Treatments in Endocrinology

, Volume 2, Issue 6, pp 389–400 | Cite as

Current and Future Strategies for the Management of Diabetic Neuropathy

  • Rayaz A. Malik
Review Article


Diabetic neuropathy is common, related to increased morbidity and mortality, and has no effective treatment at present. Interventions based on putative pathways thought to contribute to damage and repair of nerve fibres have yielded little success to date. Pain is a potentially debilitating manifestation of diabetic neuropathy and has many potential sites of origin and, hence, modulation. Its cause is unclear and it does not respond well to traditional pain therapies, proposed to mediate their benefits via multiple peripheral and central mechanisms. A better understanding of the mechanisms leading to nerve fibre degeneration and regeneration as well as pain has recently resulted in the development of a more targeted approach to the treatment of diabetic neuropathy. Thus, specific NMDA receptor antagonists and more specific neuronal serotonin and norepinephrine (noradrenaline) uptake inhibitors offer promise in the treatment of painful diabetic neuropathy. A number of treatments which include the aldose reductase inhibitors and neurotrophins have failed to reach the clinical arena. However, the antioxidant alpha-lipoic acid, as well as compounds which correct vascular dysfunction and hence neuropathy, such as ACE inhibitors and protein kinase C-β inhibitors, have demonstrated more success.


Capsaicin Gabapentin Imipramine Amitriptyline Diabetic Neuropathy 
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  1. 1.
    Diabetes Control and Complications Trial (DCCT) Research Group. The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med 1995; 122: 561–8Google Scholar
  2. 2.
    Backonja MM. Use of anticonvulsants for treatment of neuropathic pain. Neurology 2002; 10 Suppl. 2: S14–7CrossRefGoogle Scholar
  3. 3.
    Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999; 353: 1959–64PubMedCrossRefGoogle Scholar
  4. 4.
    Farber NB, Jiang XP, Heinkel C, et al. Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity. Mol Psychiatry 2002; 7: 726–33PubMedCrossRefGoogle Scholar
  5. 5.
    Coderre TJ, Melzack R. The contribution of excitatory amino acids to central sensitization and persistent nociception after formalin-induced tissue injury. J Neurosci 1992; 12: 3665–70PubMedGoogle Scholar
  6. 6.
    Sotah M, Foong FW. A mechanism of carbamazepine analgesia as shown by bradykinin-induced trigeminal pain. Brain Res Bull 1983; 10: 407–9CrossRefGoogle Scholar
  7. 7.
    Calcutt NA. Potential mechanisms of neuropathic pain in diabetes. Int Rev Neurobiol 2002; 50: 205–28PubMedCrossRefGoogle Scholar
  8. 8.
    Collins SL, Moore RA, McQuay HJ, et al. Antidepressants and anticonvulsants for diabetic neuropathy and post herpetic neuralgia: a quantitative systematic review. J Pain Symptom Manage 2000; 20: 449–58PubMedCrossRefGoogle Scholar
  9. 9.
    Wilton T. Tegretol in the treatment of diabetic neuropathy. S Afr Med J 1974; 27: 869–72Google Scholar
  10. 10.
    Rull JA, Quibrera R, Gonzalez-Millan H, et al. Symptomatic treatment of peripheral diabetic neuropathy with carbamazepine: double-blind crossover study. Diabetologia 1969; 5: 215–20PubMedCrossRefGoogle Scholar
  11. 11.
    Gomez-Perez FJ, Choza R, Rios JM, et al. Nortriptyline-fluphenazine vs. carbamazepine in the symptomatic treatment of diabetic neuropathy. Arch Med Res 1996; 27: 525–9PubMedGoogle Scholar
  12. 12.
    Kochar DK, Jain N, Agarwal RP, et al. Sodium valproate in the management of painful neuropathy in type 2 diabetes: a randomized placebo controlled study. Acta Neurol Scand 2002; 106: 248–52PubMedCrossRefGoogle Scholar
  13. 13.
    Saudek CD, Werns S, Reidenberg MM. Phenytoin in the treatment of diabetic symmetrical neuropathy. Clin Pharmacol Ther 1977; 22: 196–9PubMedGoogle Scholar
  14. 14.
