Advertisement

In vivo effects of vanadate on hepatic glycogen metabolizing and lipogenic enzymes in insulin-dependent and insulin-resistant diabetic animals

  • Ramji L. Khandelwal
  • Subbiah Pugazhenthi
Chapter
Part of the Developments in Molecular and Cellular Biochemistry book series (DMCB, volume 16)

Abstract

The insulin-mimetic action of vanadate is well established but the exact mechanism by which it exerts this effect is still not clearly understood. The role of insulin in the regulation of hepatic glycogen metabolizing and lipogenic enzymes is well known. In our study, we have, therefore, examined the effects of vanadate on these hepatic enzymes using four different models of diabetic and insulin-resistant animals. Vanadate normalized the blood glucose levels in all animal models. In streptozotocin-induced diabetic rats, the amount of liver glycogen and the activities of the active-form of glycogen synthase, both active and inactive-forms of Phosphorylase, and lipogenic enzymes like glucose 6-phosphate dehydrogenase and malic enzyme were decreased and vanadate treatment normalized all of these to near normal levels. The other three animal models (db/db mouse, sucrose-fed rats and fa/fa obese Zucker rats) were characterized by hyperinsulinemia, hypertriglyceridemia, increases in activities of lipogenic enzymes, and marginal changes in glycogen metabolizing enzymes. Vanadate treatment brought all of these values towards normal levels. It should be noted that vanadate shows differential effects in the modulation of lipogenic enzymes activities in type I and type II diabetic animals. It increases the activities of lipogenic enzymes in streptozotocin-induced diabetic animals and prevents the elevation of activities of these enzymes in hyperinsulinemic animals. The insulin-stimulated phosphorylation of insulin receptor β subunit and its tyrosine kinase activity was increased in streptozotocin-induced diabetic rats after treatment with vanadate. Our results support the view that insulin receptor is one of the sites involved in the insulin-mimetic actions of vanadate.

