Reviews in Endocrine and Metabolic Disorders

, Volume 9, Issue 4, pp 301–314 | Cite as

Mechanisms of disease: The oxidative stress theory of diabetic neuropathy

  • Claudia Figueroa-Romero
  • Mahdieh Sadidi
  • Eva L. Feldman


Diabetic neuropathy is the most common complication of diabetes, affecting 50% of diabetic patients. Currently, the only treatment for diabetic neuropathy is glucose control and careful foot care. In this review, we discuss the idea that excess glucose overloads the electron transport chain, leading to the production of superoxides and subsequent mitochondrial and cytosolic oxidative stress. Defects in metabolic and vascular pathways intersect with oxidative stress to produce the onset and progression of nerve injury present in diabetic neuropathy. These pathways include the production of advanced glycation end products, alterations in the sorbitol, hexosamine and protein kinase C pathways and activation of poly-ADP ribose polymerase. New bioinformatics approaches can augment current research and lead to new discoveries to understand the pathogenesis of diabetic neuropathy and to identify more effective molecular therapeutic targets.


Diabetes Neuropathy Oxidative stress Bioinformatics 



We thank Ms. Judith Boldt for excellent secretarial support and Dr. Kelli A. Sullivan for expert editorial advice. This work was supported by the A. Alfred Taubman Medical Research Institute, the Program for Neurology Research and Discovery and by NIH T32 NS07222 and NIH UO1 DK076160.


  1. 1.
    Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 2005;28:956–62. doi: 10.2337/diacare.28.4.956.PubMedCrossRefGoogle Scholar
  2. 2.
    Martin CL, Albers J, Herman WH, Cleary P, Waberski B, Greene DA, et al. Neuropathy among the diabetes control and complications trial cohort 8 years after trial completion. Diabetes Care 2006;29:340–4. doi: 10.2337/diacare.29.02.06.dc05-1549.PubMedCrossRefGoogle Scholar
  3. 3.
    Feldman EL, Stevens MJ, Russell JW, Peltier A, et al. Somatosensory neuropathy. In: Porte D Jr, Sherwin RS, Baron A, editors. The diabetes mellitus manual. Philadelphia: McGraw-Hill; 2005. p. 366–84.Google Scholar
  4. 4.
    Singleton JR, Smith AG, Russell J, Feldman EL. Polyneuropathy with impaired glucose tolerance: implications for diagnosis and therapy. Curr Treat Options Neurol 2005;7:33–42. doi: 10.1007/s11940-005-0004-4.PubMedCrossRefGoogle Scholar
  5. 5.
    Feldman EL, Stevens MJ, Russell JW, Greene DA, Porte D Jr, Sherwin RS, et al. Somatosensory neuropathy. In: Porte D Jr SRS, Baron A, editors. Ellenberg and Rifkin’s diabetes mellitus. Philadelphia: McGraw Hill; 2002. p. 771–88.Google Scholar
  6. 6.
    Feldman EL, Stevens MJ, Russell JW. Diabetic peripheral and autonomic neuropathy. In: Sperling MA, editor. Contemporary endocrinology. Humana Press; 2002.Google Scholar
  7. 7.
    Little AA, Edwards JL, Feldman EL. Diabetic neuropathies. Pract Neurol 2007;7:82–92.PubMedGoogle Scholar
  8. 8.
    Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care 2003;26:1553–79. doi: 10.2337/diacare.26.5.1553.PubMedCrossRefGoogle Scholar
  9. 9.
    Vinik AI, Mehrabyan A. Diabetic neuropathies. Med Clin North Am 2004;88:947–99. doi: 10.1016/j.mcna.2004.04.009xi.PubMedCrossRefGoogle Scholar
  10. 10.
    Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Greene DA. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 1994;17:1281–9. doi: 10.2337/diacare.17.11.1281.PubMedCrossRefGoogle Scholar
  11. 11.
    Hoye AT, Davoren JE, Wipf P, Fink MP, Kagan VE. Targeting mitochondria. Acc Chem Res 2008;41:87–97. doi: 10.1021/ar700135m.PubMedCrossRefGoogle Scholar
  12. 12.
    Lee MY, Griendling KK. Redox signaling, vascular function, and hypertension. Antioxidants & Redox Signaling 2008;10:1045–59.CrossRefGoogle Scholar
  13. 13.
    Lu T, Finkel T. Free radicals and senescence. Exp Cell Res 2008;314:1918–22. doi: 10.1016/j.yexcr.2008.01.011.PubMedCrossRefGoogle Scholar
  14. 14.
    Paravicini TM, Touyz RM. NADPH oxidases, reactive oxygen species, and hypertension: clinical implications and therapeutic possibilities. Diabetes Care 2008;31 (Suppl 2):S170–80. doi: 10.2337/dc08-s247.PubMedCrossRefGoogle Scholar
  15. 15.
    Skulachev VP. A biochemical approach to the problem of aging: “megaproject” on membrane-penetrating ions. The first results and prospects. Biochemistry 2007;72:1385–96.PubMedGoogle Scholar
  16. 16.
    Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001;414:813–20. doi: 10.1038/414813a.PubMedCrossRefGoogle Scholar
  17. 17.
    Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005;54:1615–25. doi: 10.2337/diabetes.54.6.1615.PubMedCrossRefGoogle Scholar
  18. 18.
    Vincent AM, Edwards JL, Sadidi M, Feldman EL. The antioxidant response as a drug target in diabetic neuropathy. Curr Drug Targets 2008;9:94–100. doi: 10.2174/138945008783431754.PubMedCrossRefGoogle Scholar
  19. 19.
    Vincent AM, Feldman EL. New insights into the mechanisms of diabetic neuropathy. Rev Endocr Metab Disord 2004;5:227–36. doi: 10.1023/B:REMD.0000032411.11422.e0.PubMedCrossRefGoogle Scholar
  20. 20.