    Chadda VS, Mathur M. Double-blind study of the effects of diphenylhydantoin sodium on diabetic neuropathy. J Assoc Physicians India 1978; 26: 403–6PubMedGoogle Scholar
  15. 15.
    Taylor CP, Gee NS, Su TZ, et al. A summary of mechanistic hypotheses of gabapentin pharmacology. Epilepsy Res 1998; 29: 233–49PubMedCrossRefGoogle Scholar
  16. 16.
    Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 1998; 280: 1831–6PubMedCrossRefGoogle Scholar
  17. 17.
    Morello CM, Leckband SG, Stoner CP, et al. Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy. Arch Intern Med 1999; 159: 1931–7PubMedCrossRefGoogle Scholar
  18. 18.
    Iacobellis D, Allen R, Lamoreaux L, et al. A double-blind, placebo-controlled trial of pregabalin for the treatment of painful diabetic peripheral neuropathy [abstract]. Neurology 2000; 54Suppl. 3: A177Google Scholar
  19. 19.
    Hemstreet B, Lapointe M. Evidence for the use of gabapentin in the treatment of diabetic peripheral neuropathy. Clin Ther 2001; 23: 520–31PubMedCrossRefGoogle Scholar
  20. 20.
    Eisenberg E, Alon N, Ishay A, et al. Lamotrigine in the treatment of painful diabetic neuropathy. Eur J Neurol 1998; 5: 167–73PubMedCrossRefGoogle Scholar
  21. 21.
    Eisenberg E, Lurie Y, Braker C, et al. Lamotrigine reduces painful diabetic neuropathy: a randomized, controlled study. Neurology 2001; 57: 505–9PubMedCrossRefGoogle Scholar
  22. 22.
    Joss JD. Tricyclic antidepressant use in diabetic neuropathy. Ann Pharmacother 1999; 33: 996–1000PubMedCrossRefGoogle Scholar
  23. 23.
    Ulugol A, Karadag HC, Tamer M, et al. Involvement of adenosine in the anti-allodynic effect of amitriptyline in streptozotocin-induced diabetic rats. Neurosci Lett 2002; 328: 129–32PubMedCrossRefGoogle Scholar
  24. 24.
    Mendel CM, Klein RF, Chappell DA, et al. A trial of amitriptyline and fluphenazine in the treatment of painful diabetic neuropathy. JAMA 1986; 255: 637–9PubMedCrossRefGoogle Scholar
  25. 25.
    Max MB, Culnane M, Schafer SC, et al. Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology 1987; 37: 589–96PubMedCrossRefGoogle Scholar
  26. 26.
    Max MB, Lynch SA, Muir J, et al. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 1992; 326: 1250–6PubMedCrossRefGoogle Scholar
  27. 27.
    Vrethem M, Boivie J, Arnqvist H, et al. A comparison of amitriptyline and maprotiline in the treatment of painful polyneuropathy in diabetics and nondiabetics. Clin J Pain 1997; 13: 313–23PubMedCrossRefGoogle Scholar
  28. 28.
    Dallocchio C, Buffa C, Mazzarello P, et al. Gabapentin vs. amitriptyline in painful diabetic neuropathy: an open-label pilot study. J Pain Symptom Manage 2000; 20: 280–5PubMedCrossRefGoogle Scholar
  29. 29.
    Kumar D, Alvaro MS, Julka IS, et al. Diabetic peripheral neuropathy. Effectiveness of electrotherapy and amitriptyline for symptomatic relief. Diabetes Care 1998; 21: 1322–5PubMedCrossRefGoogle Scholar
  30. 30.
    Max MB, Kishore-Kumar R, Schafer SC, et al. Efficacy of desipramine in painful diabetic neuropathy: a placebo-controlled trial. Pain 1991; 45: 3–9PubMedCrossRefGoogle Scholar
  31. 31.
    Sindrup SH, Gram LF, Skjold T, et al. Clomipramine vs desipramine vs placebo in the treatment of diabetic neuropathy symptoms: a double-blind cross-over study. Br J Clin Pharmacol 1990; 30: 683–91PubMedCrossRefGoogle Scholar
  32. 32.