Key words

vanadate diabetes glycogen synthase Phosphorylase lipogenic enzymes liver 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Shechter Y: Insulin-mimetic effects of vanadate. Possible implications for future treatment of diabetes. Diabetes 39: 1–5, 1990PubMedCrossRefGoogle Scholar
  2. 2.
    Brichard SM, Lederer J, Henquin JC: The insulin-like properties of vanadium: A curiosity or a perspective for the treatment of diabetes? Diabete & Metabolisme 17: 435–440, 1991Google Scholar
  3. 3.
    Heyliger CE, Tahiliani AG, McNeill JH: Effect of vanadate on elevated blood glucose and depressed cardiac performance of diabetic rats. Science 227: 1474–1477, 1985PubMedCrossRefGoogle Scholar
  4. 4.
    Meyerovitch J, Farfel Z, Sack J, Shechter Y: Oral administration of vanadate normalizes blood glucose levels in streptozotocin-treated rats. J Biol Chem 262: 6658–6662, 1987PubMedGoogle Scholar
  5. 5.
    Gil J, Miralpeix M, Carreras J, Bartrons R: Insulin-like effects of vanadate on glucokinase activity and fructose 2,6-bisphosphate levels in the liver of diabetic rats. J Biol Chem 263: 1868–1871, 1988PubMedGoogle Scholar
  6. 6.
    Brichard SM, Okitolanda W, Henquin JC: Long term improvement of glucose homeostasis by vanadate treatment in diabetic rats. Endocrinology 123: 2048–2053, 1988PubMedCrossRefGoogle Scholar
  7. 7.
    Schulz LO: Suppression of the hepatic glucose 6-phosphate system in diabetic rats by vanadate. Ann Nutr Metab 32: 289–296, 1988PubMedCrossRefGoogle Scholar
  8. 8.
    Pugazhenthi S, Khandelwal RL: Insulinlike effects of vanadate on hepatic glycogen metabolism in nondiabetic and streptozotocin-induced diabetic rats. Diabetes 39: 821–827, 1990PubMedCrossRefGoogle Scholar
  9. 9.
    Pugazhenthi S, Khandelwal RL, Angel JF: Insulin-like effect of vanadate on malic enzyme and glucose 6-phosphate dehydrogenase activities in streptozotocin-induced diabetic rat liver. Biochim Biophys Acta 1083: 310–312, 1991PubMedGoogle Scholar
  10. 10.
    Bollen M, Miralpeix M, Ventura F, Toth B, Bartrons R, Stalmans W: Oral administration of vanadate to streptozotocin-diabetic rats restores the glucose-induced activation of liver glycogen synthase. Biochem J 267: 269–271, 1990PubMedGoogle Scholar
  11. 11.
    Miralpeix M, Carballo E, Bartrons R, Crepin K, Hue L, Rosseau GG: Oral administration of vanadate to diabetic rats restores liver 6-phosphofructo-2-kinase content and mRNA. Diabetologia 35: 243–248, 1992PubMedCrossRefGoogle Scholar
  12. 12.
    Rosseti L, Laughlin MR: Correction of chronic hyperglycemia with vanadate, but not with phlorizin, normalizes in vitro glycogen synthase activity in diabetic skeletal muscle. J Clin Invest 84: 892–899, 1989CrossRefGoogle Scholar
  13. 13.
    Strout HV, Vicario PP, Biswas C, Saperstein R, Brady EJ, Pilch PF, Berger J: Vanadate treatment of streptozotocin diabetic rats restores expression of the insulin-responsive glucose transporter in skeletal muscle. Endocrinology 126: 2728–2732, 1990PubMedCrossRefGoogle Scholar
  14. 14.
    Pugazhenthi, S, Angel JF, Khandelwal RL: Effects of high sucrose diet on the insulin-like effects of vanadate in diabetic rats. Mol Cell Biochem 122: 77–84, 1993PubMedCrossRefGoogle Scholar
  15. 15.
    Ramanadham S, Mongold JJ, Brownsey RW, Cros GH, McNeill JH: Oral Vanadyl sulfate in treatment of diabetes mellitus in rats. Am J Physiol 257: H904–H911, 1989PubMedGoogle Scholar
  16. 16.
    Cros G, Mongold JJ, Serrano JJ, Ramanadham S, McNeill JH: Effects of vanadyl derivatives on animal models of diabetes. Mol Cell Biochem 109: 163–166, 1992PubMedGoogle Scholar
  17. 17.
    Sakurai H, Tsuchiya K, Nukatsuda M, Sofue M, Kawada J: Insulinlike effects of vanadyl ion on streptozotocin-induced diabetic rats. J Endocrinol 126: 451–459, 1990PubMedCrossRefGoogle Scholar
  18. 18.
    Venkatesan N, Avidan A, Davidson MB: Antidiabetic action of vanadyl in rats independent of in vivo insulin-receptor kinase activity. Diabetes 40: 492–498, 1991PubMedCrossRefGoogle Scholar