    Vincent AM, Russell JW, Low P, Feldman EL. Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr Rev 2004;25:612–28. doi: 10.1210/er.2003-0019.PubMedCrossRefGoogle Scholar
  21. 21.
    Erusalimsky JD, Moncada S. Nitric oxide and mitochondrial signaling: from physiology to pathophysiology. Arterioscler Thromb Vasc Biol 2007;27:2524–31. doi: 10.1161/ATVBAHA.107.151167.PubMedCrossRefGoogle Scholar
  22. 22.
    Lambert AJ, Brand MD. Inhibitors of the quinone-binding site allow rapid superoxide production from mitochondrial NADH:ubiquinone oxidoreductase (complex I). J Biol Chem 2004;279:39414–20. doi: 10.1074/jbc.M406576200.PubMedCrossRefGoogle Scholar
  23. 23.
    Han D, Williams E, Cadenas E. Mitochondrial respiratory chain-dependent generation of superoxide anion and its release into the intermembrane space. Biochem J 2001;353:411–6. doi: 10.1042/0264-6021:3530411.PubMedCrossRefGoogle Scholar
  24. 24.
    Muller FL, Liu Y, Van Remmen H. Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem 2004;279:49064–73. doi: 10.1074/jbc.M407715200.PubMedCrossRefGoogle Scholar
  25. 25.
    Han D, Antunes F, Canali R, Rettori D, Cadenas E. Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol. J Biol Chem 2003;278:5557–63. doi: 10.1074/jbc.M210269200.PubMedCrossRefGoogle Scholar
  26. 26.
    Faraci FM, Didion SP. Vascular protection: superoxide dismutase isoforms in the vessel wall. Arterioscler Thromb Vasc Biol 2004;24:1367–73. doi: 10.1161/ Scholar
  27. 27.
    Okado-Matsumoto A, Fridovich I. Subcellular distribution of superoxide dismutases (SOD) in rat liver. Cu,Zn-SOD in mitochondria. J Biol Chem 2001;276:38388–93. doi: 10.1074/jbc.M105395200.PubMedCrossRefGoogle Scholar
  28. 28.
    Lebovitz RM, Zhang H, Vogel H, Cartwright J Jr, Dionne L, Lu N, et al. Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice. Proc Natl Acad Sci USA 1996;93:9782–7. doi: 10.1073/pnas.93.18.9782.PubMedCrossRefGoogle Scholar
  29. 29.
    Li Y, Huang TT, Carlson EJ, Melov S, Ursell PC, Olson JL, et al. Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat Genet 1995;11:376–81. doi: 10.1038/ng1295-376.PubMedCrossRefGoogle Scholar
  30. 30.
    Suttorp N, Toepfer W, Roka L. Antioxidant defense mechanisms of endothelial cells: glutathione redox cycle versus catalase. Am J Physiol Cell Physiol 1986;251:C671–80.Google Scholar
  31. 31.
    Zhang R, Al-Lamki R, Bai L, Streb JW, Miano JM, Bradley J, et al. Thioredoxin-2 inhibits mitochondria-located ASK1-mediated apoptosis in a JNK-independent manner. Circ Res 2004;94:1483–91. doi: 10.1161/01.RES.0000130525.37646.a7.PubMedCrossRefGoogle Scholar
  32. 32.
    Vincent AM, Gong C, Brownlee M, Russell JW. Glucose induced neuronal programmed cell death is regulated by manganese superoxide dismutase and uncoupling protein-1. Endocrine Society Abstracts 2001;P1–289:210.Google Scholar
  33. 33.
    Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science (New York, NY) 2005;307:384–7.Google Scholar
  34. 34.
    Ghafourifar P, Richter C. Nitric oxide synthase activity in mitochondria. FEBS Lett 1997;418:291–6. doi: 10.1016/S0014-5793(97)01397-5.PubMedCrossRefGoogle Scholar
  35. 35.
    Poderoso JJ, Carreras MC, Schopfer F, Lisdero CL, Riobo NA, Giulivi C, et al. The reaction of nitric oxide with ubiquinol: kinetic properties and biological significance. Free Radic Biol Med 1999;26:925–35. doi: 10.1016/S0891-5849(98)00277-9.PubMedCrossRefGoogle Scholar
  36. 36.
    Poderoso JJ, Lisdero C, Schopfer F, Riobo N, Carreras MC, Cadenas E, et al. The regulation of mitochondrial oxygen uptake by redox reactions involving nitric oxide and ubiquinol. J Biol Chem 1999;274:37709–16. doi: 10.1074/jbc.274.53.37709.PubMedCrossRefGoogle Scholar
  37. 37.
    Ghafourifar P, Schenk U, Klein SD, Richter C. Mitochondrial nitric–oxide synthase stimulation causes cytochrome c release from isolated mitochondria. Evidence for intramitochondrial peroxynitrite formation. J Biol Chem 1999;274:31185–8. doi: 10.1074/jbc.274.44.31185.PubMedCrossRefGoogle Scholar
  38. 38.
    Marcondes S, Turko IV, Murad F. Nitration of succinyl-CoA:3-oxoacid CoA-transferase in rats after endotoxin administration. Proc Natl Acad Sci USA 2001;98:7146–51. doi: 10.1073/pnas.141222598.PubMedCrossRefGoogle Scholar
  39. 39.
    Aulak KS, Koeck T, Crabb JW, Stuehr DJ. Proteomic method for identification of tyrosine-nitrated proteins. Meth Mol Biol (Clifton, NJ) 2004;279:151–65.Google Scholar
  40. 40.
    Turko IV, Marcondes S, Murad F. Diabetes-associated nitration of tyrosine and inactivation of succinyl-CoA:3-oxoacid CoA-transferase. Am J Physiol Heart Circ Physiol 2001;281:H2289–94.PubMedGoogle Scholar
  41. 41.
