tamura S, Brown TA, Dubler RE, Lamer J: Insulin-like effect of vanadate on adipocyte glycogen synthase and on phosphorylation of 95,000 Dalton subunit of insulin receptor. Biochem Biophys Res Comm 113: 8042–8048, 1983Google Scholar
  10. 10.
    McNeill JH, Yuen VG, Dai S, Orvig C: Increased potency of vanadium using organic ligands. Mol Cell Biochem 153: 175–180, 1995PubMedGoogle Scholar
  11. 11.
    Orvig C, Thompson KH, Battell M, McNeill JH: Vanadium compounds as insulin mimics in 'Metal Ions in Biological Systems' In: H. Sigel and A. Sigel (eds). Marcel Dekker, Inc, 1995Google Scholar
  12. 12.
    Jackson T, Salhanick AL, Sparks JD, Sparks CE, Bolognino M, Amatrude JM: Insulin-mimetic effects of vanadate in primary cultures of rat hepatocytes. Diabetes 37: 1234–1240, 1988PubMedGoogle Scholar
  13. 13.
    Morita T, Imagawa T, Kanagawa A, Ueki H: Sodium orthovanadate increases phospholipase A2 activity in isolated rat fat pats: A role of phospholipase A2 in the vanadate stimulated release of lipoprotein lipase activity. Biol Pharm Bull 18: 347–349, 1995PubMedGoogle Scholar
  14. 14.
    Maher PA: Stimulation of endothelial cell proliferation by vanadate specific for microvascular endothelial cells. J Cell Physiol 151: 549–554, 1992PubMedGoogle Scholar
  15. 15.
    Barnes DM, Sykes DB, Schechter Y, Miller DS: Multiple sites of vanadate and peroxovanadate action in xenopus oocytes. J Cell Physiol 162: 154–161, 1995PubMedGoogle Scholar
  16. 16.
    Hajjar JJ, Fucci JC, Rowe WA, Tomicic TK: Effect of vanadate on amino acid transport in rat jejunum. Proc Natl Acad Sci USA 184: 403–409, 1987Google Scholar
  17. 17.
    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, 1994PubMedGoogle Scholar
  18. 18.
    Meyerovitch J, Farfel Z, Sack J, Schechter Y: Oral administration of vanadate normalizes blood glucose levels in streptozotocin treated rats. J Biol Chem 262: 6658–6662, 1987PubMedGoogle Scholar
  19. 19.
    Brichard SM, Okitolonda W, Henquin JC: Long term improvement of glucose homeostasis by vanadate treatment in diabetic rats. Endocrinology 123: 2048–2053, 1988PubMedGoogle Scholar
  20. 20.
    Hudson TGF: Vanadium, Toxicology and Biological Significance. New York, Elsevier, 1964Google Scholar
  21. 21.
    Battell ML, Yuen VG, McNeill JH: Treatment of BB rats with vanadyl sulfate. Pharmacol Commun 1: 291–301, 1992Google Scholar
  22. 22.
    Ramanadham S, Mongold JJ, Brownsey RW, Cros GH, McNeill JH: Oral vanadyl sulfate treatment of diabetes mellitus in rats. Am J Physiol 257: H904–H911, 1989PubMedGoogle Scholar
  23. 23.
    Ramanadham S, Brownsey RW, Cros GH, Mongold JJ, McNeill JH: Sustained prevention of myocardial abnormalities in diabetic rats following withdrawal from oral vanadyl treatment. Metabolism 38: 1022–1028, 1989PubMedGoogle Scholar
  24. 24.
    Cam MC, Pederson RA, Brownsey RW, McNeill JH: Long term effectiveness of oral vanadyl sulfate in streptozotocin-diabetic rats. Diabetologia 36: 218–224, 1993PubMedGoogle Scholar
  25. 25.
    Ramanadham S, Cros GH, Mongold JJ, Serrano JJ, McNeill JH: Enhanced in vivo sensitivity of vanadyl treated diabetic rats to insulin. Can J Physiol Pharmacol 68: 486–491, 1990PubMedGoogle Scholar
  26. 26.
