Clinical Autonomic Research

, Volume 21, Issue 1, pp 19–28

Oxidative stress and autonomic nerve function in early type 1 diabetes

  • Robert Daniel Hoeldtke
  • Kimberly D. Bryner
  • Knox VanDyke
Review Article

Abstract

Introduction

The biochemical mechanisms by which hyperglycemia causes microvascular disease and neuropathy are poorly understood. Experimental studies have established that oxidative stress is present in diabetic rodents with neuropathy, and that antioxidant therapy is protective. Oxidative stress is also present in human diabetes, but its clinical importance is uncertain.

Material and methods

We examined several biochemical measures of oxidative stress in 37 patients with recent-onset (less than 2 years) type 1 diabetes annually in a 3-year longitudinal study. We also performed a comprehensive annual evaluation of somatosensory and autonomic nerve function. A total of 41 control subjects were studied.

Results

Malondialdehyde excretion, a measure of lipid peroxidation, was 1.5l ± .1 μmol/g creatinine in the control subjects, but 2.43 ± . 3 in the diabetic patients in year one, 2.39 ± .2 in year two and 1.92 ± .15 in year three, which was different from controls across all years; p < .005. Serum NOx (nitrate and nitric) was 34.0 ± 4.9 μmol/L in the controls, but 52.4 ± 5 in the diabetics in year one, 50.0 ± 5.1 in year two, and 49.0 ± 5.2 in year three, which was different from controls; p < .01. We measured sudomotor function and observed that the poorly controlled diabetic patients had relatively increased sweating above the waist and relatively decreased sweating below the waist, a typical pattern for sympathetic nerve injury. The ratio of sweating above to sweating below the waist was .385 ± .04 in controls, 0.70 ± .14 in diabetic patients in year one, .51 ± .14 in year two and .496 ± .12 in year three (different from controls; p < .01 across all years). Urinary MDA correlated negatively with total sweat (r = −39, p < .01); NOx also correlated negatively with total sweat (r = −.34, p < .025). Abnormalities in the processing of renin (the renin/prorenin ratio), a test of renal sympathetic neurons, was also documented in early type 1 diabetes.

Conclusions

Oxidative stress and excessive serum NOx are associated with sympathetic dysfunction in early type 1 diabetes.

