Skip to main content

Pathogenesis of Human Diabetic Neuropathy

  • Chapter
Diabetic Neuropathy

Part of the book series: Clinical Diabetes ((CLD))

Abstract

Experimental studies have provided multiple mechanisms for the development of diabetic neuropathy, yet very few findings have been replicated in patients. Hyperglycemia mediated nerve damage may begin very early even prior to overt diabetes as evidenced by several recent studies in patients with impaired glucose tolerance. Polyol pathway abnormalities have been exhaustively explored in animals, but studies in man are limited and inconsistent and hence not surprisingly, clinical trials with aldose reductase inhibitors have consistently failed. Glycation is widespread and may induce a range of structural and functional changes and glycation inhibitors are being actively developed. Both large and small vessel disease have been implicated in diabetic neuropathy and treatment with ACE inhibitors has shown some benefit. Growth factors may be important in maintaining both the vascular and neuronal phenotype. Thus a range of neurotrophic and vascular growth factors have entered phase III clinical trials for human diabetic neuropathy recently.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 229.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 299.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Reference

  1. Nishikawa T, Edelstein D, Du XL, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycemic damage. Nature 2000;404:787–790.

    Article  PubMed  CAS  Google Scholar 

  2. Smith AG, Ramachandran P, Tripp S, Singleton JR. Epidermal nerve innervation in impaired glucose tolerance and diabetes-associated neuropathy. Neurology 2001;13:1701–1704.

    Google Scholar 

  3. Sumner CJ, Sheth S, Griffin JW, Cornblath DR, Polydefkis M. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 2003;60:108–111.

    PubMed  CAS  Google Scholar 

  4. Sundkvist G, Dahlin LB, Nilsson H, et al. Sorbitol and myo-inositol levels and morphology of sural nerve in relation to peripheral nerve function and clinical neuropathy in men with diabetic, impaired, and normal glucose tolerance. Diabetic Med 2000; 17:259–268.

    Article  PubMed  CAS  Google Scholar 

  5. Cappellari A, Airaghi L, Capra R, et al. Early peripheral nerve abnormalities in impaired glucose tolerance. Electromyogr Clin Neurophysiol 2005;45:241–244.

    PubMed  CAS  Google Scholar 

  6. Haslbeck KM, Schleicher E, Bierhaus A, et al. The AGE/RAGE/NF-(kappa) B pathway may contribute to the pathogenesis of polyneuropathy in impaired glucose tolerance (IGT). Exp Clin Endocrinol Diabetes 2005;113:288–291.

    Article  PubMed  CAS  Google Scholar 

  7. Dyck PJ, Kratz KM, Karnes JZ, et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology 1993;43:817–824.

    PubMed  CAS  Google Scholar 

  8. DCCT Trial Research Group. The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Int Med 1995; 122:561–568.

    Google Scholar 

  9. Navarro X, Sutherland DE, Kennedy WR. Long-term effects of pancreatic transplantation on diabetic neuropathy. Ann Neurol 1997;42:727–736.

    Article  PubMed  CAS  Google Scholar 

  10. Lee TC, Barshes NR, O’Mahony CA, et al. The effect of pancreatic islet transplantation on progression of diabetic retinopathy and neuropathy. Transplant Proc 2005;37:2263–2265.

    Article  PubMed  CAS  Google Scholar 

  11. UKPDS. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with Type 2 diabetes. Lancet 1998;352:837–853.

    Article  Google Scholar 

  12. Azad N, Emanuele NV, Abraira C, et al. The effects of intensive glycemic control on neuropathy in the VA cooperative study on type II diabetes mellitus (VA CSDM). J Diabetes Complications 1999;13:307–313.

    Article  PubMed  CAS  Google Scholar 

  13. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003; 348:383–393.

    Article  PubMed  Google Scholar 

  14. Oates PJ. Polyol pathway and diabetic peripheral neuropathy. Int Rev Neurobiol 2002;50:325–392.

    PubMed  CAS  Google Scholar 

  15. Chung SS, Chung SK. Aldose reductase in diabetic microvascular complications. Curr Drug Targets 2005;6:475–486.

    Article  PubMed  CAS  Google Scholar 

  16. Dyck PJ, Sherman WR, Hallcher LM, et al. Human diabetic endoneurial sorbitol, fructose, and myo-inositol related to sural nerve morphometry. Ann Neurol 1980;8:590–596.