    McNeill JH, Yuen VG, Hoveyda HR, Orvig C: Bis(maltolato) oxovanadium (IV) is a potent insulin mimic. J Med Chem 35: 1489–1491, 1992PubMedGoogle Scholar
  27. 27.
    Yuen VG, Orvig C, McNeill JH: Glucose lowering effects of a new organic vanadium complex bis(maltolato)oxovanadium (IV). Can J Physiol Pharmacol 71: 263–269, 1993PubMedGoogle Scholar
  28. 28.
    Yuen VG, Orvig C, McNeill JH: Comparison of the glucose lowering properties of vanadyl sulfate and bis(maltolato)oxovanadium (IV) following acute and chronic administration. Can J Physiol Pharmacol 73: 55–64, 1995PubMedGoogle Scholar
  29. 29.
    Dai S, Yuen VG, Orvig C, McNeill JH: Prevention of diabetes-induced pathology in STZ-diabetic rats by bis(maltolato)oxovanadium (IV). Pharmacol Communic 3: 311–321, 1993Google Scholar
  30. 30.
    Yuen VG, Pederson RA, Dai S, Orvig C, McNeill JH: The effects of low and high dose administration of bis(maltolato)oxovanadium (IV) on fa/fa Zucker rats. Can J Physiol Pharmacol 74: 1001–1009, 1996PubMedGoogle Scholar
  31. 31.
    Bhanot S, McNeill JH: Insulin and hypertension: A causal relationship? Cardiovasc Res 31: 212–221, 1996PubMedGoogle Scholar
  32. 32.
    DeFronzo RA, Ferrannini E: Insulin resistance: A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia and atherosclerotic cardiovascular disease. Diabetes Care 14: 173–194, 1991PubMedGoogle Scholar
  33. 33.
    Ferrannini E, Natali A: Essential hypertension, metabolic disorders and insulin resistance. Am Heart J 121:1274–1282, 1991PubMedGoogle Scholar
  34. 34.
    Bhanot S, Michoulas A, McNeill JH: Antihypertensive effects of vanadium compounds in hyperinsulinemic, hypertensive rats. Mole Cell Biochem 153: 205–209, 1995Google Scholar
  35. 35.
    Bhanot S, McNeill JH: Vanadyl sulfate lowers plasma insulin levels and blood pressure in spontaneously hypertensive rats. Hypertension 24: 625–632, 1994PubMedGoogle Scholar
  36. 36.
    Bhanot S, McNeill JH, Bryer-Ash M: Vanadyl sulfate prevents fructose induced hyperinsulinemia and hypertension in rats. Hypertension 23: 308–312, 1994PubMedGoogle Scholar
  37. 37.
    Swarup G, Cohen S, Garbers DI: Inhibition of membrane phosphotyrosyl-protein phosphatase activity by vanadate. Biochem Biophys Res Com 107: 1104–1109, 1982PubMedGoogle Scholar
  38. 38.
    Tracey AS, Gresser MJ: Interaction of vanadate with phenol and tyrosine: implications for the effects of vanadate on systems regulated by tyrosine phosphorylation. Proc Natl Acad Sci USA 83: 609–613, 1986PubMedGoogle Scholar
  39. 39.
    Ueno A, Arakaki N, Takeda Y, Fujio H: Inhibition of tyrosine autophosphorylation of the solubilized insulin receptor by an insulin stimulating peptide derived from bovine serum albumin. Biochem Biophys Res Com 144: 11–18, 1987PubMedGoogle Scholar
  40. 40.
    Gherzi R, Caratti G, Andraghetti G, Bertolini S, Montemurro A, Sesto G, Cordera R: Direct modulation of insulin receptor protein tyrosine kinase by vanadate and antiinsulin receptor monoclonal antibodies. Biochem Biophys Res Com 152: 1474–1480, 1988PubMedGoogle Scholar
  41. 41.