Keywords

Oxidative Stress Diabetic Autonomic Dysfunction 

References

  1. 1.
    Adaikalakoteswari A, Rema M, Mohan V, Balasubramanyam M (2007) Oxidative DNA damage and augmentation of poly (ADP-ribose) polymerase/nuclear factor-kappa b signaling in patients with type 2 diabetes and microangiopathy. Int J Biochem and Cell Biol 39:1673–1684CrossRefGoogle Scholar
  2. 2.
    Ames BN, Cathcart R, Schwiers E, Hochstein P (1981) Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: A hypothesis. Proc Natl Acad Sci USA 78:6858–6862CrossRefPubMedGoogle Scholar
  3. 3.
    Bennett T, Hosking DJ, Hampton JR (1975) Cardiovascular control in diabetes mellitus. Br J Med 2:585–587CrossRefGoogle Scholar
  4. 4.
    Chiarelli F, Cipollone F, Romano F, Tumini S, Costantini F, DiRicco L, Pomilio M, Pierdomenico SD, Marini M, Cuccurullo F, Mezzeti A (2002) Increased circulating nitric oxide in young patients with type I diabetes and persistent microalbuminuria. Diabetes 49:1258–1263CrossRefGoogle Scholar
  5. 5.
    Coppey LJ, Gellet JS, Davidson EP, Dunlap JA, Lund DD, Yorek MA (2001) Effect of anti oxidant treatment on streptozotocin-induced diabetic rats on endoneurial blood flow, nerve conduction velocity, and vascular reactivity of epineural arterioles of the sciatic nerve. Diabetes 50:1927–1937CrossRefPubMedGoogle Scholar
  6. 6.
    Davi G, Ciabattoni G, Consoli A, Mezzetti A, Falco A, Santarone S, Pennese E, Vitacolonna E, Bucciarelli T, Costantini F, Capani F, Patrono C (1999) In vivo formation of 8-iso-prostaglandin F2 and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. Circulation 99:224–229PubMedGoogle Scholar
  7. 7.
    DeRosa MA, Cryer PE (2004) Hypoglycemia and the sympathoadrenal system: neurogenic symptoms are largely the result of sympathetic neural rather than adrenomedulary activation. Am J Phys Endocr Metab 287:E32–E41CrossRefGoogle Scholar
  8. 8.
    Dhiman M, Estrada-Franco JG, Pando JM, Ramirez-Aguilar FJ, Spratt H, Vazquez-Corzo S, Perez-Molina G, Gallegos-Sandova R, Moreno R, Garg NJ (2009) Increased myeloperoxidase activity and proteín nitration are indicators of inflammation in patients with Chagas’ disease. Clin Vaccine Immunol 16:660–666CrossRefPubMedGoogle Scholar
  9. 9.
    Drel VR, Lupachyk S, Shevalye H, Vareniuk I, Xu W, Zhang J, Delamere NA, Shahidullah M, Slusher B, Obrosova IG (2010) New therapeutic and biomarker discovery for peripheral diabetic neuropathy: PARP inhibitor, nitrotyrosine, and tumor necrosis factor-alpha. Endocrinology 151:1–9CrossRefGoogle Scholar
  10. 10.
    Feldman E (2003) Oxidative stress and diabetic neuropathy: a new understanding of an old problem. J Clin Invest 111:431–433PubMedGoogle Scholar
  11. 11.
    Giustarini D, Dalle-Donne I, Tsikas D, Rossi R (2009) Oxidative stress and human diseases: origin, link, measurement, mechanisms, and biomarkers. Crit Rev Clin Lab Sci 46:241–281CrossRefPubMedGoogle Scholar
  12. 12.
    Goss DE, Trafford JC, Roberts VC, Flynn MD, Edmonds ME, Watkins PJ (1989) Raised ankle/brachial pressure index in insulin-treated diabetic patients. Diabetes Med 6:576–578CrossRefGoogle Scholar
  13. 13.
    Grandenetti A, Chow DC, Sletten DM, Oyama JK, Theriault AG, Schatz IJ, Low PA (2007) Impaired glucose tolerance is associated with postganglionic sudomotor impairment. Clin Auton Res 17:231–233CrossRefGoogle Scholar
  14. 14.
    Hensley K, Maidt ML, Yu Z, San H, Merkeshery WR, Floyd RA (1998) Electrochemical analysis of protein nitrotyrosine and dityrosine in the Alzheimer’s brain indicates region specific accumulation. J Neurosci 18:8126–8132PubMedGoogle Scholar
