Insulin and Diabetic Peripheral Nerve Pathologies

  • Sanjeev Kelkar


Brain and all other neural tissue consume glucose without assistance from insulin. Till about 2 decades ago, it was therefore assumed that insulin has little to do with cerebral/neural pathologies. However, there is a large body of highly beneficial evidence both in animal and human experiments of intricate nature and evidence from large trials. It is certain that for the preservation of the structure and for the preservation of its functions in an uninterrupted optimal manner of all neural tissues adequacy of insulin is an extremely important factor. This chapter highlights this importance in considerable detail, with reference to diabetic neuropathic afflictions in particular. This will or should increase the use of insulin as early, adequately and with understanding of the doctor and for the patients about the valuable positive impact of this wonderful drug on their neuropathic and overall well-being.


  1. 1.
    Grote CW, Wright DE. A role for insulin in diabetic neuropathy. Front Neurosci. 2016;
  2. 2.
    Grillo CA, Piroli GG, Lawrence RC, Wrighten SA, Green AJ, Wilson SP, et al. Hippocampal insulin resistance impairs spatial learning and synaptic plasticity. Diabetes. 2015;64:3927–36. Scholar
  3. 3.
    Obici S, Feng Z, Karkanias G, Baskin DG, Rossetti L. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci. 2002a;5:566–72. Scholar
  4. 4.
    Sugimoto K, Murakawa Y, Sima AA. Expression and localization of insulin receptor in rat dorsal root ganglion and spinal cord. J Peripher Nerv Syst. 2002;7:44–53. Scholar
  5. 5.
    Chiu SL, Cline HT. Insulin receptor signaling in the development of neuronal structure and function. Neural Dev. 2010;5:7. Scholar
  6. 6.
    Murakawa Y, Zhang W, Pierson CR, Brismar T, Ostenson CG, Efendic S, et al. Impaired glucose tolerance and insulinopenia in the GK-rat causes peripheral neuropathy. Diabetes Metab Res Rev. 2002;18:473–83. Scholar
  7. 7.
    Brussee V, Cunningham FA, Zochodne DW. Direct insulin signaling of neurons reverses diabetic neuropathy. Diabetes. 2004;53:1824–30. Scholar
  8. 8.
    Toth C, Brussee V, Zochodne DW. Remote neurotrophic support of epidermal nerve fibres in experimental diabetes. Diabetologia. 2006b;49:1081–8. Scholar
  9. 9.
    Guo G, Kan M, Martinez JA, Zochodne DW. Local insulin and the rapid regrowth of diabetic epidermal axons. Neurobiol Dis. 2011;43:414–21. Scholar
  10. 10.
    Francis GJ, Martinez JA, Liu WQ, Zochodne DW, Hanson LR, Frey WH II, et al. Motor end plate innervation loss in diabetes and the role of insulin. J Neuropathol Exp Neurol. 2011;70:323–39. Scholar
  11. 11.
    Sugimoto K, Murakawa Y, Zhang W, Xu G, Sima AA. Insulin receptor in rat peripheral nerve: its localization and alternatively spliced isoforms. Diabetes Metab Res Rev. 2000;16:354–63.<354::AID-DMRR149>3.0.CO;2-H.CrossRefPubMedGoogle Scholar
  12. 12.
    Sugimoto K, Murakawa Y, Sima AA. Expression and localization of insulin receptor in rat dorsal root ganglion and spinal cord. J Peripher Nerv Syst. 2002;7:44–53. Scholar
  13. 13.
    Shettar A, Muttagi G. Developmental regulation of insulin receptor gene in sciatic nerves and role of insulin on glycoprotein P0 in the Schwann cells. Peptides. 2012;36:46–53. Scholar
  14. 14.
    Baiou D, Santha P, Avelino A, Charrua A, Bacskai T, Matesz K, et al. Neurochemical characterization of insulin receptor-expressing primary sensory neurons in wild-type and vanilloid type 1 transient receptor potential receptor knockout mice. J Comp Neurol. 2007;503:334–47. Scholar
  15. 15.
    Sathianathan V, Avelino A, Charrua A, Santha P, Matesz K, Cruz F, et al. Insulin induces cobalt uptake in a subpopulation of rat cultured primary sensory neurons. Eur J Neurosci. 2003;18:2477–86. Scholar
  16. 16.
    Van Buren JJ, Bhat S, Rotello R, Pauza ME, Premkumar LS. Sensitization and translocation of TRPV1 by insulin and IGF-I. Mol Pain. 2005;1:17. Scholar