    Kvinesdal B, Molin J, Froland A, et al. Imipramine treatment of painful diabetic neuropathy. JAMA 1984; 251: 1727–30PubMedCrossRefGoogle Scholar
  33. 33.
    Young RJ, Clarke BF. Pain relief in diabetic neuropathy: the effectiveness of imipramine and related drugs. Diabet Med 1985; 2: 363–6PubMedCrossRefGoogle Scholar
  34. 34.
    Sindrup SH, Ejlertsen B, Froland A, et al. Imipramine treatment in diabetic neuropathy: relief of subjective symptoms without changes in peripheral and autonomic nerve function. Eur J Clin Pharmacol 1989; 37: 151–3PubMedCrossRefGoogle Scholar
  35. 35.
    Pfeifer MA, Ross DR, Schrage JP, et al. A highly successful and novel model for treatment of chronic painful diabetic peripheral neuropathy. Diabetes Care 1993; 16: 1103–15PubMedCrossRefGoogle Scholar
  36. 36.
    Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 1999; 83: 389–400PubMedCrossRefGoogle Scholar
  37. 37.
    Sindrup SH, Bjerre U, Dejgaard A, et al. The selective serotonin reuptake inhibitor citalopram relieves the symptoms of diabetic neuropathy. Clin Pharmacol Ther 1992; 52: 547–52PubMedCrossRefGoogle Scholar
  38. 38.
    Sindrup SH, Gram LF, Brosen K, et al. The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain 1990; 42: 135–44PubMedCrossRefGoogle Scholar
  39. 39.
    Goodnick PJ, Jimenez I, Kumar A. Sertraline in diabetic neuropathy: preliminary results. Ann Clin Psychiatry 1997; 9: 255–7PubMedGoogle Scholar
  40. 40.
    Goodnick PJ, Mendosa L, Kumar A, et al. Sertraline in diabetic neuropathy: response and biology. Psychosom Med 2000; 62: 461–2PubMedGoogle Scholar
  41. 41.
    Davis JL, Smith RL. Painful peripheral diabetic neuropathy treated with venlafaxine HC1 extended release capsules. Diabetes Care 1999; 22: 1909–10PubMedCrossRefGoogle Scholar
  42. 42.
    Lithner F. Venlafaxine in treatment of severe painful peripheral diabetic neuropathy. Diabetes Care 2000; 23: 1710–1PubMedCrossRefGoogle Scholar
  43. 43.
    Horiuchi J, Sato Y. Effect of mexiletine on spontaneous sensory afferent activity in spontaneous diabetic rats (WBN/Kob rats). Nippon Yakurigaku Zasshi 2000; 115: 353–9PubMedCrossRefGoogle Scholar
  44. 44.
    Oskarsson P, Ljunggren JG, Lins PE. Efficacy and safety of mexiletine in the treatment of painful diabetic neuropathy: The Mexiletine Study Group. Diabetes Care 1997; 20: 1594–7PubMedCrossRefGoogle Scholar
  45. 45.
    Stracke H, Meyer UE, Schumacher HE, et al. Mexiletine in the treatment of diabetic neuropathy. Diabetes Care 1992; 15: 1550–5PubMedCrossRefGoogle Scholar
  46. 46.
    Sang CN, Booher S, Gilron I, et al. Dextromethorphan and memantine in painful diabetic neuropathy and post herpetic neuralgia: efficacy and dose-response trials. Anesthesiology 2002; 96: 1053–61PubMedCrossRefGoogle Scholar
  47. 47.
    Harati Y, Gooch C, Swenson M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology 1998; 50: 1842–6PubMedCrossRefGoogle Scholar
  48. 48.
    Harati Y, Gooch C, Swenson M, et al. Maintenance of the long-term effectiveness of tramadol in treatment of the pain of diabetic neuropathy. J Diabetes Complications 2000; 14: 65–70PubMedCrossRefGoogle Scholar
  49. 49.
    Robbins W. Clinical applications of capsaicinoids. Clin J Pain 2000; 16: S86–9PubMedCrossRefGoogle Scholar
  50. 50.