  19. 19.
    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
  20. 20.
    Pugazhenthi 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, 1991PubMedCrossRefGoogle Scholar
  21. 21.
    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
  22. 22.
    Pugazhenthi S, Angel JF, Khandelwal RL: Effects of vanadate administration on the high sucrose diet-induced aberrations in normal rats. Mol Cell Biochem 122: 69–75, 1993PubMedCrossRefGoogle Scholar
  23. 23.
    Tolman EL, Barris E, Burns M, Pansini A, Partridge R: Effects of vanadium on glucose metabolism in vitro. Life Sci 25: 1159–1164, 1979PubMedCrossRefGoogle Scholar
  24. 24.
    Dubyak GR, Kleinzeller A: The insulin-mimetic effects of vanadate in isolated rat adipocytes. J Biol Chem 255: 5306–5312, 1980PubMedGoogle Scholar
  25. 25.
    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 synthesis in rat adipocytes. J Biol Chem 259: 6650–6658, 1984PubMedGoogle Scholar
  26. 26.
    Bernier M, Laird DM, Lane MD: Effect of vanadate on the cellular accumulation of pp 15, an apparent product of insulin receptor tyrosine kinase action. J Biol Chem 263: 13626–13634, 1988PubMedGoogle Scholar
  27. 27.
    Duckworth WC, Solomon SS, Liepnieks J, Hamel FG, Hand S and Peavy DE: Insulin-like effects of vanadate, in isolated rat adipocytes. Endocrinology 122: 2285–2289, 1988PubMedCrossRefGoogle Scholar
  28. 28.
    Fantus IG, Kadota SI, Deragon G, Foster B, Posner BI: Pervanadate (peroxides of vanadate) mimics insulin action in rat adipocytes via activation of the insulin receptor tyrosine kinase. Biochemistry 28: 8864–8871, 1989PubMedCrossRefGoogle Scholar
  29. 29.
    Mooney RA, Bordwell KL, Luhowskyi S, Casnellie JE: The insulinlike effect of vanadate on lipolysis. in rat adipocytes is not accompanied by an insulin-like effect on tyrosine phosphorylation. Endocrinology 124, 422–429, 1989PubMedCrossRefGoogle Scholar
  30. 30.
    Clausen T, Andersen TL, Sturup-Johansen M, Petkova O: The relationship between the transport of glucose and cations across cell membranes in isolated tissues. The effect of vanadate on 45Ca-efflux and sugar transport in adipose tissue and in skeletal muscle. Biochim Biophys Acta 646: 261–267, 1981PubMedCrossRefGoogle Scholar
  31. 31.
    Gomez-Foix AM, Rodriguez-Gil JE, Fillat C, Guinovart JJ, Bosch F: Vanadate raises fructose 2,6-bisphosphate concentrations and activates glycolysis in rat hepatocytes. Biochem J 255: 507–512, 1988PubMedGoogle Scholar
  32. 32.
    Rodriguez-Gil JE, Gomez-Foix AM, Fillat C, Bosch F, Guinovart JJ: Activation by vanadate of glycolysis in hepatocytes from diabetic rats. Diabetes 40: 1355–1359, 1991PubMedCrossRefGoogle Scholar
  33. 33.
    Miralpeix M, Decaux JF, Kahn A, Bartrons R: Vanadate induction of L-type pyruvate kinase mRNA in adult rat hepatocytes in primary culture. Diabetes 40: 462–464, 1991PubMedCrossRefGoogle Scholar
  34. 34.
    Hers HG: The control of glycogen metabolism in the liver. Ann Rev Biochem 45: 167–189, 1976PubMedCrossRefGoogle Scholar
  35. 35.
    Van de Werve G, Jeanrenaud B: Liver glycogen metabolism: An overview. Diabetes/Metabolism Reviews 3: 47–78, 1987PubMedCrossRefGoogle Scholar
  36. 36.
    Cohen P: The role of protein phosphorylation in the hormonal control of enzyme activity. Eur J Biochem 151: 439–448, 1985PubMedCrossRefGoogle Scholar
  37. 37.
    Roach P: Control of glycogen synthase by hierarchal protein phosphorylation. FASEB J 4: 2961–2968, 1990PubMedGoogle Scholar
  38. 38.
    Roesler WJ, Pugazhenthi S, Khandelwal RL: Hepatic glycogen metabolism in the db/db mouse. Mol Cell Biochem 92: 99–106, 1990PubMedCrossRefGoogle Scholar
  39. 39.
    Khandelwal RL, Zinman SM, Zebrowski EJ: The effect of streptozotocin-induced diabetes and of insulin supplementation on glycogen metabolism in rat liver. Biochem J 168: 541–548, 1977PubMedGoogle Scholar