  15. 15.
    Hoeldtke RD (2006) Oxidative stress in type I diabetes: a clinical perspective. In: Opara E (ed) Nutrition and diabetes: pathophysiology and treatment. Taylor and Francis, Boca Raton, pp 319–344Google Scholar
  16. 16.
    Hoeldtke RD, Bryner KD, Corum LL, Hobbs GR, VanDyke K (2009) Lipid peroxidation in early type I diabetes mellitus is unassociated with oxidative damage to DNA. Metab Clin Exp 58:731–734PubMedGoogle Scholar
  17. 17.
    Hoeldtke RD, Bryner KD, Hoeldtke ME, Christie I, Ganzer G, Hobbs G, Riggs J (2006) Sympathetic sudomotor disturbance in early type I diabetes mellitus is linked to lipid peroxidation. Metabolism Clin Exp 55:1524–1531Google Scholar
  18. 18.
    Hoeldtke RD, Bryner KD, Horvath GG, Phares RW, Broy LF, Hobbs GR (2001) Redistribution of sudomotor responses is an early sign of sympathetic dysfunction in Type I diabetes. Diabetes 50:436–443CrossRefPubMedGoogle Scholar
  19. 19.
    Hoeldtke RD, Bryner KD, McNeill DR, Hobbs GR, Riggs JE, Warehime SS, Christie I, Ganser G, VanDyke K (2002) Nitrosative stress, uric acid and peripheral nerve function in Early type I diabetes. Diabetes 51:2817–2825CrossRefPubMedGoogle Scholar
  20. 20.
    Klandorf H, Rathore DS, Iqbal M, Shi X, VanDyke K (2001) Accelerated tissue aging and increased oxidative stress in broiler chickens fed allopurinol. Comp Biochem Physiol Toxicol Pharmacol 129:93–104CrossRefGoogle Scholar
  21. 21.
    Kosugi H, Kojima T, Kikugawa K (1993) Characteristics of the thiobarbituric acid reactivity of human urine as a possible consequence of lipid peroxidation. Lipids 28:337–343CrossRefPubMedGoogle Scholar
  22. 22.
    Maejima K, Nakano S, Himeno M, Tsuda S, Makiishi H, Ito T, Nakagawa A, Kigoshi T, Ishibashi T, Nishio M, Uchida K (2001) Increased basal levels of plasma nitric oxide in Type 2 diabetic subjects. Relationship to microvascular complications. J Diabetes Complicat 15:135–143CrossRefPubMedGoogle Scholar
  23. 23.
    Marnett LJ, Wright TL, Crews BC, Tannenbaum SR, Morrow JD (2000) Regulation of prostaglandin biosynthesis by nitric oxide is revealed by targeted deletion of inducible nitric-oxide synthase. J Biol Chem 275:13427–13430CrossRefPubMedGoogle Scholar
  24. 24.
    Marra G, Cotroneo P, Pitocco D, Manto A, DiLeo MA, Ruotolo V, Caputo S, Giardna B, Ghirlandu G, Santini SA (2002) Early increase of oxidative stress and reduced antioxidant defenses in patients with uncomplicated type I diabetes: a case for gender difference. Diabetes Care 25:370–375CrossRefPubMedGoogle Scholar
  25. 25.
    Martinet W, Knaapen MWM, DeMeyer G, Herman AG, Kockx MM (2002) Elevated levels of oxidative DNA damage and DNA repair enzymes in human atherosclerotic plaques. Circulation 106:927–932CrossRefPubMedGoogle Scholar
  26. 26.
    Nishikawa T, Edelstein D, Brownlee MA (2000) Missing link: a single unifying mechanism for diabetic complications. Kidney Int 58(Suppl 77):S26–S30CrossRefGoogle Scholar
  27. 27.
    Obrosova IG (2008) Diabetes and the peripheral nerve (2009). Biochem Biophys Acta 1792:931–940PubMedGoogle Scholar
  28. 28.
    O’Bryne S, Forte P, Roberts LJ II, Morrow JD, Johnston A, Anggard E, Leslie RDG, Benjamin N (2000) Nitric oxide synthesis and isoprostane production in subjects with type 1 diabetes and normal urinary albumin excretion. Diabetes 49:857–862CrossRefGoogle Scholar
  29. 29.
    Pitocco D, DiStasio E, Romitelli F, Zaccardi F, Tavazzi B, Manto A, Caputo S, Musella T, Zuppi C, Santini SA, Ghirlanda G (2008) Hypouricemia linked to overproduction of nitric oxide is an early marker of oxidative stress in female subjects with type I diabetes. Diabetes Metab Res Rev 24:318–323CrossRefPubMedGoogle Scholar