  17. 17.
    Lilja J, Laulund F, Forsby A. Insulin and insulin-like growth factor type-I up-regulate the vanilloid receptor-1 (TRPV1) in stably TRPV1-expressing SH-SY5Y neuroblastoma cells. J Neurosci Res. 2007;85:1413–9. Scholar
  18. 18.
    Pabbidi RM, Yu SQ, Peng S, Khardori R, Pauza ME, Premkumar LS. Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity. Mol Pain. 2008;4:9. Scholar
  19. 19.
    Singh B, Xu Y, McLaughlin T, Singh V, Martinez JA, Krishnan A, et al. Resistance to trophic neurite outgrowth of sensory neurons exposed to insulin. J Neurochem. 2012;121:263–76. Scholar
  20. 20.
    Snyder EY, Kim SU. Insulin: is it a nerve survival factor. Brain Res. 1980;196:565–71. Scholar
  21. 21.
    Bothwell M. Insulin and somatomedin MSA promote nerve growth factor independent neurite formation by cultured chick dorsal root ganglionic sensory neurons. J Neurosci Res. 1982;8:225–31. Scholar
  22. 22.
    Recio-Pinto E, Lang FF, Ishii DN. Insulin and insulin-like growth factor II permit nerve growth factor binding and the neurite formation response in cultured human neuroblastoma cells. Proc Natl Acad Sci U S A. 1984;81:2562–6. Scholar
  23. 23.
    Recio-Pinto E, Rechler MM, Ishii DN. Effects of insulin, insulin like growth factor-II, and nerve growth factor on neurite formation and survival in cultured sympathetic and sensory neurons. J Neurosci. 1986;6:1211–9.CrossRefGoogle Scholar
  24. 24.
    Jones DM, Tucker BA, Rahimtula M, Mearow KM. The synergistic effects of NGF and IGF-1 on neurite growth in adult sensory neurons: convergence on the PI 3-kinase signaling pathway. J Neurochem. 2003;86:1116–28. Scholar
  25. 25.
    Fernyhough P, Mill JF, Roberts JL, Ishii DN. Stabilization of tubulin mRNAs by insulin and insulin-like growth factor I during neurite formation. Brain Res Mol Brain Res. 1989;6:109–20. Scholar
  26. 26.
    Li ZG, Zhang W, Sima AA. C-peptide enhances insulin-mediated cell growth and protection against high glucose-induced apoptosis in SH-SY5Y cells. Diabetes Metab Res Rev. 2003;19:375–85. Scholar
  27. 27.
    Skaper SD, Selak I, Varon S. Molecular requirements for survival of cultured avian and rodent dorsal root ganglionic neurons responding to different trophic factors. J Neurosci Res. 1982;8:251–61. Scholar
  28. 28.
    Huang TJ, Verkhratsky A, Fernyhough P. Insulin enhances mitochondrial inner membrane potential and increases ATP levels through phosphoinositide 3-kinase in adult sensory neurons. Mol Cell Neurosci. 2005;28:42–54. Scholar
  29. 29.
    Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997;91:231–41. Scholar
  30. 30.
    Eckersley L. Role of the Schwann cell in diabetic neuropathy. Int Rev Neurobiol. 2002;50:293–321. Scholar
  31. 31.
    Shetter AR, Muttagi G, Sagar CB. Expression and localization of insulin receptors in dissociated primary cultures of rat Schwann cells. Cell Biol Int. 2011;35:299–304. Scholar
  32. 32.
    Ogata T, Iijima S, Hoshikawa S, Miura T, Yamamoto S, Oda H, et al. Opposing extracellular signal-regulated kinase and Akt pathways control Schwann cell myelination. J Neurosci. 2004;24:6724–32. Scholar
  33. 33.
    Liang G, Cline GW, Macica CM. IGF-1 stimulates de novo fatty acid biosynthesis by Schwann cells during myelination. Glia. 2007;55:632–41. Scholar
  34. 34.
    Rachana KS, Manu MS, Advirao GM. Insulin influenced expression of myelin proteins in diabetic peripheral neuropathy. Neurosci Lett. 2016;629:110–5. Scholar
  35. 35.
    Xu QG, Li XQ, Kotecha SA, Cheng C, Sun HS, Zochodne DW. Insulin as an in vivo growth factor. Exp Neurol. 2004;188:43–51. Scholar
  36. 36.
    Toth C, Brussee V, Martinez JA, McDonald D, Cunningham FA, Zochodne DW. Rescue and regeneration of injured peripheral nerve axons by intrathecal insulin. Neuroscience. 2006a;139:429–49. Scholar
  37. 37.