  40. 40.
    Lavoie L, Bollen M, Stalmans W, Van de Werve G: Increased synthase phosphatase activity is responsible for the super-activation of glycogen synthase in hepatocytes from fasted obese Zucker rats. Endocrinology 129: 2674–2678, 1991PubMedCrossRefGoogle Scholar
  41. 41.
    Hems DA, Whitton PD: Control of hepatic glycogenolysis. Physiol Rev 60: 1–50, 1980PubMedGoogle Scholar
  42. 42.
    Roesler WJ, Khandelwal RL: Regulation of rat liver glycogen Phosphorylase concentration by in vivo relative levels of glucagon and insulin. Endocrinology 121, 227–232, 1987PubMedCrossRefGoogle Scholar
  43. 43.
    Roesler WJ, Nijjar MS, Khandelwal RL: The rate of degradation of liver glycogen Phosphorylase is specifically decreased in the C57BL/ KsJ-db/db mouse. Mol Cell biochem 87: 147–152, 1989PubMedCrossRefGoogle Scholar
  44. 44.
    Spence JT, Pitot HC: Induction of lipogenic enzymes in primary cultures of rat hepatocytes. Relationship between lipogenesis and carbohydrate metabolism. Eur J Biochem 128: 15–20, 1982PubMedCrossRefGoogle Scholar
  45. 45.
    Katsurada A, Iritani N, Fukuda H, Matsumura Y, Noguchi T, Tanaka T: Effects of insulin and fructose on transcriptional and post-transcriptional regulation of malic enzyme synthesis in diabetic rat liver. Biochim Biophys Acta 1004: 103–107, 1989PubMedGoogle Scholar
  46. 46.
    Katsurada A, Iritani N, Fukuda H, Matsumura Y, Noguchi T, Tanaka T: Effects of nutrients and insulin on transcriptional and post-transcriptional regulation of glucose-6-phosphate dehydrogenase synthesis in rat liver. Biochim Biophys Acta 1006: 104–111, 1989PubMedGoogle Scholar
  47. 47.
    Gherzi R, Caratti Ca, Andraghetti G, Bertolini S, Montemurro A, Sesti G, Cordera R: Direct modulation of insulin-receptor protein tyrosine kinase by vanadate and anti-insulin receptor monoclonal antibodies. Biochem Biophys Res Commun 152: 1474–1480, 1988PubMedCrossRefGoogle Scholar
  48. 48.
    Pugazhenthi S, Khandelwal RL: Does the insulin-mimetic action of vanadate involve insulin receptor kinase? Mol Cell Biochem 217/ 218: 211–218, 1993CrossRefGoogle Scholar
  49. 49.
    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
  50. 50.
    Hummel KP, Dickie MM, Coleman DL: Diabetes, a new mutation in the mouse. Science 153: 1127–1128, 1966PubMedCrossRefGoogle Scholar
  51. 51.
    Coleman, DL, Hummel KP: Studies with the mutation, diabetes, in the mouse. Diabetologia 3: 238–248, 1967PubMedCrossRefGoogle Scholar
  52. 52.
    Wyse BM, Dulin WE: The influence of age and dietary conditions on diabetes in the db/db mouse. Diabetologia 6: 268–273, 1970PubMedCrossRefGoogle Scholar
  53. 53.
    Roesler WJ, Khandelwal RL: Age-related changes in hepatic glycogen metabolism in the genetically diabetic (db/db) mouse. Diabetes 34: 395–402, 1985PubMedCrossRefGoogle Scholar
  54. 54.
    Bray GA: The Zucker-fatty rat: a review. Federation Proc. 36:148–153, 1977Google Scholar
  55. 55.
    Triscari J, Stern JS, Johnson PR, Sullivan AC: Carbohydrate metabolism in lean and obese Zucker rats. Metabolism 28: 183–189, 1979PubMedCrossRefGoogle Scholar
  56. 56.
    Martin RJ: In vivo lipogenesis and enzyme levels in adipose and liver tissues from pair-fed genetically obese and lean rats. Life Sci 14:1447–1453, 1974PubMedCrossRefGoogle Scholar
  57. 57.
    Ramanadham S, Brownsey RW, Cros GH, Mongold JJ, McNeill JH: Sustained prevention of myocardial abnormalities in diabetic rats following withdrawl from oral vanadyl treatment. Metabolism 38: 1022–1028, 1989PubMedCrossRefGoogle Scholar
  58. 58.
    Meyerovitch J, Shechter Y, Amir S: Vanadate stimulates in vivo glucose uptake in brain and arrests food intake and body weight gain in rats. Physiol Behav 45: 1113–1116, 1989PubMedCrossRefGoogle Scholar
  59. 59.
    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
  60. 60.