    Mannick JB, Schonhoff C, Papeta N, Ghafourifar P, Szibor M, Fang K, et al. S-Nitrosylation of mitochondrial caspases. J Cell Biol 2001;154:1111–6. doi: 10.1083/jcb.200104008.PubMedCrossRefGoogle Scholar
  42. 42.
    Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000;404:787–90. doi: 10.1038/35008121.PubMedCrossRefGoogle Scholar
  43. 43.
    Obrosova IG, Drel VR, Oltman CL, Mashtalir N, Tibrewala J, Groves JT, et al. Role of nitrosative stress in early neuropathy and vascular dysfunction in streptozotocin-diabetic rats. Am J Physiol 2007;293:E1645–55. doi: 10.1152/ajpcell.00165.2007.CrossRefGoogle Scholar
  44. 44.
    Obrosova IG, Drel VR, Pacher P, Ilnytska O, Wang ZQ, Stevens MJ, et al. Oxidative-nitrosative stress and poly(ADP-ribose) polymerase (PARP) activation in experimental diabetic neuropathy: the relation is revisited. Diabetes 2005;54:3435–41. doi: 10.2337/diabetes.54.12.3435.PubMedCrossRefGoogle Scholar
  45. 45.
    Leinninger GM, Edwards JL, Lipshaw MJ, Feldman EL. Mechanisms of disease: mitochondria as new therapeutic targets in diabetic neuropathy. Nat Clin Prac 2006;2:620–8.CrossRefGoogle Scholar
  46. 46.
    Edwards JL, Vincent AM, Cheng HL, Feldman EL. Diabetic neuropathy: Mechanisms to management. Pharmacol Ther. 2008 (in press).Google Scholar
  47. 47.
    Leinninger GM, Backus C, Sastry AM, Yi YB, Wang CW, Feldman EL. Mitochondria in DRG neurons undergo hyperglycemic mediated injury through Bim, Bax and the fission protein Drp1. Neurobiol Dis 2006;23:11–22. doi: 10.1016/j.nbd.2006.01.017.PubMedCrossRefGoogle Scholar
  48. 48.
    Arnoult D, Rismanchi N, Grodet A, Roberts RG, Seeburg DP, Estaquier J, et al. Bax/Bak-dependent release of DDP/TIMM8a promotes Drp1-mediated mitochondrial fission and mitoptosis during programmed cell death. Curr Biol 2005;15:2112–8. doi: 10.1016/j.cub.2005.10.041.PubMedCrossRefGoogle Scholar
  49. 49.
    Brussee V, Guo G, Dong Y, Cheng C, Martinez JA, Smith D, et al. Distal degenerative sensory neuropathy in a long-term type 2 diabetes rat model. Diabetes 2008;57:1664–73. doi: 10.2337/db07-1737.PubMedCrossRefGoogle Scholar
  50. 50.
    Cheng C, Zochodne DW. Sensory neurons with activated caspase-3 survive long-term experimental diabetes. Diabetes 2003;52:2363–71. doi: 10.2337/diabetes.52.9.2363.PubMedCrossRefGoogle Scholar
  51. 51.
    Gumy LF, Bampton ET, Tolkovsky AM. Hyperglycaemia inhibits Schwann cell proliferation and migration and restricts regeneration of axons and Schwann cells from adult murine DRG. Mol Cell Neurosci 2008;37:298–311. doi: 10.1016/j.mcn.2007.10.004.PubMedCrossRefGoogle Scholar
  52. 52.
    Sullivan KA, Hayes JM, Wiggin TD, Backus C, Su Oh S, Lentz SI, et al. Mouse models of diabetic neuropathy. Neurobiol Dis 2007;28:276–85. doi: 10.1016/j.nbd.2007.07.022.PubMedCrossRefGoogle Scholar
  53. 53.
    Vincent AM, Russell JW, Sullivan KA, Backus C, Hayes JM, McLean LL, et al. SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy. Exp Neurol 2007;208:216–27.PubMedGoogle Scholar
  54. 54.
    Wiggin TD, Kretzler M, Pennathur S, Sullivan KA, Brosius FC, Feldman EL. Rosiglitazone treatment reduces diabetic neuropathy in STZ Treated DBA/2J Mice. Endocrinology. 2008 (in press).Google Scholar
  55. 55.
    Gardiner NJ, Wang Z, Luke C, Gott A, Price SA, Fernyhough P. Expression of hexokinase isoforms in the dorsal root ganglion of the adult rat and effect of experimental diabetes. Brain Res 2007;1175:143–54. doi: 10.1016/j.brainres.2007.08.015.PubMedCrossRefGoogle Scholar
  56. 56.
    Saini AK, Kumar HSA, Sharma SS. Preventive and curative effect of edaravone on nerve functions and oxidative stress in experimental diabetic neuropathy. Eur J Pharmacol 2007;568:164–72. doi: 10.1016/j.ejphar.2007.04.016.PubMedCrossRefGoogle Scholar
  57. 57.
    Kumar A, Kaundal RK, Iyer S, Sharma SS. Effects of resveratrol on nerve functions, oxidative stress and DNA fragmentation in experimental diabetic neuropathy. Life Sci 2007;80:1236–44. doi: 10.1016/j.lfs.2006.12.036.PubMedCrossRefGoogle Scholar
  58. 58.
    Coppey LJ, Davidson EP, Rinehart TW, Gellett JS, Oltman CL, Lund DD, et al. ACE inhibitor or angiotensin II receptor antagonist attenuates diabetic neuropathy in streptozotocin-induced diabetic rats. Diabetes 2006;55:341–8. doi: 10.2337/diabetes.55.02.06.db05-0885.PubMedCrossRefGoogle Scholar
  59. 59.