    Article  PubMed  CAS  Google Scholar 

  17. Mayhew JA, Gillon KR, Hawthorne JN. Free and lipid inositol, sorbitol and sugars in sciatic nerve obtained post-mortem from diabetic patients and control subjects. Diabetologia 1983;24:13–15.

    Article  PubMed  CAS  Google Scholar 

  18. Hale PJ, Nattrass M, Silverman SH, et al. Peripheral nerve concentrations of glucose, fructose, sorbitol and myoinositol in diabetic and non-diabetic patients. Diabetologia 1987;30:464–467.

    Article  PubMed  CAS  Google Scholar 

  19. Dyck PJ, Zimmerman BR, Vilen TH, et al. Nerve glucose, fructose, sorbitol, myo-inositol, and fiber degeneration and regeneration in diabetic neuropathy. N Engl J Med 1988;319:542–548.

    Article  PubMed  CAS  Google Scholar 

  20. Sivenius K, Pihlajamaki J, Partanen J, Niskanen L, Laakso M, Uusitupa M. Aldose reductase gene polymorphisms and peripheral nerve function in patients with type 2 diabetes. Diabetes Care 2004;27:2021–2026.

    Article  PubMed  CAS  Google Scholar 

  21. Kasajima H, Yamagishi S, Sugai S, Yagihashi N, Yagihashi S. Enhanced in situ expression of aldose reductase in peripheral nerve and renal glomeruli in diabetic patients. Virchows Arch 2001;439:46–54.

    Article  PubMed  CAS  Google Scholar 

  22. Shimizu H, Ohtani KI, Tsuchiya T, et al. Aldose reductase mRNA expression is associated with rapid development of diabetic microangiopathy in Japanese Type 2 diabetic (T2DM) patients. Diabetes Nutr Metab 2000; 13:75–79.

    PubMed  CAS  Google Scholar 

  23. Airey M, Bennett C, Nicolucci A, Williams R. Aldose reductase inhibitors for the prevention and treatment of diabetic peripheral neuropathy. Cochrane Database Syst Rev 2000;(2): CD002182.

    Google Scholar 

  24. Sima AA, Bril V, Nathaniel V, et al. Regeneration and repair of myelinated fibers in suralnerve biopsy specimens from patients with diabetic neuropathy treated with sorbinil. N Engl J Med 1988;319:548–555.

    Article  PubMed  CAS  Google Scholar 

  25. Greene DA, Arezzo JC, Brown MB. Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Zenarestat Study Group. Neurology 1999;53:580–591.

    PubMed  CAS  Google Scholar 

  26. Hotta N, Toyota T, Matsuoka K, et al. The SNK-860 Diabetic Neuropathy Study Group. 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;24:1776–1782.

    Article  PubMed  CAS  Google Scholar 

  27. Kinekawa F, Kubo F, Matsuda K, et al. Effect of an aldose reductase inhibitor on esophageal dysfunction in diabetic patients. Hepatogastroenterology 2005;52:471–474.

    PubMed  CAS  Google Scholar 

  28. Okamoto H, Nomura M, Nakaya Y, et al. Effects of epalrestat, an aldose reductase inhibitor, on diabetic neuropathy and gastroparesis. Intern Med 2003;42:655–664.

    Article  PubMed  CAS  Google Scholar 

  29. Johnson BF, Nesto RW, Pfeifer MA, et al. Cardiac abnormalities in diabetic patients with neuropathy: effects of aldose reductase inhibitor administration. Diabetes Care 2004;27: 448–454.

    Article  PubMed  CAS  Google Scholar 

  30. Wada R, Yagihashi S. Role of advanced glycation end products and their receptors in development of diabetic neuropathy. Ann NY Acad Sci 2005; 1043:598–604.

    Article  PubMed  CAS  Google Scholar 

  31. McLennan SV, Martell SK, Yue DK. Effects of mesangium glycation on matrix metalloproteinase activities: possible role in diabetic nephropathy. Diabetes 2002;51:2612–2618.

    Article  PubMed  CAS  Google Scholar 

  32. Portero-Otin M, Pamplona R, Bellmunt MJ, et al. Advanced glycation end product precursors impair epidermal growth factor receptor signaling. Diabetes 2002;51:1535–1542.

    Article  PubMed  CAS  Google Scholar 

  33. Sugimoto K, Nishizawa Y, Horiuchi S, Yagihashi S. Localization in human diabetic peripheral nerve of N (epsilon)-carboxymethyllysine-protein adducts, an advanced glycation end product. Diabetologia 1997;40:1380–1387.