    Smith DM, Sale GJ: Evidence that a novel serine kinase catalyses phosphorylation of the insulin receptor in an insulin dependent and tyrosine kinase dependent manner. Biochem J 256: 903–909, 1988PubMedGoogle Scholar
  42. 42.
    Green A: The insulin like effect of sodium vanadate on adipocyte transport is mediated at a post insulin receptor level. Biochem J 238: 663–669, 1993Google Scholar
  43. 43.
    Mooney RA, Bordwell KL, Luhowskyj S, Casnelle JE: The insulin like effect of vanadate on lipolysis in rat adipocytes is not accompanied by an insulin like effect on tyrosine phosphorylation. Endocrinology 124: 422–429, 1989PubMedGoogle Scholar
  44. 44.
    Shisheva A, Shechter Y: Role of cytosolic tyrosine kinase in mediating the insulin like actions of vanadate in rat adipocytes. J Biol Chem 268: 6463–6469, 1993PubMedGoogle Scholar
  45. 45.
    Shechter Y, Shisheva A, Lazar R, Libman J, Shanzer A: Hydrophobic carriers of vanadyl ions augment the insulinomimetic actions of vanadyl ions in rat adipocytes. Biochemistry 31: 2063–2068, 1982Google Scholar
  46. 46.
    Sekar N, Li J, Schechter Y: Vanadium salts as insulin substitutes: Mechanism of action, a scientific and therapeutic tool in diabetes mellitus research. Critical Rev Biochem Mol Biol 31: 339–359, 1996Google Scholar
  47. 47.
    Hei YJ, Chen X, Pelech SL, Diamond J, McNeill JH: Skeletal muscle mitogen activated protein kinases and ribosomal S6 kinases suppression in chronic diabetes and reversal by vanadium. Diabetes 44: 1147–1155, 1995PubMedGoogle Scholar
  48. 48.
    Hei YJ, Diamond J, McNeill JH: Distribution of MAP kinase, S6 kinase and casein kinase 2 in rat tissues: activation by insulin in spleen. Biochem Cell Biol 72: 49–53, 1994PubMedGoogle Scholar
  49. 49.
    Cam MC, Li WM, McNeill JH: Partial preservation of pancreatic beta cells by vanadium: Evidence for chronic amelioration of diabetes. Metabolism 46: 1–11, 1997Google Scholar
  50. 50.
    Goldfine AB, Simonson DC, Folli F, Patti ME, Khan CR: Metabolic effects of sodium metavanadate in humans with insulin dependent and non insulin dependent diabetes mellitus in vivo and in vitro studies. J Clin Endocrinol Metab 80: 3311–3320, 1995PubMedGoogle Scholar
  51. 51.
    Cohen N, Halberstam M, Shlimovich P, Chang CJ, Shamoon H, Rossetti L: Oral vanadyl sulfate improves hepatic and peripheral insulin sensitivity in patients with non insulin dependent diabetes mellitus. J Clin Invest 95: 2501–2509, 1995PubMedGoogle Scholar
  52. 52.
    Boden G, Chen S, Ruiz J, George DV, Rossum V, Turco S: Effects of vanadyl sulfate on carbohydrate and lipid metabolism in patients with non insulin dependent diabetes mellitus. Metabolism 45: 1130–1135, 1996PubMedGoogle Scholar
  53. 53.
    Halberstam M, Cohen N, Shlimovich P, Rossetti L, Shamoon H: Oral vanadyl sulfate improves insulin sensitivity in NIDDM but not in obese non diabetic subjects. Diabetes 45: 659–666, 1996PubMedGoogle Scholar
  54. 54.
    Malabu US, Dryden S, McCarthy HD, Kilpatrick A, Williams G: Effects of chronic vanadate administration in the STZ diabetic rat. The antihyperglycemic action of vanadate is attributable entirely to its suppression of feeding. Diabetes 43: 9–15, 1994PubMedGoogle Scholar
  55. 55.
