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Effects of diabetes, vanadium, and insulin on glycogen synthase activation in Wistar rats

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Abstract

In vivo effects of insulin and vanadium treatment on glycogen synthase (GS), glycogen synthase kinase-3 (GSK-3) and protein phosphatase-1 (PP1) activity were determined in Wistar rats with streptozotocin (STZ)-induced diabetes. The skeletal muscle was freeze-clamped before or following an insulin injection (5 U/kg i.v.). Diabetes, vanadium, and insulin in vivo treatment did not affect muscle GSK-3β activity as compared to controls. Following insulin stimulation in 4-week STZ-diabetic rats muscle GS fractional activity (GSFA) was increased 3 fold (p < 0.05), while in 7-week diabetic rats it remained unchanged, suggesting development of insulin resistance in longer term diabetes. Muscle PP1 activity was increased in diabetic rats and returned to normal after vanadium treatment, while muscle GSFA remained unchanged. Therefore, it is possible that PP1 is involved in the regulation of some other cellular events of vanadium (other than regulation of glycogen synthesis). The lack of effect of vanadium treatment in stimulating glycogen synthesis in skeletal muscle suggests the involvement of other metabolic pathways in the observed glucoregulatory effect of vanadium.

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References

  1. Garvey WT: Glucose transport and NIDDM. Diab Care 15: 396–417, 1992

    Google Scholar 

  2. Bak JF, Jacobsen UK, Jorgensen FS, Pedersen O: Insulin receptor function and glycogen synthase activity in skeletal muscle biopsies from patients with insulin-dependent diabetes mellitus: Effects of physical training. J Clin Endocrinol Metab 69: 158–164, 1989

    Google Scholar 

  3. Vestergaard H, Andersen PH, Lund S, Vedel P, Pedersen O: Expression of glycogen synthase and phosphofructokinase in muscle from Type 1 (insulin-dependent) diabetic patients before and after intensive insulin treatment. Diabetologia 37: 82–90, 1994

    Google Scholar 

  4. Parker PJ, Caudwell FB, Cohen P: Glycogen synthase from rabbit skeletal muscle; effect of insulin on the state of phosphorylation of the seven phosphoserine residues in vivo. Eur J Biochem 130: 227–234, 1983

    Google Scholar 

  5. Skurat AV, Roach PJ: Phosphorylation of sites 3a and 3b (Ser640 and Ser644) in the control of rabbit muscle glycogen synthase. J Biol Chem 270: 12491–12497, 1995

    Google Scholar 

  6. Embi N, Rylatt DB, Cohen P: Glycogen synthase kinase-3 from rabbit skeletal muscle. iSeparation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur J Biochem 107: 519–527, 1980

    Google Scholar 

  7. Woodgett JR: Molecular cloning and expression of glycogen synthase kinase-3/factor A. Embo J 9: 2431–2438, 1990

    Google Scholar 

  8. Borthwick AC, Wells AM, Rochford JJ, Hurel SJ, Turnbull DM, Yeaman SJ: Inhibition of glycogen synthase kinase-3 by insulin in cultured human skeletal muscle myoblasts. Biochem Biophys Res Commun 210: 738–745, 1995

    Google Scholar 

  9. Welsh GI, Proud CG: Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B. Biochem J 294: 625–629, 1993

    Google Scholar 

  10. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA: Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378: 785–789, 1995

    Google Scholar 

  11. Murai H, Okazaki M, Kikuchi A: Tyrosine dephosphorylation of glycogen synthase kinase-3 is involved in its extracellular signal-dependent inactivation. FEBS Lett 392: 153–160, 1996

    Google Scholar 

  12. Cross DA, Watt PW, Shaw M, van der Kaay J, Downes CP, Holder JC, Cohen P: Insulin activates protein kinase B, inhibits glycogen synthase kinase-3 and activates glycogen synthase by rapamycin-insensitive pathways in skeletal muscle and adipose tissue. FEBS Lett 406: 211–215, 1997

    Google Scholar 

  13. Lawrence JC Jr, Skurat AV, Roach PJ, Azpiazu I, Manchester J: Glycogen synthase: Activation by insulin and effect of transgenic overexpression in skeletal muscle. Biochem Soc Trans 25: 14–19, 1997

    Google Scholar 

  14. Dent P, Lavoinne A, Nakielny S, Caudwell FB, Watt P, Cohen P: The molecular mechanism by which insulin stimulates glycogen synthesis in mammalian skeletal muscle. Nature 348: 302–308, 1990

    Google Scholar 

  15. Ragolia L, Begum N: Protein phosphatase-1 and insulin action. Mol Cell Biochem 182: 49–58, 1998

    Google Scholar 

  16. Heyliger CE, Tahiliani AG, McNeill JH: Effect of vanadate on elevated blood glucose and depressed cardiac performance of diabetic rats. Science 227: 1474–1477, 1985

    Google Scholar 

  17. 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, 1987

    Google Scholar 

  18. Meyerovitch J, Rothenberg P, Shechter Y, Bonner-Weir S, Kahn CR: Vanadate normalizes hyperglycemia in two mouse models of noninsulin-dependent diabetes mellitus. J Clin Invest 87: 1286–1294, 1991

    Google Scholar 

  19. Yuen VG, Vera E, Battell ML, Li WM, McNeill JH: Acute and chronic oral administration of bis(maltolato)oxovanadium(IV) in Zucker diabetic fatty (ZDF) rats. Diabetes Res Clin Pract 43: 9–19, 1999

    Google Scholar 

  20. Goldfine AB, Simonson DC, Folli F, Patti ME, Kahn 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, 1995

    Google Scholar 

  21. Rossetti L, Lauglin 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, 1989

    Google Scholar 

  22. 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, 1995

    Google Scholar 

  23. Hei YJ, McNeill JH, Sanghera JS, Diamond J, Bryer-Ash M, Pelech SL: Characterization of insulin-stimulated seryl/threonyl protein kinases in rat skeletal muscle. J Biol Chem 268: 13203–13213, 1993

    Google Scholar 

  24. Van Lint J, Khandelwal RL, Merlevede W, Vandenheede JR: A specific immunoprecipitation assay for the protein kinase FA/glycogen synthase kinase 3. Anal Biochem 208: 132–137, 1993

    Google Scholar 

  25. Bhanot S, Salh BS, Verma S, McNeill JH, Pelech SL: In vivo regulation of protein-serine kinases by insulin in skeletal muscle of fructosehypertensive rats. Am J Physiol 277: E299–E307, 1999

    Google Scholar 

  26. Laemmli UK: Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227: 680–685, 1970

    Google Scholar 

  27. Gregory JS, Boulton TG, Sang BC, Cobb MH: An insulin-stimulated ribosomal protein S6 kinase from rabbit liver. J Biol Chem 264: 18397–18401, 1989

    Google Scholar 

  28. Pelech SL, Krebs EG: Mitogen-activated S6 kinase is stimulated via protein kinase C-dependent and independent pathways in Swiss 3T3 cells. J Biol Chem 262: 11598–11606, 1987

    Google Scholar 

  29. Ortmeyer HK, Bodkin NL, Hansen BC: Insulin-mediated glycogen synthase activity in muscle of spontaneously insulin-resistant and diabetic rhesus monkeys. Am J Physiol 265: R552–R558, 1993

    Google Scholar 

  30. Foulkes JG, Jefferson LS: Protein phosphatase-1 and-2A activities in heart, liver, and skeletal muscle extracts from control and diabetic rats. Diabetes 33: 576–579, 1984

    Google Scholar 

  31. Cohen P, Klumpp S, Schelling DL: An improved procedure for identifying and quantitating protein phosphatases in mammalian tissues. FEBS Lett 250: 596–600, 1989

    Google Scholar 

  32. Sutherland C, Cohen P: The alpha-isoform of glycogen synthase kinase-3 from rabbit skeletal muscle is inactivated by p70 S6 kinase or MAP kinase-activated protein kinase-1 in vitro. FEBS Lett 338: 37–42, 1994

    Google Scholar 

  33. Villar-Palasi C, Larner J: Insulin-mediated effect on the activity of UDPG-glycogen transglucosylase of muscle. Biochim Biophys Acta 39: 171–173, 1960

    Google Scholar 

  34. 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, 1993

    Google Scholar 

  35. Cam MC, Rodrigues B, McNeill JH: Distinct glucose lowering and beta cell protective effects of vanadium and food restriction in streptozotocindiabetes. Eur J Endocrinol 141: 546–554, 1999

    Google Scholar 

  36. Yki-Jarvinen H, Koivisto VA: Natural course of insulin resistance in Type I diabetes. N Engl J Med 315: 224–230, 1986

    Google Scholar 

  37. Vestergaard H, Lund S, Larsen FS, Bjerrum OJ, Pedersen O: Glycogen synthase and phosphofructokinase protein and mRNA levels in skeletal muscle from insulin-resistant patients with non-insulin-dependent diabetes mellitus. J Clin Invest 91: 2342–2350, 1993

    Google Scholar 

  38. Kim YB, Nikoulina SE, Ciaraldi TP, Henry RR, Kahn BB: Normal insulin-dependent activation of Akt/protein kinase B, with diminished activation of phosphoinositide 3-kinase, in muscle in Type 2 diabetes. J Clin Invest 104: 733–741, 1999

    Google Scholar 

  39. Beck-Nielsen H: General characteristics of the insulin resistance syndrome: Prevalence and heritability. European Group for the study of Insulin Resistance (EGIR). Drugs 58: 7–10; discussion 75-82, 1999

    Google Scholar 

  40. Petersen KF, Hendler R, Price T, Perseghin G, Rothman DL, Held N, Amatruda JM, Shulman GI: 13C/31P NMR studies on the mechanism of insulin resistance in obesity. Diabetes 47: 381–386, 1998

    Google Scholar 

  41. Goldfine AB, Patti ME, Zuberi L, Goldstein BJ, LeBlanc R, Landaker EJ, Jiang ZY, Willsky GR, Kahn CR: Metabolic effects of vanadyl sulfate in humans with non-insulin-dependent diabetes mellitus: In vivo and in vitro studies. Metabolism 49: 400–410, 2000

    Google Scholar 

  42. Nikoulina SE, Ciaraldi TP, Mudaliar S, Mohideen P, Carter L, Henry RR: Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of Type 2 diabetes. Diabetes 49: 263–271, 2000

    Google Scholar 

  43. Nakielny S, Campbell DG, Cohen P: The molecular mechanism by which adrenalin inhibits glycogen synthesis. Eur J Biochem 199: 713–722, 1991

    Google Scholar 

  44. Picton C, Woodgett J, Hemmings B, Cohen P: Multisite phosphorylation of glycogen synthase from rabbit skeletal muscle. Phosphorylation of site 5 by glycogen synthase kinase-5 (casein kinase-II) is a prerequisite for phosphorylation of sites 3 by glycogen synthase kinase-3. FEBS Lett 150: 191–196, 1982

    Google Scholar 

  45. Harwood AJ: Signal transduction: Life, the universe and... development. Curr Biol 10: R116–R119, 2000

    Google Scholar 

  46. Eldar-Finkelman H, Schreyer SA, Shinohara MM, LeBoeuf RC, Krebs EG: Increased glycogen synthase kinase-3 activity in diabetes-and obesity-prone C57BL/6J mice. Diabetes 48: 1662–1666, 1999

    Google Scholar 

  47. Semiz S, McNeill, J. H.: Oral treatment with vanadium of Zucker fatty rats activates muscle glycogen synthesis and insulin-stimulated protein phosphatase-1 activity. Mol Cell Biochem 2002 (submitted)

  48. Marzban L, Bhanot S, McNeill JH: In vivo effects of insulin and bis(maltolato)oxovanadium(IV) on PKB activity in the skeletal muscle and liver of diabetic rats. Mol Cell Biochem, 2001 (in press)

  49. Lawrence JC Jr, Larner J: Activation of glycogen synthase in rat adipocytes by insulin and glucose involves increased glucose transport and phosphorylation. J Biol Chem 253: 2104–2113, 1978

    Google Scholar 

  50. Sun Q, Sekar N, Goldwaser I, Gershonov E, Fridkin M, Shechter Y: Vanadate restores glucose 6-phosphate in diabetic rats: A mechanism to enhance glucose metabolism. Am J Physiol Endocrinol Metab 279: E403–E410, 2000

    Google Scholar 

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Semiz, S., Orvig, C. & McNeill, J.H. Effects of diabetes, vanadium, and insulin on glycogen synthase activation in Wistar rats. Mol Cell Biochem 231, 23–35 (2002). https://doi.org/10.1023/A:1014437019586

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