    Article  PubMed  CAS  Google Scholar 

  34. Misur I, Zarkovic K, Barada A, Batelja L, Milicevic Z, Turk Z. Advanced glycation end products in peripheral nerve in type 2 diabetes with neuropathy. Acta Diabetol 2004;41: 158–166.

    Article  PubMed  CAS  Google Scholar 

  35. Amano S, Kaji Y, Oshika T, et al. Advanced glycation end products in human optic nerve head. Br J Ophthalmol 2001;85:52–55.

    Article  PubMed  CAS  Google Scholar 

  36. Bierhaus A, Haslbeck KM, Humpert PM, et al. Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily. J Clin Invest 2004; 114: 1741–1751.

    Article  PubMed  CAS  Google Scholar 

  37. Cameron NE, Gibson TM, Nangle MR, Cotter MA. Inhibitors of advanced glycation end product formation and neurovascular dysfunction in experimental diabetes. Ann NY Acad Sci 2005;1043:784–792.

    Article  PubMed  CAS  Google Scholar 

  38. Vincent AM, Russell JW, Low P, Feldman EL. Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr Rev 2004;25:612–628.

    Article  PubMed  CAS  Google Scholar 

  39. Ziegler D, Sohr CG, Nourooz-Zadeh J. Oxidative stress and antioxidant defense in relation to the severity of diabetic polyneuropathy and cardiovascular autonomic neuropathy. Diabetes Care 2004;27:2178–2183.

    Article  PubMed  CAS  Google Scholar 

  40. Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia 1995;38:1425–1433.

    Article  PubMed  CAS  Google Scholar 

  41. 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. Diabetic Med 1999;16:1040–1043.

    Article  PubMed  CAS  Google Scholar 

  42. 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 doubleblind placebo-controlled trial (ALADIN II). Free Radic Res 1999;31:171–179.

    Article  PubMed  CAS  Google Scholar 

  43. 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: 1296–1301.

    Article  PubMed  CAS  Google Scholar 

  44. Ametov AS, Barinov A, Dyck PJ, et al. SYDNEY Trial Study Group. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care 2003;26:770–776.

    Article  PubMed  CAS  Google Scholar 

  45. Malik RA, Tomlinson DR. Angiotensin-converting enzyme inhibitors: are there credible mechanisms for beneficial effects in diabetic neuropathy? Int Rev Neurobiol 2002;50: 415–430.

    PubMed  CAS  Google Scholar 

  46. Young MJ, Veves A, Walker MG, Boulton AJM. Correlations between nerve function and tissue oxygenation in diabetic patients: further clues to the etiology of diabetic neuropathy? Diabetologia 1992;35:1146–1150.

    Article  PubMed  CAS  Google Scholar 

  47. Akbari CM, Gibbons GW, Habershaw GM, LoGerfo FW, Veves A. The effect of arterial reconstruction on the natural history of diabetic neuropathy. Arch Surg 1997; 132:148–152.

    PubMed  CAS  Google Scholar 

  48. Veves A, Donaghue VM, Sarnow MR, Giurini JM, Campbell DR, LoGerfo FW. The impact of reversal of hypoxia by revascularization on the peripheral nerve function of diabetic patients. Diabetologia 1996;39:344–348.

    Article  PubMed  CAS  Google Scholar 

  49. Arora S, Pomposelli F, LoGerfo FW, Veves A. Cutaneous microcirculation in the neuropathic diabetic foot improves significantly but not completely after successful lower extremity revascularization. J Vasc Surg 2002;35:501–505.

    Article  PubMed  Google Scholar 

  50. Jarmuzewska EA, Mangoni AA. Pulse pressure is independently associated with sensorimotor peripheral neuropathy in patients with type 2 diabetes. J Intern Med 2005;258: 38–44.

    Article  PubMed  CAS  Google Scholar 

  51. Tesfaye S, Chaturvedi N, Eaton SE, et al. EURODIAB Prospective Complications Study Group. Vascular risk factors and diabetic neuropathy. N Engl J Med 2005;352:341–350.

    Article  PubMed  CAS  Google Scholar 

  52. Thrainsdottir S, Malik RA, Dahlin LB, et al. Endoneurial capillary abnormalities presage deterioration of glucose tolerance and accompany peripheral neuropathy in man. Diabetes 2003;52:2615–2622.

    Article  PubMed  CAS  Google Scholar 

  53. Malik RA, Tesfaye S, Newrick PG, et al. Sural nerve pathology in diabetic patients with minimal but progressive neuropathy. Diabetologia 2005;48:578–585.