    Sancho R, Lucena C, Macho A, et al. Immunosuppressive activity of capsaicinoids: capsiate derived from sweet peppers inhibits NF-kappaB activation and is a potent anti-inflammatory compound in vivo. Eur J Immunol 2002; 32: 1753–63PubMedCrossRefGoogle Scholar
  51. 51.
    The Capsaicin Study Group. Treatment of painful diabetic neuropathy with topical capsaicin: a multicentre, double-blind, vehicle-controlled study. Arch Intern Med 1991; 151: 2225–9CrossRefGoogle Scholar
  52. 52.
    Capsaicin Study Group. Effect of treatment with capsaicin on daily activities of patients with painful diabetic neuropathy. Diabetes Care 1992; 15: 159–65CrossRefGoogle Scholar
  53. 53.
    Hughes A, Macleod A, Growcott J, et al. Assessment of the reproducibility of intradermal administration of capsaicin as a model for inducing human pain. Pain 2002; 99: 323–31PubMedCrossRefGoogle Scholar
  54. 54.
    Kaada B, Eielsen O. In search of mediators of skin vasodilatation induced by transcutaneous nerve stimulation: II. Serotonin implicated. Gen Pharmacol 1983; 14: 635–41PubMedCrossRefGoogle Scholar
  55. 55.
    Alvaro M, Kumar D, Julka IS. Transcutaneous electro stimulation: emerging treatment for diabetic neuropathic pain. Diabetes Technol Ther 1999; 1: 77–80PubMedCrossRefGoogle Scholar
  56. 56.
    Hamza MA, White PF, Craig WF, et al. Percutaneous electrical nerve stimulation: a novel analgesic therapy for diabetic neuropathic pain. Diabetes Care 2000; 23: 365–70PubMedCrossRefGoogle Scholar
  57. 57.
    Goodnick PJ, Breakstone K, Wen XL, et al. Acupuncture and neuropathy. Am J Psychiatry 2000; 157: 1342–3PubMedCrossRefGoogle Scholar
  58. 58.
    Ceccherelli F, Gagliardi G, Ruzzante L, et al. Acupuncture modulation of capsaicin-induced inflammation: effect of intraperitoneal and local administration of naloxone in rats: a blinded controlled study. J Altern Complement Med 2002; 8: 341–9PubMedCrossRefGoogle Scholar
  59. 59.
    Abuaisha BB, Costanzi JB, Boulton AJ. Acupuncture for the treatment of chronic painful peripheral diabetic neuropathy: a long-term study. Diabetes Res Clin Pract 1998; 39: 115–21PubMedCrossRefGoogle Scholar
  60. 60.
    Foster AV, Eaton C, McConville DO, et al. Application of OpSite film: a new and effective treatment of painful diabetic neuropathy. Diabet Med 1994; 11: 768–72PubMedCrossRefGoogle Scholar
  61. 61.
    Yuen KC, Baker NR, Rayman G. Treatment of chronic painful diabetic neuropathy with isosorbide dinitrate spray: a double-blind placebo-controlled cross-over study. Diabetes Care 2002; 25: 1699–703PubMedCrossRefGoogle Scholar
  62. 62.
    Eaton SE, Harris ND, Rajbhandari SM, et al. Spinal-cord involvement in diabetic peripheral neuropathy. Lancet 2001; 358: 35–6PubMedCrossRefGoogle Scholar
  63. 63.
    Freshwater JD, Svensson CI, Malmberg AB, et al. Elevated spinal cyclooxygenase and prostaglandin release during hyperalgesia in diabetic rats. Diabetes 2002; 51: 2249–55PubMedCrossRefGoogle Scholar
  64. 64.
    Tesfaye S, Watt J, Benbow SJ, et al. Electrical spinal-cord stimulation for painful diabetic peripheral neuropathy. Lancet 1996; 348: 1698–701PubMedCrossRefGoogle Scholar
  65. 65.
    Boulton AJM, Malik RA. Diabetic neuropathy. Med Clin N Amer 1998; 82: 909–29PubMedCrossRefGoogle Scholar
  66. 66.