    White MF. IRS proteins and the common path to diabetes. Am J Physiol Endocrinol Metab. 2002;283:E413–22. Scholar
  38. 38.
    Plum L, Schubert M, Brüning JC. The role of insulin receptor signaling in the brain. Trends Endocrinol Metab. 2005;16:59–65. Scholar
  39. 39.
    Choeiri C, Staines W, Messier C. Immunohistochemical localization and quantification of glucose transporters in the mouse brain. Neuroscience. 2002;111:19–34. Scholar
  40. 40.
    Leloup C, Arluison M, Kassis N, Lepetit N, Cartier N, Ferré P, et al. Discrete brain areas express the insulin-responsive glucose transporter GLUT4. Brain Res Mol Brain Res. 1996;38:45–53. Scholar
  41. 41.
    Baura GD, Foster DM, Porte D Jr, Kahn SE, Bergman RN, Cobelli C, et al. Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain. J Clin Invest. 1993;92:1824–30. Scholar
  42. 42.
    Wang YY, Lui PC, Li JY. Receptor-mediated therapeutic transport across the blood-brain barrier. Immunotherapy. 2009;1:983–93. Scholar
  43. 43.
    Luchsinger JA, Tang MX, Stern Y, Shea S, Mayeux R. Diabetes mellitus and risk of Alzheimer’s disease and dementia with stroke in a multiethnic cohort. Am J Epidemiol. 2001;154:635–41. Scholar
  44. 44.
    Hu G, Jousilahti P, Bidel S, Antikainen R, Tuomilehto J. Type 2 diabetes and the risk of Parkinson's disease. Diabetes Care. 2007;30:842–7. Scholar
  45. 45.
    Jolivalt CG, Lee CA, Beiswenger KK, Smith JL, Orlov M, Torrance MA, et al. Defective insulin signaling pathway and increased glycogen synthase kinase-3 activity in the brain of diabetic mice: parallels with Alzheimer’s disease and correction by insulin. J Neurosci Res. 2008;86:3265–74. Scholar
  46. 46.
    Jolivalt CG, Hurford R, Lee CA, Dumaop W, Rockenstein E, Masliah E. Type 1 diabetes exaggerates features of Alzheimer’s disease in APP transgenic mice. Exp Neurol. 2010;223:422–31. Scholar
  47. 47.
    Jolivalt CG, Calcutt NA, Masliah E. Similar pattern of peripheral neuropathy in mouse models of type 1 diabetes and Alzheimer’s disease. Neuroscience. 2012;202:405–12. Scholar
  48. 48.
    Fadel JR, Jolivalt CG, Reagan LP. Food for thought: the role of appetitive peptides in age-related cognitive decline. Ageing Res Rev. 2013;12:764–76. Scholar
  49. 49.
    Akter K, Lanza EA, Martin SA, Myronyuk N, Rua M, Raffa RB. Diabetes mellitus and Alzheimer's disease: shared pathology and treatment? Br J Clin Pharmacol. 2011;71:365–76. Scholar
  50. 50.
    Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, et al. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 2012;122:1316–38. Scholar
  51. 51.
    Sato T, Hanyu H, Hirao K, Kanetaka H, Sakurai H, Iwamoto T. Efficacy of PPAR-gamma agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging. 2011;32:1626–33. Scholar
  52. 52.
    Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012;69:29–38. Scholar
  53. 53.
    Zochodne DW. Mechanisms of diabetic neuron damage: molecular pathways. Handb Clin Neurol. 2014;126:379–99. Scholar
  54. 54.
    Zochodne DW. Diabetes and the plasticity of sensory neurons. Neurosci Lett. 2015;596:60–5. Scholar
  55. 55.
    Diabetes Control Complications Trial Research Group. The effect of intensive diabetes therapy on the development, and progression of neuropathy. Ann Intern Med. 1995a;122:561–8. Scholar
  56. 56.
    Diabetes Control Complications Trial Research Group. Effect of intensive diabetes treatment on nerve conduction in the diabetes control and complications trial. Ann Neurol. 1995b;38:869–80. Scholar
  57. 57.
    Romanovsky D, Wang J, Al-Chaer ED, Stimers JR, Dobretsov M. Comparison of metabolic and neuropathy profiles of rats with streptozotocin-induced overt and moderate insulinopenia. Neuroscience. 2010;170:337–47. Scholar
  58. 58.
    Romanovsky D, Cruz NF, Dienel GA, Dobretsov M. Mechanical hyperalgesia correlates with insulin deficiency in normoglycemic streptozotocin-treated rats. Neurobiol Dis. 2006;24:384–94. Scholar