    Article  PubMed  CAS  Google Scholar 

  54. Schofield I, Malik R, Izzard A, Austin C, Heagerty A. Vascular structural and functional changes in type 2 diabetes mellitus: evidence for the roles of abnormal myogenic responsiveness and dyslipidemia. Circulation 2002;106:3037–3043.

    Article  PubMed  Google Scholar 

  55. Malik RA, Schofield IJ, Izzard A, Austin C, Bermann G, Heagerty AM. Effects of angiotensin type-1 receptor antagonism on small artery function in patients with type 2 diabetes mellitus. Hypertension 2005;45:264–269.

    Article  PubMed  CAS  Google Scholar 

  56. Reja A, Tesfaye S, Harris N, Ward JD. Improvement in nerve conduction and quantitative sensory tests after treatment with lisinopril. Diabetic Med 1995; 12:307–309.

    Article  PubMed  CAS  Google Scholar 

  57. Malik RA, Williamson S, Abbott CA, et al. Effect of angiotensin-converting enzyme (ACE) inhibitor trandalopril on human diabetic neuropathy: randomised double-blind controlled trial. Lancet 1998;352:1978–1981.

    Article  PubMed  CAS  Google Scholar 

  58. Estaci RO, Jeffers BW, Gifford N, Schrier RW. Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care 2000;23:B54–B64.

    Google Scholar 

  59. Eichberg J. Protein kinase C changes in diabetes: is the concept relevant to neuropathy? Int Rev Neurobiol 2002;50:61–82.

    Article  PubMed  CAS  Google Scholar 

  60. 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;18:315–323.

    Article  PubMed  CAS  Google Scholar 

  61. Vinik AI, Bril V, Kempler P, et al. the MBBQ Study Group. 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;27:1164–1180.

    Article  PubMed  CAS  Google Scholar 

  62. Economides PA, Caselli A, Tiani E, Khaodhiar L, Horton ES, Veves A. The effects of atorvastatin on endothelial function in diabetic patients and subjects at risk for type 2 diabetes. J Clin Endocrinol Metab 2004;89:740–747.

    Article  PubMed  CAS  Google Scholar 

  63. Okamoto T, Yamagishi SI, Inagaki Y, et al. Angiogenesis induced by advanced glycation end products and its prevention by cerivastatin. FASEB J 2002; 16:1928–1930.

    PubMed  CAS  Google Scholar 

  64. Fried LF, Forrest KY, Ellis D, Chang Y, Silvers N, Orchard TJ. Lipid modulation in insulindependent diabetes mellitus: effect on microvascular outcomes. J Diabetes Complications 2001;15:113–119.

    Article  PubMed  CAS  Google Scholar 

  65. Schmidt RE, Dorsey DA, Beaudet LN, Peterson RG. Analysis of the Zucker Diabetic Fatty (ZDF) type 2 diabetic rat model suggests a neurotrophic role for insulin/IGF-I in diabetic autonomic neuropathy. Am J Pathol 2003; 163:21–28.

    PubMed  CAS  Google Scholar 

  66. Delaney CL, Russell JW, Cheng HL, Feldman EL. Insulin-like growth factor-I and overexpression of Bcl-xL prevent glucose-mediated apoptosis in Schwann cells. J Neuropathol Exp Neurol 2001;60:147–160.

    PubMed  CAS  Google Scholar 

  67. Grandis M, Nobbio L, Abbruzzese M, et al. Insulin treatment enhances expression of IGF-I in sural nerves of diabetic patients. Muscle Nerve 2001;24:622–629.

    Article  PubMed  CAS  Google Scholar 

  68. Wahren J, Shafqat J, Johansson J, Chibalin A, Ekberg K, Jornvall H. Molecular and cellular effects of C-peptide—new perspectives on an old peptide. Exp Diabesity Res 2004;5: 15–23.

    Article  PubMed  CAS  Google Scholar 

  69. Sima AA. C-peptide and diabetic neuropathy. Expert Opin Investig Drugs 2003;12:1471–1488.

    Article  PubMed  CAS  Google Scholar 

  70. Cotter MA, Ekberg K, Wahren J, Cameron NE. Effects of proinsulin C-peptide in experimental diabetic neuropathy: vascular actions and modulation by nitric oxide synthase inhibition. Diabetes 2003;52:1812–1817.

    Article  PubMed  CAS  Google Scholar 

  71. Ekberg K, Brismar T, Johansson BL, Jonsson B, Lindstrom P, Wahren J. Amelioration of sensory nerve dysfunction by C-Peptide in patients with type 1 diabetes. Diabetes 2003;52:536–541.