    Nishikawa T, Edelstein D, Du XL, et al. Normalizing mitochondrial Superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000; 404: 787–90PubMedCrossRefGoogle Scholar
  67. 67.
    UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS33). Lancet 1998; 352(9131): 837–53CrossRefGoogle Scholar
  68. 68.
    Oyibo SO, Prasad YD, Jackson NJ, et al. The relationship between blood glucose excursions and painful diabetic peripheral neuropathy: a pilot study. Diabet Med 2002; 19: 870–3PubMedCrossRefGoogle Scholar
  69. 69.
    Airey M, Bennett C, Nicolucci A, Williams R. Aldose reductase inhibitors for the prevention and treatment of diabetic peripheral neuropathy. The Cochrane Database of Systematic Reviews. Available in The Cochrane Library [database on disk and CD ROM]. Updated quarterly. The Cochrane Collaboration; issue 2. Oxford: Update Software, 2000: CD002182Google Scholar
  70. 70.
    Greene DA, Arezzo JC, Brown MB. Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy: Zenarestat Study Group. Neurology 1999; 53: 580–91PubMedCrossRefGoogle Scholar
  71. 71.
    Hotta N, Toyota T, Matsuoka K, et al. Clinical efficacy of fidarestat, a novel aldose reductase inhibitor, for diabetic peripheral neuropathy: a 52-week multicentre placebo-controlled double-blind parallel group study. Diabetes Care 2001; 24: 1776–82PubMedCrossRefGoogle Scholar
  72. 72.
    Curzen NC, Timmis A. Endothelial dysfunction in chronic heart failure. In: Coats A, Cleland JGF, editors. Controversies in the management of heart failure. New York: Churchill Livingstone, 1997: 25–40Google Scholar
  73. 73.
    Vanhoutte PM, Feletou M, Boulanger CM, Hoffner U, Rubanyi GM. Existence of multiple endothelium-derived relaxing factors. In: Vanhoutte PM, editor. Endothelium-derived hyperpolarizing factor. Amsterdam: Harwood Academic Publishers, 1996: 1–10Google Scholar
  74. 74.
    Reja A, Tesfaye S, Harris N, et al. Is ACE inhibition with lisinopril helpful in diabetic neuropathy? Diabetic Med 1995; 12: 307–9PubMedCrossRefGoogle Scholar
  75. 75.
    Al-Memar A, Wimalaratna HSK, Millward BA. Lisinopril improves nerve function in insulin-dependent diabetic patients with neuropathy: a preferential effect on small fibres [abstract]. Diabetic Med 1996; S38: P90Google Scholar
  76. 76.
    Malik RA, Williamson S, Abbott CA, et al. Effect of angiotensin-converting enzyme (ACE) inhibitor trandolapril on human diabetic neuropathy: randomised double-blind controlled trial. Lancet 1998; 352: 1978–81PubMedCrossRefGoogle Scholar
  77. 77.
    Estacio RO, Jeffers BW, Gifford N, et al. Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care 2000; 23Suppl. 2: B54–64PubMedGoogle Scholar
  78. 78.
    Apfel SC. Neurotrophic factors in peripheral neuropathies: therapeutic implications. Brain Pathol 1999; 9: 393–413PubMedCrossRefGoogle Scholar
  79. 79.
    Tomlinson DR, Fernyhough P, Diemel LT. Neurotrophins and peripheral neuropathy. Philos Trans R Soc Lond B Biol sci 1996; 351: 455–62PubMedCrossRefGoogle Scholar
  80. 80.
    Anand P, Terenghi G, Warner G, et al. The role of endogenous nerve growth factor in human diabetic neuropathy. Nat Med 1996; 2: 703–7PubMedCrossRefGoogle Scholar
  81. 81.
    Diemel LT, Cai F, Anand P, et al. Increased nerve growth factor mRNA in lateral calf skin biopsies from diabetic patients. Diabet Med 1999; 16: 113–8PubMedCrossRefGoogle Scholar
  82. 82.
    Kennedy AJ, Wellmer A, Facer P, et al. Neurotrophin-3 is increased in skin in human diabetic neuropathy. J Neurol Neurosurg Psychiatry 1998; 65: 393–5PubMedCrossRefGoogle Scholar
  83. 83.