    Ilnytska O, Lyzogubov VV, Stevens MJ, Drel VR, Mashtalir N, Pacher P, et al. Poly(ADP-ribose) polymerase inhibition alleviates experimental diabetic sensory neuropathy. Diabetes 2006;55:1686–94. doi: 10.2337/db06-0067.PubMedCrossRefGoogle Scholar
  60. 60.
    Kuzumoto Y, Kusunoki S, Kato N, Kihara M, Low PA. Effect of the aldose reductase inhibitor fidarestat on experimental diabetic neuropathy in the rat. Diabetologia 2006;49:3085–93. doi: 10.1007/s00125-006-0400-7.PubMedCrossRefGoogle Scholar
  61. 61.
    Sayyed SG, Kumar A, Sharma SS. Effects of U83836E on nerve functions, hyperalgesia and oxidative stress in experimental diabetic neuropathy. Life Sci 2006;79:777–83. doi: 10.1016/j.lfs.2006.02.033.PubMedCrossRefGoogle Scholar
  62. 62.
    Sharma SS, Sayyed SG. Effects of trolox on nerve dysfunction, thermal hyperalgesia and oxidative stress in experimental diabetic neuropathy. Clin Exp Pharmacol Physiol 2006;33:1022–8. doi: 10.1111/j.1440-1681.2006.04481.x.PubMedCrossRefGoogle Scholar
  63. 63.
    Schmeichel AM, Schmelzer JD, Low PA. Oxidative injury and apoptosis of dorsal root ganglion neurons in chronic experimental diabetic neuropathy. Diabetes 2003;52:165–71. doi: 10.2337/diabetes.52.1.165.PubMedCrossRefGoogle Scholar
  64. 64.
    Obrosova IG, Mabley JG, Zsengeller Z, Charniauskaya T, Abatan OI, Groves JT, et al. Role for nitrosative stress in diabetic neuropathy: evidence from studies with a peroxynitrite decomposition catalyst. FASEB J 2005;19:401–3.PubMedGoogle Scholar
  65. 65.
    Kellogg AP, Wiggin TD, Larkin DD, Hayes JM, Stevens MJ, Pop-Busui R. Protective effects of cyclooxygenase-2 gene inactivation against peripheral nerve dysfunction and intraepidermal nerve fiber loss in experimental diabetes. Diabetes 2007;56:2997–3005. doi: 10.2337/db07-0740.PubMedCrossRefGoogle Scholar
  66. 66.
    Ho EC, Lam KS, Chen YS, Yip JC, Arvindakshan M, Yamagishi S, et al. Aldose reductase-deficient mice are protected from delayed motor nerve conduction velocity, increased c-Jun NH2-terminal kinase activation, depletion of reduced glutathione, increased superoxide accumulation, and DNA damage. Diabetes 2006;55:1946–53. doi: 10.2337/db05-1497.PubMedCrossRefGoogle Scholar
  67. 67.
    Obrosova IG, Li F, Abatan OI, Forsell MA, Komjati K, Pacher P, et al. Role of poly(ADP-ribose) polymerase activation in diabetic neuropathy. Diabetes 2004;53:711–20. doi: 10.2337/diabetes.53.3.711.PubMedCrossRefGoogle Scholar
  68. 68.
    Oltman CL, Coppey LJ, Gellett JS, Davidson EP, Lund DD, Yorek MA. Progression of vascular and neural dysfunction in sciatic nerves of Zucker diabetic fatty and Zucker rats. Am J Physiol 2005;289:E113–22. doi: 10.1152/ajpcell.00040.2005.CrossRefGoogle Scholar
  69. 69.
    Vareniuk I, Pavlov IA, Drel VR, Lyzogubov VV, Ilnytska O, Bell SR, et al. Nitrosative stress and peripheral diabetic neuropathy in leptin-deficient (ob/ob) mice. Exp Neurol 2007;205:425–36. doi: 10.1016/j.expneurol.2007.03.019.PubMedCrossRefGoogle Scholar
  70. 70.
    Drel VR, Mashtalir N, Ilnytska O, Shin J, Li F, Lyzogubov VV, et al. The leptin-deficient (ob/ob) mouse: a new animal model of peripheral neuropathy of type 2 diabetes and obesity. Diabetes 2006;55:3335–43. doi: 10.2337/db06-0885.PubMedCrossRefGoogle Scholar
  71. 71.
    Obrosova IG, Ilnytska O, Lyzogubov VV, Pavlov IA, Mashtalir N, Nadler JL, et al. High-fat diet induced neuropathy of pre-diabetes and obesity: effects of “healthy” diet and aldose reductase inhibition. Diabetes 2007;56:2598–608. doi: 10.2337/db06-1176.PubMedCrossRefGoogle Scholar
  72. 72.
    Ahmed N. Advanced glycation endproducts—role in pathology of diabetic complications. Diabetes Res Clin Pract 2005;67:3–21. doi: 10.1016/j.diabres.2004.09.004.PubMedCrossRefGoogle Scholar
  73. 73.
    Toth C, Rong LL, Yang C, Martinez J, Song F, Ramji N, et al. Receptor for advanced glycation end products (RAGEs) and experimental diabetic neuropathy. Diabetes. 2008;57(4):1002–17, Apr.PubMedCrossRefGoogle Scholar
  74. 74.
    Yao D, Taguchi T, Matsumura T, Pestell R, Edelstein D, Giardino I, et al. High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A. J Biol Chem 2007;282:31038–45. doi: 10.1074/jbc.M704703200.PubMedCrossRefGoogle Scholar
  75. 75.
    Ramasamy R, Yan SF, Schmidt AM. Arguing for the motion: yes, RAGE is a receptor for advanced glycation endproducts. Mol Nutr Food Res 2007;51:1111–5. doi: 10.1002/mnfr.200700008.PubMedCrossRefGoogle Scholar
  76. 76.