    Article  PubMed  CAS  Google Scholar 

  72. Ekberg K, Juntti-Berggren L, Norrby A, et al. C-peptide improves sensory nerve function in type 1 diabetes and neuropathy. Diabetologia 2005;48:A81.

    Google Scholar 

  73. Malik RA, Li C, Aziz W, et al. Elevated plasma CD105 and vitreous VEGF levels in diabetic retinopathy. J Cell Mol Med 2005;9:692–697.

    Article  PubMed  CAS  Google Scholar 

  74. Carmeliet P, Storkebaum E. Vascular and neuronal effects of VEGF in the nervous system: implications for neurological disorders. Semin Cell Dev Biol 2002;13:39–53.

    Article  PubMed  CAS  Google Scholar 

  75. Veves A, King GL. Can VEGF reverse diabetic neuropathy in human subjects? J Clin Invest 2001;107:1215–1218.

    PubMed  CAS  Google Scholar 

  76. Chavez JC, Almhanna K, Berti-Mattera LN. Transient expression of hypoxia-inducible factor-1 alpha and target genes in peripheral nerves from diabetic rats. Neurosci Lett 2005;374:179–182.

    Article  PubMed  CAS  Google Scholar 

  77. 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;262:159–162.

    Article  PubMed  CAS  Google Scholar 

  78. Schratzberger P, Walter DH, Rittig K, et al. Reversal of experimental diabetic neuropathy by VEGF gene transfer. J Clin Invest 2001;107:1083–1092.

    PubMed  CAS  Google Scholar 

  79. Simovic D, Isner JM, Ropper AH, Pieczek A, Weinberg DH. Improvement in chronic ischemic neuropathy after intramuscular phVEGF165 gene transfer in patients with critical limb ischemia. Arch Neurol 2001;8:761–768.

    Article  Google Scholar 

  80. Isner JM, Ropper A, Hirst K. VEGF gene transfer for diabetic neuropathy. Hum Gene Ther 2001;12:1593–1594.

    PubMed  CAS  Google Scholar 

  81. Apfel SC. Neurotrophic factors in peripheral neuropathies: therapeutic implications. Brain Pathol 1999;9:393–413.

    Article  PubMed  CAS  Google Scholar 

  82. Anand P, Terenghi G, Warner G, Kopelman P, Williams-Chestnut RE, Sinicropi DV. The role of endogenous nerve growth factor in human diabetic neuropathy. Nat Med 1996;2:703–707.

    Article  PubMed  CAS  Google Scholar 

  83. Diemel LT, Cai F, Anand P, et al. Increased nerve growth factor mRNA in lateral calf skin biopsies from diabetic patients. Diabetic Med 1999;16:113–118.

    Article  PubMed  CAS  Google Scholar 

  84. Kennedy AJ, Wellmer A, Facer P, et al. Neurotrophin-3 is increased in skin in human diabetic neuropathy. J Neurol Neurosurg Psychiatry 1998;65:393–395.

    PubMed  CAS  Google Scholar 

  85. Lee DA, Gross L, Wittrock DA, Windebank AJ. 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;55:915–923.

    PubMed  CAS  Google Scholar 

  86. Terenghi G, Mann D, Kopelman PG, Anand P. trkA and trkC expression is increased in human diabetic skin. Neurosci Lett 1997;228:33–36.

    Article  PubMed  CAS  Google Scholar 

  87. Apfel SC, Kessler JA, Adornato BT, Litchy WJ, Sanders C, Rask CA. Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. NGF Study Group. Neurology 1998;51:695–702.

    PubMed  CAS  Google Scholar 

  88. 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;284:2215–2221.

    Article  PubMed  CAS  Google Scholar 

  89. Wellmer A, Misra VP, Sharief MK, Kopelman PG, Anand P. A double-blind placebocontrolled clinical trial of recombinant human brain-derived neurotrophic factor (rhBDNF) in diabetic polyneuropathy. J Peripher Nerv Syst 2001;6:204–210.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Malik, R.A., Veves, A. (2007). Pathogenesis of Human Diabetic Neuropathy. In: Veves, A., Malik, R.A. (eds) Diabetic Neuropathy. Clinical Diabetes. Humana Press. https://doi.org/10.1007/978-1-59745-311-0_13

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-311-0_13

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-626-9

  • Online ISBN: 978-1-59745-311-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics