The relationship between insulin and vanadium metabolism in insulin target tissues

  • Frederick G. Hamel
  • William C. Duckworth
Part of the Developments in Molecular and Cellular Biochemistry book series (DMCB, volume 16)


Vanadium (V) is an orally effective treatment for diabetes, but relatively little is known about the mechanisms controlling its normal metabolism nor the long term pharmacokinetics of oral administration. We have examined the accumulation of V in various organs from rats fed liquid diet for up to 18 days, containing no additional V, 1.6, 80, or 160 µmole/kg/day as either sodium orthovanadate (SOV) or vanadyl sulfate (VS). V content was assayed using a sensitive neutron activation analysis method. The organs of the nonsupplemented animals contained widely varying concentrations (ng of V/g dry tissue weight) with brain < fat < blood < heart < muscle < lung < liver < testes < spleen < kidney. All organs accumulated V in a dose dependent manner. Not all organs showed steady state amount of V at 18 days, so additional rats were fed SOV or VS, switched to control diet, and assayed at 0,4 and 8 days. From this data we calculated organ half lives of V Insulin sensitive tissue tissues, such as liver and fat, had shorter half-lives than tissues that are relatively less insulin sensitive, such as spleen, brain and testes. SOV and VS fed rats showed similar patterns, but VS had somewhat shorter t1/2’s. Additional studies of old and young rats fed control diet for 45 days show accumulation of V in spleen and testes. These results indicate that vanadium metabolism varies widely among different organs, and that insulin, either directly or indirectly has effects on the retention of vanadium. This may have impact on the therapeutic use of vanadium in Type I diabetics with no insulin, or Type II patients who may be relatively hyperinsulinemic.