    Vincent AM, Perrone L, Sullivan KA, Backus C, Sastry AM, Lastoskie C, et al. Receptor for advanced glycation end products activation injures primary sensory neurons via oxidative stress. Endocrinology 2007;148:548–58. doi: 10.1210/en.2006-0073.PubMedCrossRefGoogle Scholar
  77. 77.
    Ramasamy R, Vannucci SJ, Yan SS, Herold K, Yan SF, Schmidt AM. Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation. Glycobiology 2005;15:16R–28R. doi: 10.1093/glycob/cwi053.PubMedCrossRefGoogle Scholar
  78. 78.
    Tanji N, Markowitz GS, Fu C, Kislinger T, Taguchi A, Pischetsrieder M, et al. Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease. J Am Soc Nephrol 2000;11:1656–66.PubMedGoogle Scholar
  79. 79.
    Coughlan MT, Forbes JM, Cooper ME. Role of the AGE crosslink breaker, alagebrium, as a renoprotective agent in diabetes. Kidney Int 2007;72:S54–60. doi: 10.1038/ Scholar
  80. 80.
    Hudson BI, Schmidt AM. RAGE: a novel target for drug intervention in diabetic vascular disease. Pharm Res 2004;21:1079–86. doi: 10.1023/B:PHAM.0000032992.75423.9b.PubMedCrossRefGoogle Scholar
  81. 81.
    Bucciarelli LG, Wendt T, Qu W, Lu Y, Lalla E, Rong LL, et al. RAGE blockade stabilizes established atherosclerosis in diabetic apolipoprotein E-null mice. Circulation 2002;106:2827–35. doi: 10.1161/01.CIR.0000039325.03698.36.PubMedCrossRefGoogle Scholar
  82. 82.
    Sugimoto K, Yasujima M, Yagihashi S. Role of advanced glycation end products in diabetic neuropathy. Curr Pharm Des 2008;14:953–61. doi: 10.2174/138161208784139774.PubMedCrossRefGoogle Scholar
  83. 83.
    Djordjevic VB. Free radicals in cell biology. Int Rev Cytol 2004;237:57–89. doi: 10.1016/S0074-7696(04)37002-6.PubMedCrossRefGoogle Scholar
  84. 84.
    Mathers J, Fraser JA, McMahon M, Saunders RD, Hayes JD, McLellan LI. Antioxidant and cytoprotective responses to redox stress. Biochem Soc Symp 2004;71:157–76.PubMedGoogle Scholar
  85. 85.
    Nakamura J, Kato K, Hamada Y, Nakayama M, Chaya S, Nakashima E, et al. A protein kinase C-beta-selective inhibitor ameliorates neural dysfunction in streptozotocin-induced diabetic rats. Diabetes 1999;48:2090–5. doi: 10.2337/diabetes.48.10.2090.PubMedCrossRefGoogle Scholar
  86. 86.
    Feldman EL, Stevens MJ, Greene DA. Pathogenesis of diabetic neuropathy. Clin Neurosci (New York, NY) 1997;4:365–70.Google Scholar
  87. 87.
    Uehara K, Yamagishi S, Otsuki S, Chin S, Yagihashi S. Effects of polyol pathway hyperactivity on protein kinase C activity, nociceptive peptide expression, and neuronal structure in dorsal root ganglia in diabetic mice. Diabetes 2004;53:3239–47. doi: 10.2337/diabetes.53.12.3239.PubMedCrossRefGoogle Scholar
  88. 88.
    Yamagishi S, Uehara K, Otsuki S, Yagihashi S. Differential influence of increased polyol pathway on protein kinase C expressions between endoneurial and epineurial tissues in diabetic mice. J Neurochem 2003;87:497–507. doi: 10.1046/j.1471-4159.2003.02011.x.PubMedCrossRefGoogle Scholar
  89. 89.
    Demaine AG. Polymorphisms of the aldose reductase gene and susceptibility to diabetic microvascular complications. Curr Med Chem 2003;10:1389–98. doi: 10.2174/0929867033457359.PubMedCrossRefGoogle Scholar
  90. 90.
    Donaghue KC, Margan SH, Chan AK, Holloway B, Silink M, Rangel T, et al. The association of aldose reductase gene (AKR1B1) polymorphisms with diabetic neuropathy in adolescents. Diabet Med 2005;22:1315–20. doi: 10.1111/j.1464-5491.2005.01631.x.PubMedCrossRefGoogle Scholar
  91. 91.
    Thamotharampillai K, Chan AK, Bennetts B, Craig ME, Cusumano J, Silink M, et al. Decline in neurophysiological function after 7 years in an adolescent diabetic cohort and the role of aldose reductase gene polymorphisms. Diabetes Care 2006;29:2053–7. doi: 10.2337/dc06-0678.PubMedCrossRefGoogle Scholar
  92. 92.
    Oates PJ. Aldose reductase, still a compelling target for diabetic neuropathy. Curr Drug Targets 2008;9:14–36.PubMedCrossRefGoogle Scholar
  93. 93.
    Thornalley PJ. The potential role of thiamine (vitamin B(1)) in diabetic complications. Curr Diabetes Rev 2005;1:287–98. doi: 10.2174/157339905774574383.PubMedCrossRefGoogle Scholar
  94. 94.
    Kolm-Litty V, Sauer U, Nerlich A, Lehmann R, Schleicher ED. High glucose-induced transforming growth factor beta1 production is mediated by the hexosamine pathway in porcine glomerular mesangial cells. J Clin Invest 1998;101:160–9. doi: 10.1172/JCI119875.PubMedCrossRefGoogle Scholar
  95. 95.
    Sayeski PP, Kudlow JE. Glucose metabolism to glucosamine is necessary for glucose stimulation of transforming growth factor-alpha gene transcription. J Biol Chem 1996;271:15237–43. doi: 10.1074/jbc.271.25.15237.PubMedCrossRefGoogle Scholar
  96. 96.