    Lee DA, Gross L, Wittrock DA, et al. Localization and expression of ciliary neurotrophic factor (CNTF) in postmortem sciatic nerve from patients with motor neuron disease and diabetic neuropathy. J Neuropathol Exp Neurol 1996; 55: 915–23PubMedGoogle Scholar
  84. 84.
    Terenghi G, Mann D, Kopelman PG, et al. trkA and trkC expression is increased in human diabetic skin. Neurosci Lett 1997; 228: 33–6PubMedCrossRefGoogle Scholar
  85. 85.
    Apfel SC, Kessler JA, Adornato BT, et al. Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy: NGF Study Group. Neurology 1998; 51: 695–702PubMedCrossRefGoogle Scholar
  86. 86.
    Apfel SC, Schwartz S, Adornato BT, et al. Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: a randomized controlled trial. JAMA 2000; 284: 2215–21PubMedCrossRefGoogle Scholar
  87. 87.
    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: 393–413PubMedCrossRefGoogle Scholar
  88. 88.
    Wellmer A, Misra VP, Sharief MK, et al. A double-blind placebo-controlled clinical trial of recombinant human brain-derived neurotrophic factor (rhBDNF) in diabetic polyneuropathy. J Peripher Nerv Syst 2001; 6: 204–10PubMedCrossRefGoogle Scholar
  89. 89.
    Packer L, Kraemer K, Rimbach G. Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition 2001; 17: 888–95PubMedCrossRefGoogle Scholar
  90. 90.
    Coppey LJ, Gellett JS, Davidson EP, et al. Effect of antioxidant treatment of streptozotocin-induced diabetic rats on endoneurial blood flow, motor nerve conduction velocity, and vascular reactivity of epineurial arterioles of the sciatic nerve. Diabetes 2001; 50: 1927–37PubMedCrossRefGoogle Scholar
  91. 91.
    Heitzer T, Finckh B, Albers S, et al. Beneficial effects of alpha-lipoic acid and ascorbic acid on endothelium-dependent, nitric oxide-mediated vasodilatation in diabetic patients: relation to parameters of oxidative stress. Free Radie Biol Med 2001; 31: 53–61CrossRefGoogle Scholar
  92. 92.
    Haak E, Usadel KH, Kusterer K, et al. Effects of alpha-lipoic acid on microcirculation in patients with peripheral diabetic neuropathy. Exp Clin Endocrinol Diabetes 2000; 108: 168–74PubMedCrossRefGoogle Scholar
  93. 93.
    Klein W. Treatment of diabetic neuropathy with oral alpha-lipoic acid. MMW Munch Med Wochenschr 1975; 117: 957–8PubMedGoogle Scholar
  94. 94.
    Sachse G, Willms B. Efficacy of thioctic acid in the therapy of peripheral diabetic neuropathy. Horm Metab Res Suppl 1980; 9: 105–7PubMedGoogle Scholar
  95. 95.
    Studt J, Heuer LJ. Diabetic autonomie neuropathy of the heart and its treatment with thioctic acid. Dtsch Z Verdau Stoffwechselkr 1984; 44: 173–80PubMedGoogle Scholar
  96. 96.
    Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid: a 3-week multi-centre randomized controlled trial (ALADIN Study). Alpha Lipoic Acid in Diabetic Neuropathy. Diabetologia 1995; 38: 1425–33PubMedCrossRefGoogle Scholar
  97. 97.
    Ruhnau KJ, Meissner HP, Finn JR, et al. Effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic polyneuropathy. Diabet Med 1999; 16: 1040–3PubMedCrossRefGoogle Scholar
  98. 98.
    Reljanovic M, Reichel G, Rett K, et al. Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): a two year multicentre randomized double-blind placebo-controlled trial (ALADIN II). Free Radic Res 1999; 31: 171–9PubMedCrossRefGoogle Scholar
  99. 99.
    Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicentre randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Diabetes Care 1999; 22: 1296–301PubMedCrossRefGoogle Scholar
  100. 100.