Key words

vanadium insulin radiochemical neutron activation analysis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Nielsen F, Uthus E: The essentiality and metabolism of vanadium. In: N.D. Chasteen (ed.). Vanadium in Biological Systems. Kluwer Academic Publishers, Dordrecht, p. 51–62, 1990Google Scholar
  2. 2.
    Nielsen F: Nutritional requirements for boron, silicon, vanadium, nickel and arsenic: Current knowledge and speculation. Biological and Trace Element Research. 26(27): 599–611, 1990CrossRefGoogle Scholar
  3. 3.
    Nielsen F: Nutritional requirements for boron, silicon, vanadium, nickel, and arsenic: Current knowledge and speculation. FASEB. 5(12): 2661–2667, 1991Google Scholar
  4. 4.
    Neve J: Clinical implications of trace elements in endocrinology. Biological and Trace Element Research 32: 173–185, 1992CrossRefGoogle Scholar
  5. 5.
    McKeehan W, McKeehan K, Hammond S, Ham R: Improved medium for clonal growth of human diploid fibroblasts at low concentrations of serum protein. In Vitro. 3: 399–416, 1977CrossRefGoogle Scholar
  6. 6.
    Carpenter G, Vanadate EGF: The stimulation of DNA synthesis. Biochem Biophys Res Communications. 102: 1115–1121, 1981CrossRefGoogle Scholar
  7. 7.
    Mountjoy K, Flier J: Vanadate regulates glucose transporter (Glut-1) expression in NIH3T3 mouse fibroblasts. Endocrinology 127(4): 2025–2034, 1990PubMedCrossRefGoogle Scholar
  8. 8.
    Smith J: Vanadium ions stimulate DNA synthesis in Swiss mouse 3T3 and 3T6 cells. PNAS 80: 6162–6166, 1983PubMedCrossRefGoogle Scholar
  9. 9.
    Canalis E: The effect of sodium vanadate on deoxyribonucleic acid and protein synthesis in cultured rat calvaraie. Endocrinology 116: 855–862, 1985PubMedCrossRefGoogle Scholar
  10. 10.
    Kato Y, Iwamoto M, Koike T, Suzuki F: Effect of vanadateoncartilage-matrix proteoglycan synthesis in rabbit costal chondrocyte cultures. Journal of Cell Biology. 104: 311–319, 1987PubMedCrossRefGoogle Scholar
  11. 11.
    Lau K, Tanimoto H, Baylink D: Vanadate stimulates bone cell proliferation and bone collagen synthesis in vitro. Endocrinology 123: 2858–2867, 1988PubMedCrossRefGoogle Scholar
  12. 12.
    Nechay B, Norcross-Nechay K, Nechay P, Jena D: Presented at the Spurenelement Symposium, 1989Google Scholar
  13. 13.
    Shechter Y: Insulin-mimetic effects of vanadate. Possible implications for future treatmentof diabetes. Diabetes.39(1): 1–5, 1990PubMedCrossRefGoogle Scholar
  14. 14.
    Robertson R, Klein O: Treatment of diabetes mellitus. Diabetologia 35(Sup. 2): S8–S17, 1992PubMedCrossRefGoogle Scholar
  15. 15.
    Brichard S, Lederer J, Henquin J: The insulin-like properties of vanadium: A Curiosity or a perspective for the treatment of diabetes? Diabetes Metabolism. 17(5): 435–440, 1991Google Scholar
  16. 16.
    Vialettes B, Silvestre P: Pharmacological approach in the treatment of insulin resistance. Horm Res 38(1–2): 51–56, 1992PubMedCrossRefGoogle Scholar
  17. 17.
    Shechter Y, Shisheva A: Vanadium salts and the future treatment of diabetes. Endeavour 17(1): 27–31, 1993PubMedCrossRefGoogle Scholar
  18. 18.
    Heyliger C, Tahiliani A, McNeill J: Effect of vanadate on elevated blood glucose and depressed cardiac performance of diabetic rats. Science 227: 1474–1477, 1985PubMedCrossRefGoogle Scholar
  19. 19.
    Meyerovitch J, Farfel Z, Sack J, Schechter Y: Oral administration of vanadate normalizes blood glucose levels in streptozotocin-treated rats: Characteristics and mode of action. Journal of Biological Chemistry 262: 6658–6662, 1987PubMedGoogle Scholar
  20. 20.
    Blondel O, Bailbe D, Portha B: In vivo insulin resistance in streptozotocin-diabetic rats: Evidence for reversal following oral vanadate treatment. Diabetologia. 32(3): 185–190, 1989PubMedCrossRefGoogle Scholar
  21. 21.
    Brichard, S., Okitolonda, W., and Henquin, J. Long term improvement of glucose homeostasis by vanadate treatment in diabetic rats. Endocrinology. 123(4): 2048–2053, 1988.PubMedCrossRefGoogle Scholar
  22. 22.
    Ramanadham S, Mongole J, Brownsey R, Cros G, MeNeill J: Oral vanadyl sulfate in the treatment of diabetes mellitus in rats. Am J Physiol 257(3):H904–911, 1989PubMedGoogle Scholar
  23. 23.
    Pederson, R., Ramanadham, S., Buchan, A., and McNeill, J. Long-term effects of vanadyl treatment on streptozotocin-induced diabetes in rats. Diabetes. 38(11):1390–1395, 1989PubMedCrossRefGoogle Scholar
  24. 24.
    Ramanadham S, Brownsey R, Cros G, Mongold J, McNeill J: Sustained prevention of myocardial and metabolic abnormalities in diabetic rats following withdrawal from oral vanadyl treatment. Metabolism. 38(10): 1022–1028, 1989PubMedCrossRefGoogle Scholar
  25. 25.
    Sakurai H, Tsuchiya K, Nukatsuke M, Sofue M, Kawada J: Insulin-like effect of vanadyl ion on streptozotocin-induced diabetic rats. J. Endocrinol. 126(3): 451–459, 1990PubMedCrossRefGoogle Scholar
  26. 26.
    Ramanadham S, Cros G, Mongold J, Serrano J, McNeill J: Enhanced in vivo sensitivity of vanadyl-treated diabetic rats to insulin. Can J Physiol-Pharmacol 68(4): 486–491, 1990PubMedCrossRefGoogle Scholar
  27. 27.
    Venkatesan N, Avidan A, Davidson M: Antidiabetic action of vanadyl in rats independent of in vivo insulin-receptor kinase activity. Diabetes 40(4): 492–498, 1991PubMedCrossRefGoogle Scholar