    Dias WB, Hart GW. O-GlcNAc modification in diabetes and Alzheimer’s disease. Mol Biosyst 2007;3:766–72. doi: 10.1039/b704905f.PubMedCrossRefGoogle Scholar
  97. 97.
    Love DC, Hanover JA. The hexosamine signaling pathway: deciphering the “O-GlcNAc code”. Sci STKE 2005;2005:re13. doi: 10.1126/stke.3122005re13.PubMedCrossRefGoogle Scholar
  98. 98.
    Du XL, Edelstein D, Rossetti L, Fantus IG, Goldberg H, Ziyadeh F, et al. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci USA 2000;97:12222–6. doi: 10.1073/pnas.97.22.12222.PubMedCrossRefGoogle Scholar
  99. 99.
    Hafer-Macko CE, Ivey FM, Sorkin JD, Macko RF. Microvascular tissue plasminogen activator is reduced in diabetic neuropathy. Neurology 2007;69:268–74. doi: 10.1212/01.wnl.0000266391.20707.83.PubMedCrossRefGoogle Scholar
  100. 100.
    Maser RE, Ellis D, Erbey JR, Orchard TJ. Do tissue plasminogen activator-plasminogen activator inhibitor-1 complexes relate to the complications of insulin-dependent diabetes mellitus? Pittsburgh Epidemiology of Diabetes Complications Study. J Diabetes Complications 1997;11:243–9. doi: 10.1016/S1056-8727(96)00040-2.PubMedCrossRefGoogle Scholar
  101. 101.
    Aso Y, Matsumoto S, Fujiwara Y, Tayama K, Inukai T, Takemura Y. Impaired fibrinolytic compensation for hypercoagulability in obese patients with type 2 diabetes: association with increased plasminogen activator inhibitor-1. Metabolism 2002;51:471–6. doi: 10.1053/meta.2002.31334.PubMedCrossRefGoogle Scholar
  102. 102.
    Erem C, Hacihasanoglu A, Celik S, Ovali E, Ersoz HO, Ukinc K, et al. Coagulation and fibrinolysis parameters in type 2 diabetic patients with and without diabetic vascular complications. Med Princ Pract 2005;14:22–30. doi: 10.1159/000081919.PubMedCrossRefGoogle Scholar
  103. 103.
    Nilsson A, Moller K, Dahlin L, Lundborg G, Kanje M. Early changes in gene expression in the dorsal root ganglia after transection of the sciatic nerve; effects of amphiregulin and PAI-1 on regeneration. Brain Res 2005;136:65–74. doi: 10.1016/j.molbrainres.2005.01.008.CrossRefGoogle Scholar
  104. 104.
    Kanwar YS, Wada J, Sun L, Xie P, Wallner EI, Chen S, et al. Diabetic nephropathy: mechanisms of renal disease progression. Exp Biol Med (Maywood, NJ) 2008;233:4–11.CrossRefGoogle Scholar
  105. 105.
    Zhu Y, Usui HK, Sharma K. Regulation of transforming growth factor beta in diabetic nephropathy: implications for treatment. Semin Nephrol 2007;27:153–60. doi: 10.1016/j.semnephrol.2007.01.008.PubMedCrossRefGoogle Scholar
  106. 106.
    Anjaneyulu M, Berent-Spillson A, Inoue T, Choi J, Cherian K, Russell JW. Transforming growth factor-beta induces cellular injury in experimental diabetic neuropathy. Exp Neurol 2008;211:469–79. doi: 10.1016/j.expneurol.2008.02.011.PubMedCrossRefGoogle Scholar
  107. 107.
    Arikawa E, Ma RC, Isshiki K, Luptak I, He Z, Yasuda Y, et al. Effects of insulin replacements, inhibitors of angiotensin, and PKCbeta’s actions to normalize cardiac gene expression and fuel metabolism in diabetic rats. Diabetes 2007;56:1410–20. doi: 10.2337/db06-0655.PubMedCrossRefGoogle Scholar
  108. 108.
    Das Evcimen N, King GL. The role of protein kinase C activation and the vascular complications of diabetes. Pharmacol Res 2007;55:498–510. doi: 10.1016/j.phrs.2007.04.016.PubMedCrossRefGoogle Scholar
  109. 109.
    Veves A, King GL. Can VEGF reverse diabetic neuropathy in human subjects? J Clin Invest 2001;107:1215–8. doi: 10.1172/JCI13038.PubMedCrossRefGoogle Scholar
  110. 110.
    Cameron NE, Cotter MA. Effects of protein kinase Cbeta inhibition on neurovascular dysfunction in diabetic rats: interaction with oxidative stress and essential fatty acid dysmetabolism. Diabetes Metab Res Rev 2002;18:315–23. doi: 10.1002/dmrr.307.PubMedCrossRefGoogle Scholar
  111. 111.
    Cortright RN, Azevedo JL Jr, Zhou Q, Sinha M, Pories WJ, Itani SI, et al. Protein kinase C modulates insulin action in human skeletal muscle. Am J Physiol 2000;278:E553–62.Google Scholar
  112. 112.
    Naruse K, Rask-Madsen C, Takahara N, Ha SW, Suzuma K, Way KJ, et al. Activation of vascular protein kinase C-beta inhibits Akt-dependent endothelial nitric oxide synthase function in obesity-associated insulin resistance. Diabetes 2006;55:691–8. doi: 10.2337/diabetes.55.03.06.db05-0771.PubMedCrossRefGoogle Scholar
  113. 113.
    Casellini CM, Barlow PM, Rice AL, Casey M, Simmons K, Pittenger G, et al. A 6-month, randomized, double-masked, placebo-controlled study evaluating the effects of the protein kinase C-beta inhibitor ruboxistaurin on skin microvascular blood flow and other measures of diabetic peripheral neuropathy. Diabetes Care 2007;30:896–902. doi: 10.2337/dc06-1699.PubMedCrossRefGoogle Scholar
  114. 114.