    Chan TM, Young KM, Hutson NJ, Brumley FT, Exton JH: Hepatic metabolism of genetically diabetic (db/db) mice. I. Carbohydrate metabolism. Am J Physiol 229: 1702–1712, 1975PubMedGoogle Scholar
  61. 61.
    Sterns SB, Benzo CA: Structural and chemical alterations associated with hepatic glycogen metabolism in genetically diabetic (db/db) and in streptozotocin-induced diabetic mice. Lab Invest 37: 180–187, 1977Google Scholar
  62. 62.
    Roesler WJ, Helgason C, Gulka M, Khandelwal RL: Aberrations in the diurnal rhythms of plasma glucose, plasma insulin, liver glycogen and hepatic glycogen synthase and Phosphorylase activities in genetically diabetic (db/db) mice. Horm Metab Res 17: 572–575, 1985PubMedCrossRefGoogle Scholar
  63. 63.
    Bosch F, Hatzoglou M, Park EA, Hanson RW: Vanadate inhibits expression of the gene for phosphoenolpyruvate carboxykinase (GTP) in rat hepatoma cells. J Biol Chem 265: 13677–13682, 1990PubMedGoogle Scholar
  64. 64.
    Swarup G, Cohen S, Garbers DL: Inhibition of membrane phosphotyrosyl protein phosphatase activity by vanadate. Biochem Biophys Res Commun 107: 1104–1109, 1982PubMedCrossRefGoogle Scholar
  65. 65.
    King MJ, Sale GJ: Dephosphorylation of insulin-receptor autophosphorylation sites by particulate and soluble phosphotyrosyl protein phosphatases. Biochem J 266: 251–259, 1990PubMedGoogle Scholar
  66. 66.
    Meyerovitch J, Backer JM, Kahn CR: Hepatic phosphotyrosine phosphatase activity and its alterations in diabetic rats. J Clin Invest 84: 976–983, 1989PubMedCrossRefGoogle Scholar
  67. 67.
    Begum N, Sussman KE, Draznin B: Differential effects of diabetes on adipocyte and liver phosphotyrosine and phosphoserine phosphatase activities. Diabetes 40: 1620–1629, 1991PubMedCrossRefGoogle Scholar
  68. 68.
    Donofrio F, Le MQU, Chiasson JL, Srivastava AK: Activation of mitogen activated protein (Map) kinases by vanadate is independent of insulin receptor autophosphorylation. FEBS Lett 340: 269–275, 1994CrossRefGoogle Scholar
  69. 69.
    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
  70. 70.
    Cordera R, Andraghetti G, DeFronzo RA, Rosseti L: Effect of in vivo vanadate treatment on insulin receptor tyrosine kinase activity in partially pancreatectamized diabetic rats. Endocrinology 126: 2177–2183, 1990PubMedCrossRefGoogle Scholar
  71. 71.
    Paternain JL, Domingo JL, Gomez M, Ortega A, Corbella J: Developmental toxicity of vanadium in mice after oral administration. J Appl Toxicol 10: 181–186, 1990PubMedCrossRefGoogle Scholar
  72. 72.
    Domingo JL, Gomez M, Llobet JM, Corbella J, Keen CL: Improvement of glucose homeostasis by oral vanadyl or vanadate treatment in diabetic rats is accompanied by negative side effects. Pharmacol and Toxicol 68: 249–253, 1991CrossRefGoogle Scholar
  73. 73.
    Rosseti L, Giaccari A, Klein-Robbenhaar E, Vogel LR: Insulino-mimetic properties of trace elements and characterization of their in vivo mode of action. Diabetes 39: 1243–1250, 1990CrossRefGoogle Scholar
  74. 74.
    Domingo JL, Gomez M, Sanchez DJ, Llobet JM, Keen CL: Tiron administration minimizes the toxicity of vanadate but not its insulinmimetic properties in diabetic rats. Life Sci 50: 1311–1317, 1992PubMedCrossRefGoogle Scholar
  75. 75.
    King MJ, Pugazhenthi S, Khandelwal RL, Sharma RK: Membrane-associated N-myristoyltransferase activity is reduced in obese (fa/fa) Zucker rat liver. Biochem Biophys Res Commun 196: 665–670, 1993PubMedCrossRefGoogle Scholar
  76. 76.
    Pugazhenthi S, HussainA, Yu B, Brownsey RW, Angel JF, Khandelwal RL: Vanadate induces normolipidemia and a reduction in levels of hepatic lipogenic enzymes in obese Zucker rat. Mol Cell Biochem 153: 125–129, 1995PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1995

Authors and Affiliations

  • Ramji L. Khandelwal
    • 1
  • Subbiah Pugazhenthi
    • 1
  1. 1.Department of Biochemistry, College of MedicineUniversity of SaskatchewanSaskatoonCanada

Personalised recommendations