  28. 28.
    Ozansoy G, Karasu C, Ozcelikay A: The effect of oral vanadyl treatment on the reactivity of tracheal smooth muscle obtained from insulin dependent diabetic rats. Gen Pharmacol 24(1): 115–119, 1993PubMedCrossRefGoogle Scholar
  29. 29.
    Domingo J, Gomez M, Llobet J, Corbella J, Keen C: Oral vanadium administration to streptozotocin-diabetic rats has marked negative side-effects which are independent of the form of vanadium used. Toxicology 66(3): 279–287, 1991PubMedCrossRefGoogle Scholar
  30. 30.
    Domingo J, Gomez M, Llobet J, Corbella J, Keen C: Improvement of glucose homeostasis by oral vanadyl or vanadate treatment in diabetic rats is accompanied by negative side effects. Pharmacology-Toxicology 68(4): 249–253, 1991PubMedCrossRefGoogle Scholar
  31. 31.
    Sanchez D, Ortega A, Domingo J, Corbella J: Developmental toxicity evaluation of orthovanadate in the mouse. Biological and Trace Element Research.30: 219–226, 1991CrossRefGoogle Scholar
  32. 32.
    Llobet J, Colomina M, Sirvent J, Domingo J, Corbella J: Reproductivetoxicity evaluation of vanadium in mab mice. Toxicology 80: 199–206, 1993PubMedCrossRefGoogle Scholar
  33. 33.
    Leonard A, Gerber G: Mutagenicity, carcinogenicity and teratogenicity of vanadium compounds. Mutation Research 317(1): 81–88, 1994PubMedGoogle Scholar
  34. 34.
    Cohen, M., Wei, C., Tom, H., and Kao, K. Effect of ammonium meta vanadate on the murine immune response. J Tox Envir Health 19: 279–288, 1986CrossRefGoogle Scholar
  35. 35.
    Cohen M, Chen C, Wei C: Decreased resistance to Listeria monocytogenes in mice following vanadate exposure and effects upon the function of macrophages. Int J Immunopharmac 11:185–292, 1989CrossRefGoogle Scholar
  36. 36.
    Wang E, Choppin P: Effect of vanadate on intracellular distribution and function of 10 nm filaments. Proc Natl Acad Sciences USA 78: 2363–2367, 1981CrossRefGoogle Scholar
  37. 37.
    Cohen M, Wei C: Effects of ammonium metavanadate treatment upon macrophage glutations redox cycle activity, superoxide production, and intracellular glutation status. J Leukocyte Biol 44: 122–129, 1988PubMedGoogle Scholar
  38. 38.
    Cohen M, Parsons E, Schlesinger R, Zelikoff J: Immunotoxicity of in vitro vanadium exposures: Effects on interleukin-1, tumor necrosis factor-α and prostaglandin E2 production by WEHI-3 macrophages. Int J Immunopharmac 15(3): 437–446, 1993CrossRefGoogle Scholar
  39. 39.
    Blotcky AJ, Duckworth WC, Ebrahim A, Hamel FG, Rack EP, Sharma RB: Determination of vanadium in serum by pre-irradiation and post-irradiation chemistryand neutron activation analysis. Journal of Radioanalytical and Nuclear Chemistry. 134(1): 151–160, 1989CrossRefGoogle Scholar
  40. 40.
    Peavy DE, Edmondson JW, Duckworth WC: Selective effects of inhibitors of hormone processing on insulin action in isolated hepatocytes. Endocrinology 114: 753–760, 1984PubMedCrossRefGoogle Scholar
  41. 41.
    World Health Organization. International Programme on Chemical Safety, Environmental Health Criteria 81 Vanadium 1988Google Scholar
  42. 42.
    Hamel F, Solomon S, Jespersen A, Blotcky A, Rack E, Duckworth W: Alteration of tissue vanadium content in diabetes. Metabolism 42(12): 1503–1505, 1993PubMedCrossRefGoogle Scholar
  43. 43.
    Shisheva A, Ikonomow O, Schechter Y: The Protein tyrosine phosphatase inhibitor, pervanadate, is a powerful antidiabetic agent in streptozotocin-treated diabetic rats. Endocrinology 134(1): 507–10, 1994PubMedCrossRefGoogle Scholar
  44. 44.
    Posner BI, Faure R, Burgess JW, Bevan AP, Lachance D, Zhang-Sun G, Fantus IG, Ng, JB, Hall DA, Lum BS: Peroxovanadium compounds. A new class of potent phosphotyrosine phosphatase inhibitors which are insulin mimetics. J Biol Chem 269(6): 4596–4604, 1994PubMedGoogle Scholar
  45. 45.
    Yuen VG, Orvig C, Thompson KH, McNeill JH: Improvement in cardiac dysfunction in streptozotocin-induced diabetic rats following chronic oral administraiton of bis (maltolato) oxovanadium (IV). Can J Physiol Pharmacol 71(3–4): 270–276, 1993PubMedCrossRefGoogle Scholar
  46. 46.
    Yuen V, Orvig C, McNeill J: Glucose-lowering effects of a new organic vanadium complex, bis(maltolato) oxovanadium (IV). Can J Physiol Pharmacol 71(3–4): 263–269, 1993PubMedCrossRefGoogle Scholar
  47. 47.
    Cam M, Cros G, Serrano J, Lazaro R, McNeill J: In vivo antidiabetic actions of naglivan, an organic vanadyl compound in streptozotocin-induced diabetes. Diabetes Res Clin Pract 20(2): 111–121, 1993PubMedCrossRefGoogle Scholar
  48. 48.
    D’Onofrio F, Le MQ, Chiasson JL, Srivastava AK: Activation of mitogen activated protein (MAP) kinases by vanadate is independent of insulin receptor autophosphorylation. FEBS Letters 340(3): 269–75, 1994PubMedCrossRefGoogle Scholar
  49. 49.
    Shisheva A, Shechter Y: Mechanism of Pervanadate stimulation and potentiation of insulin-activated glucose transport in rat adipocytes: Dissociation from vanadate effect. Endocrinology 133(4): 1334–1562, 1993CrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1995

Authors and Affiliations

  • Frederick G. Hamel
    • 1
  • William C. Duckworth
    • 1
  1. 1.Veterans Administration Medical CenterOmahaUSA

Personalised recommendations