    Ziegler D, Schatz H, Conrad F, et al. Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomie neuropathy in NIDDM patients: a 4-month randomized controlled multicentre trial (DEKAN Study). Diabetes Care 1997; 20: 369–73PubMedCrossRefGoogle Scholar
  101. 101.
    Eichberg J. Protein kinase C changes in diabetes: is the concept relevant to neuropathy? Int Rev Neurobiol 2002; 50: 61–82PubMedCrossRefGoogle Scholar
  102. 102.
    Aiello LP, Bursell SE, Clermont A, et al. Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor. Diabetes 1997; 46: 1473–80PubMedCrossRefGoogle Scholar
  103. 103.
    Cameron NE, Cotter MA. Effects of protein kinase C beta inhibition on neurovascular dysfunction in diabetic rats: interaction with oxidative stress and essential fatty acid dysmetabolism. Diabetes Metab Res Rev 2002; 18: 315–23PubMedCrossRefGoogle Scholar
  104. 104.
    Litchy W, Dyck PJ, Tesfaye S, et al. Diabetic peripheral neuropathy (DPN) assessed by neurological examination (NE) and composite scores (CS) is improved with LY333531 treatment [abstract]. Diabetes 2002; 45Suppl. 2: 197Google Scholar
  105. 105.
    Duh E, Aiello LP. Vascular endothelial growth factor and diabetes: the agonist versus antagonist paradox. Diabetes 1999; 48: 1899–906PubMedCrossRefGoogle Scholar
  106. 106.
    Samii A, Unger J, Lange W. Vascular endothelial growth factor expression in peripheral nerves and dorsal root ganglia in diabetic neuropathy in rats. Neurosci Lett 1999; 262: 159–62PubMedCrossRefGoogle Scholar
  107. 107.
    Schratzberger P, Walter DH, Rittig K, et al. Reversal of experimental diabetic neuropathy by VEGF gene transfer. J Clin Invest 2001; 107: 1083–92PubMedCrossRefGoogle Scholar
  108. 108.
    Sondell M, Lundborg G, Kanje M. Vascular endothelial growth factor stimulates Schwann cell invasion and neovascularization of acellular nerve grafts. Brain Res 1999; 846: 219–28PubMedCrossRefGoogle Scholar
  109. 109.
    Sondell M, Sundler F, Kanje M. Vascular endothelial growth factor is a neurotrophic factor which stimulates axonal outgrowth through the flk-1 receptor. Eur J Neurosci 2000; 12: 4243–54PubMedCrossRefGoogle Scholar
  110. 110.
    Funatsu H, Yamashita H, Ikeda T, et al. Angiotensin II and vascular endothelial growth factor in the vitreous fluid of patients with diabetic macular oedema and other retinal disorders. Am J Ophthalmol 2002; 133: 537–43PubMedCrossRefGoogle Scholar
  111. 111.
    Hogeboom van Buggenum IM, Polak BC, Reichert-Thoen JW, et al. Angiotensin converting enzyme inhibiting therapy is associated with lower vitreous vascular endothelial growth factor concentrations in patients with proliferative diabetic retinopathy. Diabetologia 2002; 45: 203–9CrossRefGoogle Scholar
  112. 112.
    Chaturvedi N, Fuller JH, Pokras F, et al. Circulating plasma vascular endothelial growth factor and microvascular complications of type 1 diabetes mellitus: the influence of ACE inhibition. The EUCLID Study Group. Diabet Med 2001; 18: 288–94PubMedCrossRefGoogle Scholar
  113. 113.
    Okamoto T, Yamagishi SI, Inagaki Y, et al. Angiogenesis induced by advanced glycation end products and its prevention by cerivastatin. FASEB J 2002; 16: 1928–30PubMedGoogle Scholar
  114. 114.
    Fried LF, Forrest KY, Ellis D, et al. Lipid modulation in insulin-dependent diabetes mellitus: effect on microvascular outcomes. J Diabetes Complications 2001; 15: 113–9PubMedCrossRefGoogle Scholar

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© Adis Data Information BV 2003

Authors and Affiliations

  1. 1.Department of MedicineManchester Royal InfirmaryManchesterUK

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