    Vinik AI, Bril V, Kempler P, Litchy WJ, Tesfaye S, Price KL, et al. Treatment of symptomatic diabetic peripheral neuropathy with the protein kinase C beta-inhibitor ruboxistaurin mesylate during a 1-year, randomized, placebo-controlled, double-blind clinical trial. Clin Ther 2005;27:1164–80. doi: 10.1016/j.clinthera.2005.08.001.PubMedCrossRefGoogle Scholar
  115. 115.
    Obrosova IG, Julius UA. Role for poly(ADP-ribose) polymerase activation in diabetic nephropathy, neuropathy and retinopathy. Curr Vasc Pharmacol 2005;3:267–83. doi: 10.2174/1570161054368634.PubMedCrossRefGoogle Scholar
  116. 116.
    Southan GJ, Szabo C. Poly(ADP-ribose) polymerase inhibitors. Curr Med Chem 2003;10:321–40.PubMedGoogle Scholar
  117. 117.
    Du X, Matsumura T, Edelstein D, Rossetti L, Zsengeller Z, Szabo C, et al. Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest 2003;112:1049–57.PubMedGoogle Scholar
  118. 118.
    Garcia Soriano F, Virag L, Jagtap P, Szabo E, Mabley JG, Liaudet L, et al. Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. Nat Med 2001;7:108–13. doi: 10.1038/83241.PubMedCrossRefGoogle Scholar
  119. 119.
    Apfel SC. Nerve growth factor for the treatment of diabetic neuropathy: what went wrong, what went right, and what does the future hold? Int Rev Neurobiol 2002;50:393–413. doi: 10.1016/S0074-7742(02)50083-0.PubMedCrossRefGoogle Scholar
  120. 120.
    Li F, Drel VR, Szabo C, Stevens MJ, Obrosova IG. Low-dose poly(ADP-ribose) polymerase inhibitor-containing combination therapies reverse early peripheral diabetic neuropathy. Diabetes 2005;54:1514–22. doi: 10.2337/diabetes.54.5.1514.PubMedCrossRefGoogle Scholar
  121. 121.
    Pacher P, Liaudet L, Soriano FG, Mabley JG, Szabo E, Szabo C. The role of poly(ADP-ribose) polymerase activation in the development of myocardial and endothelial dysfunction in diabetes. Diabetes 2002;51:514–21. doi: 10.2337/diabetes.51.2.514.PubMedCrossRefGoogle Scholar
  122. 122.
    Zheng L, Szabo C, Kern TS. Poly(ADP-ribose) polymerase is involved in the development of diabetic retinopathy via regulation of nuclear factor-kappaB. Diabetes 2004;53:2960–7. doi: 10.2337/diabetes.53.11.2960.PubMedCrossRefGoogle Scholar
  123. 123.
    Pacher P. Poly(ADP-ribose) polymerase inhibition as a novel therapeutic approach against intraepidermal nerve fiber loss and neuropathic pain associated with advanced diabetic neuropathy: a commentary on “PARP Inhibition or gene deficiency counteracts intraepidermal nerve fiber loss and neuropathic pain in advanced diabetic neuropathy”. Free Radic Biol Med 2008;44:969–71. doi: 10.1016/j.freeradbiomed.2007.12.020.PubMedCrossRefGoogle Scholar
  124. 124.
    Pacher P, Szabo C. Role of the peroxynitrite-poly(ADP-ribose) polymerase pathway in human disease. Am J Pathol 2008;173:2–13. doi: 10.2353/ajpath.2008.080019.PubMedCrossRefGoogle Scholar
  125. 125.
    Gonzalez-Clemente JM, Mauricio D, Richart C, Broch M, Caixas A, Megia A, et al. Diabetic neuropathy is associated with activation of the TNF-alpha system in subjects with type 1 diabetes mellitus. Horumon To Rinsho 2005;63:525–9.Google Scholar
  126. 126.
    Gomes MB, Piccirillo LJ, Nogueira VG, Matos HJ. Acute-phase proteins among patients with type 1 diabetes. Diabetes Metab 2003;29:405–11. doi: 10.1016/S1262-3636(07)70051-4.PubMedCrossRefGoogle Scholar
  127. 127.
    Gruden G, Bruno G, Chaturvedi N, Burt D, Schalkwijk C, Pinach S, et al. Serum heat shock protein 27 and diabetes complications in the EURODIAB prospective complications study: a novel circulating marker for diabetic neuropathy. Diabetes. 2008;57(7):1966–70, Jul.PubMedCrossRefGoogle Scholar
  128. 128.
    Lee KM, Kang BS, Lee HL, Son SJ, Hwang SH, Kim DS, et al. Spinal NF-kB activation induces COX-2 upregulation and contributes to inflammatory pain hypersensitivity. Eur J Neurosci 2004;19:3375–81. doi: 10.1111/j.0953-816X.2004.03441.x.PubMedCrossRefGoogle Scholar
  129. 129.
    Kellogg AP, Pop-Busui R. Peripheral nerve dysfunction in experimental diabetes is mediated by cyclooxygenase-2 and oxidative stress. Antioxidants & Redox Signaling 2005;7:1521–9.CrossRefGoogle Scholar
  130. 130.
    Matsunaga A, Kawamoto M, Shiraishi S, Yasuda T, Kajiyama S, Kurita S, et al. Intrathecally administered COX-2 but not COX-1 or COX-3 inhibitors attenuate streptozotocin-induced mechanical hyperalgesia in rats. Eur J Pharmacol 2007;554:12–7. doi: 10.1016/j.ejphar.2006.09.072.PubMedCrossRefGoogle Scholar
  131. 131.
