Pathogenesis of Diabetic Neuropathies

  • Sanjeev Kelkar


The pathological hallmarks of diabetic neuropathy are microangiopathy of the vasa nervorum, loss of axons or axonal atrophy, and demyelination. These changes can occur at different points of time, can be gradual or sudden as in closure of vasa nervorum, and occur singly or more often simultaneously in varying combinations and temporally at different stages. These changes result from a combination of widely different mechanisms of tissue damage. These factors are also responsible and are common to all long-term complications of diabetes as well. The changes occur at the cellular, subcellular, or on other epi-structures of the nerves. The details included will give an in-depth understanding of the Diabetic State as a whole with particular reference to nerves and the organs secondarily damaged and a good understanding of the therapeutics of the neuropathies and the organ and organ system as well.


  1. 1.
    Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, Lauria G, Malik RA, Spallone V, Vinik A, Bernardi L, Valensi P. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010;33:2285–93. PMID 20876709.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Basit A, Hydrie MZ, Hakeem R, Ahmedani MY, Masood Q. Frequency of chronic complications of type II diabetes. J Coll Physicians Surg Pak. 2004;14(2):79–83.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Booya F, Bandarian F, Larijani B, Pajouhi M, Nooraei M, Lotfi J. Potential risk factors for diabetic neuropathy: a case control study. BMC Neurol. 2005;5:24.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Aaberg ML, Burch DM, Hud ZR, Zacharias MP. Gender differences in the onset of diabetic neuropathy. J Diabetes Complicat. 2008;22(2):83–7.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Kiziltan ME, Benbir G. Clinical and electrophysiological differences in male and female patients with diabetic foot. Diabetes Res Clin Pract. 2008;79(1):e17–8.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Kiziltan ME, Gunduz A, Kiziltan G, Akalin MA, Uzun N. Peripheral neuropathy in patients with diabetic foot ulcers: clinical and nerve conduction study. J Neurol Sci. 2007;258(1–2):75–9.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Albers JW, Brown MB, Sima AA, Greene DA. Nerve conduction measures in mild diabetic neuropathy in the Early Diabetes Intervention Trial: the effects of age, sex, type of diabetes, disease duration, and anthropometric factors. Tolrestat Study Group for the Early Diabetes Intervention Trial. Neurology. 1996;46(1):85–91.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Brandt U, Trumpower B. The proton motive Q cycle in mitochondria and bacteria. Crit Rev Biochem Mol Biol. 2008;29(3):165–97.CrossRefGoogle Scholar
  9. 9.
    Shah MS, Brownlee M. Molecular and cellular mechanisms of cardiovascular disorders in diabetes. Circ Res. 2016;118(11):1808–29.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Juranek J, Ray R, Banach M, Rai V. Receptor for advanced glycation end-products in neurodegenerative diseases. Rev Neurosci. 2015;26(6):691–8.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Fernyhough P. Mitochondrial dysfunction in diabetic neuropathy: a series of unfortunate metabolic events. Curr Diabetes Rep. 2015;15(11):89.CrossRefGoogle Scholar
  12. 12.
    Fernyhough P, Roy Chowdhury SK, Schmidt RE. Mitochondrial stress and the pathogenesis of diabetic neuropathy. Expert Rev Endocrinol Metab. 2010;5(1):39–49.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Cashman CR, Hoke A. Mechanisms of distal axonal degeneration in peripheral neuropathies. Neurosci Lett. 2015;596:33–50.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Edwards JL, Vincent AM, Cheng HT, Feldman EL. Diabetic neuropathy: mechanisms to management. Pharmacol Ther. 2008;120(1):1–34.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Soriano FG, Virág L, Szabó C. Diabetic endothelial dysfunction: role of reactive oxygen and nitrogen species production and activation. J Mol Med. 2001;79(8):437–48.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Dimitropoulos G, Tahrani AA, Stevens MJ. Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes. 2014;5(1):17–39.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Østergaard L, Finnerup NB, Terkelsen AJ, Olesen RA, Drasbek KR, Knudsen L, Jespersen SN, Frystyk J, Charles M, Thomsen RW, Christiansen JS, Beck-Nielsen H, Jensen TS, Andersen H. The effects of capillary dysfunction on oxygen and glucose extraction in diabetic neuropathy. Diabetologia. 2015;58:666–77. PMID: 25512003.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Ekberg K, Johansson BL. Effect of C-peptide on diabetic neuropathy in patients with type 1 diabetes. Exp Diabetes Res. 2008;2008:457912. PMID: 18350117.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Vinik AI, Park TS, Stansberry KB, Pittenger GL. Diabetic neuropathies. Diabetologia. 2000;43:957–73. PMID: 10990072.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Vinik AI, Erbas T, Casellini CM. Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. J Diabetes Investig. 2013;4(1):4–18.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Zhu T, Meng Q, Ji J, Lou X, Zhang L. Toll-like receptor 4 and tumor necrosis factor-alpha as diagnostic biomarkers for diabetic peripheral neuropathy. Neurosci Lett. 2015;585:28–32. PMID: 25445373.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Spallone V. Update on the impact, diagnosis and management of cardiovascular autonomic neuropathy in diabetes: what is defined, what is new, and what is unmet. Diabetes Metab J. 2019;43:3–30. Scholar
  23. 23.
    Wahren J, Ekberg K, Johansson J, Henriksson M, Pramanik A, Johansson BL, Rigler R, Jörnvall H. Role of C-peptide in human physiology. Am J Physiol Endocrinol Metab. 2000;278:E759–68. PMID: 10780930.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Krishnan AV, Kiernan MC. Altered nerve excitability properties in established diabetic neuropathy. Brain. 2005;128:1178–87. PMID: 15758031.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Cameron NE, Cotter MA, Jack AM, Basso MD, Hohman TC. Protein kinase C effects on nerve function, perfusion, Na(+), K(+) ATPase activity and glutathione content in diabetic rats. Diabetologia. 1999;42:1120–30. PMID: 10447525.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Koya D, King GL. Protein kinase C activation and the development of diabetic complications. Diabetes. 1998;47:859–66. PMID: 9604860.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Møller HJ. Soluble CD163. Scand J Clin Lab Invest. 2012;72:1–13. PMID: 22060747.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Etzerodt A, Moestrup SK. CD163 and inflammation: biological, diagnostic, and therapeutic aspects. Antioxid Redox Signal. 2013;18:2352–63. PMID: 22900885.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Llauradó G, González-Clemente JM, Maymó-Masip E, Subías D, Vendrell J, Chacón MR. Serum levels of TWEAK and scavenger receptor CD163 in type 1 diabetes mellitus: relationship with cardiovascular risk factors: a case-control study. PLoS One. 2012;7:e43919. PMID: 22937125.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Osztovits J, Horváth T, Littvay L, et al. Effects of genetic vs. environmental factors on cardiovascular autonomic function: a twin study. Diabet Med. 2011;28(10):1241–8.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Dogrul A, Gul H, Yesilyurt O, Ulas UH, Yildiz O. Systemic and spinal administration of etanercept, a tumor necrosis factor alpha inhibitor, blocks tactile allodynia in diabetic mice. Acta Diabetol. 2011;48:135–42. PMID: 21104419.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Husebye ES, Winqvist O, Sundkvist G, Kämpe O, Karlsson FA. Autoantibodies against adrenal medulla in type 1 and type 2 diabetes mellitus: no evidence for an association with autonomic neuropathy. J Intern Med. 1996;239:139–46. PMID: 8568481.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Tanaka Y, Niwa S, Dong M, Farkhondeh A, Wang L, Zhou R, Hirokawa N. The molecular motor KIF1A transports the TrkA neurotrophin receptor. Neuron. 2016;90(6):1215–29.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Solomon Tesfaye MD, Nish Chaturvedi MD, Simon EM, Eaton DM, John D, Ward MD, Christos Manes MD, Ionescu-Tirgoviste C, Witte DR, Fuller JH. Vascular risk factors and diabetic neuropathy. N Engl J Med. 2005;352(4):341–50. Scholar
  35. 35.
    Ciccacci C, Morganti R, Di Fusco D, et al. Common polymorphisms in MIR146a, and MIR27a genes contribute to neuropathy susceptibility in type 2 diabetes. Acta Diabetol. 2014;51(4):663–71.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Politi C, Ciccacci C, D’Amato C, Novelli G, Borgiani P, Spallone V. Recent advances in exploring the genetic susceptibility to diabetic neuropathy. Diabetes Res Clin Pract. 2016;120:198–208.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Doria A. Genetics of diabetes complications. Curr Diabetes Rep. 2010;10(6):467–75.CrossRefGoogle Scholar
  38. 38.
    Donaghue KC, Margan SH, Chan AK, Holloway B, Silink M, Rangel T, Bennetts B. The association of aldose reductase gene (AKR1B1) polymorphisms with diabetic neuropathy in adolescents. Diabet Med. 2005;22(10):1315–20.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Themistocleous AC, Ramirez JD, Serra J, Bennett DL. The clinical approach to small fibre neuropathy and painful channelopathy. Pract Neurol. 2014;14(6):368–79.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Nilsen KB, Nicholas AK, Woods CG, Mellgren SI, Nebuchennykh M, Aasly J. Two novel SCN9A mutations causing insensitivity to pain. Pain. 2009;143(1–2):155158.Google Scholar
  41. 41.
    Ji ZY, Li HF, Lei Y, Rao YW, Tan ZX, Liu HJ, Yao GD, Hou B, Sun ML. Association of adiponectin gene polymorphisms with an elevated risk of diabetic peripheral neuropathy in type 2 diabetes patients. J Diabetes Complicat. 2015;29:887–92.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Gosselin S, Kyle RA, Dyck PJ. Neuropathy associated with monoclonal gammopathies of undetermined significance. Ann Neurol. 1991;30(1):54–61. Scholar
  43. 43.
    Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354(13):1362–9. Scholar
  44. 44.
    International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;121(5):749–57.CrossRefGoogle Scholar
  45. 45.
    Rison RA, Beydoun SR. Paraproteinemic neuropathy: a practical review. BMC Neurol. 2016;16:13. Scholar
  46. 46.
    Gorson KC. An update on the management of chronic inflammatory demyelinating polyneuropathy. Ther Adv Neurol Disord. 2012;5(6):359–73. Scholar
  47. 47.
    Martyn CN, Hughes RA. Epidemiology of peripheral neuropathy. J Neurol Neurosurg Psychiatry. 1997;62(4):310–8.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Rison RA, Beydoun SR. Amyotrophic lateral sclerosis-motor neuron disease, monoclonal gammopathy, hyperparathyroidism, and B12 deficiency: case report and review of the literature. J Med Case Rep. 2010;4:298. Scholar
  49. 49.
    Hadden RD, Nobile-Orazio E, Sommer C. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on Management of Paraproteinaemic demyelinating neuropathies. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. J Periph Nerv. 2010;15:185–95.CrossRefGoogle Scholar
  50. 50.
    Kelly JJ Jr, Kyle RA, O’Brien PC, Dyck PJ. Prevalence of monoclonal protein in peripheral neuropathy. Neurology. 1981;31(11):1480–3.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Ferri C, La Civita L, Cirafisi C, Siciliano G, Longombardo G, Bombardieri S, et al. Peripheral neuropathy in mixed cryoglobulinemia: clinical and electrophysiologic investigations. J Rheumatol. 1992;19(6):889–95.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Delmont E, Jeandel PY, Hubert AM, Marcq L, Boucraut J, Desnuelle C. Successful treatment with rituximab of one patient with CANOMAD neuropathy. J Neurol. 2010;257(4):655–7. Scholar
  53. 53.
    Yeung KB, Thomas PK, King RH, Waddy H, Will RG, Hughes RA, et al. The clinical spectrum of peripheral neuropathies associated with benign monoclonal IgM, IgG and IgA paraproteinaemia. Comparative clinical, immunological and nerve biopsy findings. J Neurol. 1991;238(7):383–91.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Soubrier MJ, Dubost JJ, Sauvezie BJ. POEMS syndrome: a study of 25 cases and a review of the literature. French Study Group on POEMS Syndrome. Am J Med. 1994;97(6):543–53.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Kelly JJ, Karcher DS. Lymphoma and peripheral neuropathy: a clinical review. Muscle Nerve. 2005;31(3):301–13. Scholar
  56. 56.
    D’Souza A, Hayman SR, Buadi F, Mauermann M, Lacy MQ, Gertz MA, et al. The utility of plasma vascular endothelial growth factor levels in the diagnosis and follow-up of patients with POEMS syndrome. Blood. 2011;118(17):4663–5. Scholar
  57. 57.
    Vinik AI, Casellini C, Parson HK, Colberg SR, Nevoret M-L. Cardiac autonomic neuropathy in diabetes: a predictor of cardiometabolic events. Front Neurosci. 2018;12:591.
  58. 58.
    Antonelli Incalzi R, Fuso L, Pitocco D, Basso S, Trové A, Longobardi A, et al. Decline of neuroadrenergic bronchial innervation and respiratory function in type 1 diabetes mellitus: a longitudinal study. Diabetes Metab Res Rev. 2007;23:311–6. Scholar
  59. 59.
    Tantucci C, Scionti L, Bottini P, Dottorini ML, Puxeddu E, Casucci G, et al. Influence of autonomic neuropathy of different severities on the hypercapnea drive to breathing in diabetic patients. Chest. 1997;112:145–53. Scholar
  60. 60.
    Maser RE, Lenhard MJ. Cardiovascular autonomic neuropathy due to diabetes mellitus: clinical manifestations, consequences, and treatment. J Clin Endocrinol Metab. 2005;90(10):5896–903.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Koneczny I. A new classification system for IgG4 autoantibodies. Front Immunol. 9:97.
  62. 62.
    Asati A, Kachurina O, Kachurin A. Simultaneous measurements of auto-immune and infectious disease specific antibodies using a high throughput multiplexing tool. PLoS One. 2012;7(8):e42681. Scholar
  63. 63.
    Ejskjaer N, Arif S, Dodds W, et al. Prevalence of autoantibodies to autonomic nervous tissue structures in type 1 diabetes mellitus. Diabet Med. 1999;16(7):544–9.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Zanone MM, Raviolo A, Coppo E, et al. Association of autoimmunity to autonomic nervous structures with nerve function in patients with type 1 diabetes: a 16-year prospective study. Diabetes Care. 2014;37(4):1108–15.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Zanone MM, Peakman M, Purewal T, Watkins PJ, Vergani D. Autoantibodies to nervous tissue structures are associated with autonomic neuropathy in type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1993;36:564–9. PMID:8335180.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Report from an Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Neurology. 1991;41(5):617–8.Google Scholar
  67. 67.
    Sharma KR, Cross J, Farronay O, Ayyar DR, Shebert RT, Bradley WG. Demyelinating neuropathy in diabetes mellitus. Arch Neurol. 2002;59:758–65. PMID 12020257.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Adamus G, Brown L, Schiffman J, Iannaccone A. Diversity in autoimmunity against retinal, neuronal, and axonal antigens in acquired neuro-retinopathy. J Ophthal Inflamm Infect. 2011;1:111–21. Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  • Sanjeev Kelkar
    • 1
  1. 1.Independent Health ResearcherPuneIndia

Personalised recommendations