  30. 30.
    Safinowski M, Wilhelm B, Reimer T, Weise A, Thome N, Hanel H, Forst T, Pfutzner A (2009) Determination of nitrotyrosine concentrations in plasma samples of diabetes mellitus patients by four different immunoassays leads to contradictive results and disqualifies the majority of the tests. Clin Chem Lab Med 47:483–488CrossRefPubMedGoogle Scholar
  31. 31.
    Santos CXC, Anjos EI, Augusto O (1999) Uric acid oxidation by peroxynitrite: multiple reactions, free radical formation, and amplification of lipid peroxidation. Arch Biochem Biophys 372:285–294CrossRefPubMedGoogle Scholar
  32. 32.
    Shelley WB, Florence R (1960) Compensatory hyperhidrosis after sympathectomy. New Engl J Med 263:1056–1058CrossRefGoogle Scholar
  33. 33.
    Shishehbor MH, Aviles RJ, Brennan ML, Fu X, Goormastic M, Pearce GL, Gokce KeaneyJF, Penn MS, Sprecher DL, Vita JA, Hazen SL (2003) Association of nitrotyrosine levels with cardiovascular disease and modulation by statin therapy. JAMA 289:1675–1680CrossRefPubMedGoogle Scholar
  34. 34.
    Suto T, Losonczy G, Qiu C, Hill C, Samsell L, Ruby J, Charon N, Venuto R, Baylis C (1995) Acute changes in urinary excretion of nitrite + nitrate do not necessarily predict renal vascular NO production. Kidney Int 48:1272–1277CrossRefPubMedGoogle Scholar
  35. 35.
    Tesfaye S, Malik R, Harris N, Jakubowski JJ, Mody C, Rennie IG, Ward JD (1996) Arteriovenous shunting and proliferating new vessels in acute painful neuropathy of rapid glycemic control (insulin neuritis). Diabetologia 39:329–335CrossRefPubMedGoogle Scholar
  36. 36.
    Thum T, Fraccarollo D, Schultheiss M, Froese S, Galuppo P, Widder JD, Tsikas D, Ertl G, Bauersachs J (2007) Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes. Diabetes 56:666–674CrossRefPubMedGoogle Scholar
  37. 37.
    Tuncayengin A, Biri H, Onaran M, Seni I, Tucayengin O, Polat F, Erbas D, Bozkirli I (2003) Cavernosal tissue nitrite, nitrate, malondialdehyde and glutathione levels in diabetic and on diabetic erectile function. Int J Androl 26:250–254CrossRefPubMedGoogle Scholar
  38. 38.
    Vincent AM, Russell JW, Low P, Feldman EL (2004) Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr Rev 25:612–628CrossRefPubMedGoogle Scholar
  39. 39.
    Vinik AI, Erbas T, Park TS, Stansberry KB, Scanelli JA, Pittenger GL (2001) Dermal neurovascular dysfunction in type 2 diabetes. Diabetes Care 24:1468–1475CrossRefPubMedGoogle Scholar
  40. 40.
    Vinik AI, Maser RE, Mitchell BD, Freeman R (2003) Diabetic autonomic neuropathy. Diabetes Care 26:1553–1579CrossRefPubMedGoogle Scholar
  41. 41.
    Waring WS, McKnight JA, Webb DJ, Maxwell SR (2006) Uric acid restores endothelial function in patients with type I diabetes and regular smokers. Diabetes 55:3127–3132CrossRefPubMedGoogle Scholar
  42. 42.
    Watkins PJ (1992) Clinical observations and experiments in diabetic neuropathy. Diabetologia 35:2–11CrossRefPubMedGoogle Scholar
  43. 43.
    Zeballos GA, Bernstein RD, Thompson CI, Forfia PR, Seyedi N, Shen W, Kaminsi PM, Wolin MS, Hintze TH (1995) Pharmacodynamics of plasma nitrate/nitrite as an indication of nitric oxide formation in conscious dogs. Circulation 91:2982–2988Google Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Robert Daniel Hoeldtke
    • 1
  • Kimberly D. Bryner
    • 2
  • Knox VanDyke
    • 2
  1. 1.LSU Medical SchoolShreveportUSA
  2. 2.West Virginia University Medical SchoolMorgantownUSA

Personalised recommendations