    Yuen VG, Orvig C, McNeill JH: Effects of bis(maltolato) oxovanadium (IV) are distinct from food restriction in STZ-diabetic rats. Am J Physiol 272: E30–E35, 1997PubMedGoogle Scholar
  56. 56.
    Mravoca A, Jirova D, Janci H and Lener J: Effect of orally administered vanadium on the immune system and bone metabolism in experimental animals. The Science of the Total Environment (Supplement), Elsevier Publishers, Amsterdam, 1993, pp 663–669Google Scholar
  57. 57.
    Yuen VG, Orvig C, Thompson KH, McNeill JH: Improvement in cardiac dysfunction in STZ-induced diabetic rats following chronic oral administration of bis(maltolato)oxovanadium (IV). Can J Physiol Pharmacol 71: 270–276, 1993PubMedGoogle Scholar
  58. 58.
    Mongold JJ, Cros GH, Vian L, Tep A, Ramanadham S, Siou G, Diaz J, McNeill JH, Serrano JJ; Toxicological aspects of vanadyl sulfate on diabetic rats-Effects on vanadium levels and pancreatic B-cell morphology. Pharmacol Toxicol 67: 192–198, 1990PubMedGoogle Scholar
  59. 59.
    Blondel O, Bailbe D, Portha B: In vivo insulin resistance in streptozotocin-diabetic rats-evidence for reversal following vanadate treatment. Diabetologia 32: 185–190, 1989PubMedGoogle Scholar
  60. 60.
    Gil J, Miralpeix M, Carreras J, Bartrons R: Insulin like effects of vanadate on glucokinase activity and fructose 2,6 biphosphate levels in livers of diabetic rats. J Biol Chem 263: 1868–1871, 1988PubMedGoogle Scholar
  61. 61.
    Pugazhenthi S, Khandelwal R: Insulin like effects of vanadate on hepatic glycogen metabolism in non-diabetic and streptozotocininduced diabetic rats. Diabetes 39: 821–827, 1990PubMedGoogle Scholar
  62. 62.
    Brichard SM, Debuquois B, Girard J: Vanadate treatment of diabetic rats reverses the impaired expression of genes involved in hepatic glucose metabolism: effects on glycolytic and gluconeogenic enzymes and on glucose transporter GLUT2. Mol Cell Endocrinol 91: 91–97, 1993PubMedGoogle Scholar
  63. 63.
    Thompson KH and McNeill JH: Effect of vanadyl sulfate feeding on susceptibility to peroxidative change in diabetic rats. Res Comm Chem Path Pharmacol 80: 187–200, 1993Google Scholar
  64. 64.
    Rossetti L, McLaughlin MR: Correction of chronic hyperglycemia by 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, 1989PubMedGoogle Scholar
  65. 65.
    Blondel O, Simon J, Chevalier B, Portha B: Impaired insulin action but normal insulin receptor activity in diabetic rat liver: Effect of vanadate. Am J Physiol 258: E459–E467, 1990PubMedGoogle Scholar
  66. 66.
    Brichard SM, Pottier AM, Henquin JC: Long term improvement of glucose homeostasis by vanadate in obese hyperinsulinemic fa/fa rats. Endocrinology 125: 2510–2516, 1989PubMedGoogle Scholar
  67. 67.
    Brichard SM, Bailey CJ, Henquin JC: Marked improvement of glucose homeostasis in diabetic ob/ob mice given oral vanadate. Diabetes 39: 1326–1332, 1990PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1998

Authors and Affiliations

  • Patrick Poucheret
    • 1
  • Subodh Verma
    • 1
  • Marc D. Grynpas
    • 2
  • John H. McNeill
    • 1
  1. 1.Faculty of Pharmaceutical SciencesThe University of British ColumbiaVancouver
  2. 2.Samuel Lunenfeld Research Institute, Mount Sinai HospitalTorontoCanada

Personalised recommendations