    Hasnis E, Bar-Shai M, Burbea Z, Reznick AZ. Mechanisms underlying cigarette smoke-induced NF-kappaB activation in human lymphocytes: the role of reactive nitrogen species. J Physiol Pharmacol 2007;58 Suppl 5:275–87.PubMedGoogle Scholar
  132. 132.
    Kim YW, Zhao RJ, Park SJ, Lee JR, Cho IJ, Yang CH, Kim SG, Kim SC. Anti-inflammatory effects of liquiritigenin as a consequence of the inhibition of NF-kappaB-dependent iNOS and proinflammatory cytokines production. Br J Pharmacol. 2008;154(1):165–73, May.PubMedCrossRefGoogle Scholar
  133. 133.
    Levy D, Zochodne DW. NO pain: potential roles of nitric oxide in neuropathic pain. Pain Pract 2004;4:11–8. doi: 10.1111/j.1533-2500.2004.04002.x.PubMedCrossRefGoogle Scholar
  134. 134.
    Zochodne DW, Levy D. Nitric oxide in damage, disease and repair of the peripheral nervous system. Cell Mol Biol (Noisy-le-Grand, France) 2005;51:255–67.Google Scholar
  135. 135.
    McDonald DS, Cheng C, Martinez JA, Zochodne DW. Regenerative arrest of inflamed peripheral nerves: role of nitric oxide. Neuroreport 2007;18:1635–40.PubMedCrossRefGoogle Scholar
  136. 136.
    Wang Y, Schmeichel AM, Iida H, Schmelzer JD, Low PA. Enhanced inflammatory response via activation of NF-kappaB in acute experimental diabetic neuropathy subjected to ischemia–reperfusion injury. J Neurol Sci 2006;247:47–52. doi: 10.1016/j.jns.2006.03.011.PubMedCrossRefGoogle Scholar
  137. 137.
    Yamagishi S, Ogasawara S, Mizukami H, Yajima N, Wada R, Sugawara A, et al. Correction of protein kinase C activity and macrophage migration in peripheral nerve by pioglitazone, peroxisome proliferator activated-gamma-ligand, in insulin-deficient diabetic rats. J Neurochem 2008;104:491–9.PubMedGoogle Scholar
  138. 138.
    Kawamura N, Dyck PJ, Schmeichel AM, Engelstad JK, Low PA, Dyck PJ. Inflammatory mediators in diabetic and non-diabetic lumbosacral radiculoplexus neuropathy. Acta Neuropathol 2008;115:231–9. doi: 10.1007/s00401-007-0326-2.PubMedCrossRefGoogle Scholar
  139. 139.
    Tesch GH. Role of macrophages in complications of type 2 diabetes. Clin Exp Pharmacol Physiol 2007;34:1016–9. doi: 10.1111/j.1440-1681.2007.04729.x.PubMedCrossRefGoogle Scholar
  140. 140.
    Conti G, Scarpini E, Baron P, Livraghi S, Tiriticco M, Bianchi R, et al. Macrophage infiltration and death in the nerve during the early phases of experimental diabetic neuropathy: a process concomitant with endoneurial induction of IL-1beta and p75NTR. J Neurol Sci 2002;195:35–40. doi: 10.1016/S0022-510X(01)00684-0.PubMedCrossRefGoogle Scholar
  141. 141.
    Cameron NE, Cotter MA. Pro-inflammatory mechanisms in diabetic neuropathy: focus on the nuclear factor kappa B pathway. Curr Drug Targets 2008;9(1):60–7, Jan.PubMedCrossRefGoogle Scholar
  142. 142.
    Price SA, Zeef LA, Wardleworth L, Hayes A, Tomlinson DR. Identification of changes in gene expression in dorsal root ganglia in diabetic neuropathy: correlation with functional deficits. J Neuropathol Exp Neurol 2006;65:722–32. doi: 10.1097/01.jnen.0000228199.89420.90.PubMedCrossRefGoogle Scholar
  143. 143.
    Sullivan KA, Lentz SI, Roberts JL Jr, Feldman EL. Criteria for creating and assessing mouse models of diabetic neuropathy. Curr Drug Targets 2008;9:3–13. doi: 10.2174/138945008783431763.PubMedCrossRefGoogle Scholar
  144. 144.
    Cohen CD, Klingenhoff A, Boucherot A, Nitsche A, Henger A, Brunner B, et al. Comparative promoter analysis allows de novo identification of specialized cell junction-associated proteins. Proc Natl Acad Sci USA 2006;103:5682–7. doi: 10.1073/pnas.0511257103.PubMedCrossRefGoogle Scholar
  145. 145.
    Schmid H, Cohen CD, Henger A, Irrgang S, Schlondorff D, Kretzler M. Validation of endogenous controls for gene expression analysis in microdissected human renal biopsies. Kidney Int 2003;64:356–60. doi: 10.1046/j.1523-1755.2003.00074.x.PubMedCrossRefGoogle Scholar
  146. 146.
    Schmid H, Henger A, Cohen CD, Frach K, Grone HJ, Schlondorff D, et al. Gene expression profiles of podocyte-associated molecules as diagnostic markers in acquired proteinuric diseases. J Am Soc Nephrol 2003;14:2958–66. doi: 10.1097/01.ASN.0000090745.85482.06.PubMedCrossRefGoogle Scholar
  147. 147.
    Schmid H, Henger A, Kretzler M. Molecular approaches to chronic kidney disease. Curr Opin Nephrol Hypertens 2006;15:123–9. doi: 10.1097/01.mnh.0000214770.11609.fb.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Claudia Figueroa-Romero
    • 1
  • Mahdieh Sadidi
    • 1
  • Eva L. Feldman
    • 1
  1. 1.Department of NeurologyUniversity of MichiganAnn ArborUSA

Personalised recommendations