  59. 59.
    Chen DK, Frizzi KE, Guernsey LS, Ladt K, Mizisin AP, Calcutt NA. Repeated monitoring of corneal nerves by confocal microscopy as an index of peripheral neuropathy in type-1 diabetic rodents and the effects of topical insulin. J Peripher Nerv Syst. 2013;18:306–15. Scholar
  60. 60.
    Hoybergs YM, Meert TF. The effect of low-dose insulin on mechanical sensitivity and allodynia in type I diabetes neuropathy. Neurosci Lett. 2007;417:149–54. Scholar
  61. 61.
    Nicholls DG, Budd SL. Mitochondria and neuronal survival. Physiol Rev. 2000;80:315–60.CrossRefGoogle Scholar
  62. 62.
    Kalichman MW, Powell HC, Mizisin AP. Reactive, degenerative, and proliferative Schwann cell responses in experimental galactose and human diabetic neuropathy. Acta Neuropathol. 1998;95:47–56.CrossRefGoogle Scholar
  63. 63.
    Chowdhury SK, Zherebitskaya E, Smith DR, Akude E, Chattopadhyay S, Jolivalt CG, et al. Mitochondrial respiratory chain dysfunction in dorsal root ganglia of streptozotocin-induced diabetic rats and its correction by insulin treatment. Diabetes. 2010;59:1082–91. Scholar
  64. 64.
    Grote CW, Morris JK, Ryals JM, Geiger PC, Wright DE. Insulin receptor substrate 2 expression and involvement in neuronal insulin resistance in diabetic neuropathy. Exp Diabetes Res. 2011;2011:212571. Scholar
  65. 65.
    Kim B, McLean LL, Philip SS, Feldman EL. Hyperinsulinemia induces insulin resistance in dorsal root ganglion neurons. Endocrinology. 2011;152:3638–47. Scholar
  66. 66.
    Aoki TT, Grecu EO, Arcangeli MA, Benbarka MM, Prescott P, Ahn JH. Chronic intermittent intravenous insulin therapy: a new frontier in diabetes therapy. Diabetes Technol Ther. 2001;3(1). Mary Ann Liebert, Inc.Google Scholar
  67. 67.
    Navarro X, DER S, Kennedy WR. Long-term effects of pancreatic transplantation on diabetic neuropathy. Ann Neurol. 1997;42(5):727.CrossRefGoogle Scholar
  68. 68.
    Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive Insulin Therapy in Critically Ill Patients. N Engl J Med. 2001;345:1359–67. Scholar
  69. 69.
    Dabbya R, Sadeha M, Lampla Y, Gilad R, Watemberg N. Acute painful neuropathy induced by rapid correction of serum glucose levels in diabetes patients. Biomed Pharmacother. 2009;63(10):707–9.CrossRefGoogle Scholar
  70. 70.
    Archer A, Watkins PJ, Thomas PK. The natural history of acute painful neuropathy in diabetes mellitus. J Neurol Neurosurg Psychiatr. 1983;46(6):491–9.CrossRefGoogle Scholar
  71. 71.
    Leow MKS, Wyckoff J. Under-recognised paradox of neuropathy from rapid glycemic control. Postgrad Med J. 2005;81(952):103–7.CrossRefGoogle Scholar
  72. 72.
    Larsen PR, Kronenberg HM, et al. Williams Textbook of Endocrinology. 10th ed. Philadelphia; 2002.Google Scholar
  73. 73.
    Ibitoye R, Rajbhandari SM. Neuropathic truncal pain – a case series. Q J Med. 2012;105(10):1027–31.CrossRefGoogle Scholar
  74. 74.
    Watkins. ABC of diabetes. 5th ed. London: BMJ Publishing Group; 2003. p. 32–7.Google Scholar

Further Reading

  1. He is also referred to the chapter on Physiology of Insulin in the author’s volume on – ‘Towards Optimal Management of Diabetes in Surgery,’ also published by SpringerNature.Google Scholar
  2. National Guidelines for Management of Diabetic Foot Diabetic Foot Society of India in November 2017.Google Scholar
  3. The reader is referred to this paper [66.Oki Thomas et al., see ref. below for an excellent expose of the physiology of insulin in normal and its changes after the development of diabetes.Google Scholar
  4. Towards ‘Optimal Management of Diabetes in Surgery’ published by Springer in August 2019.Google Scholar
  5. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive Insulin Therapy in Critically Ill Patients. N Engl J Med. 2001;345:1359–67. Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

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

Personalised recommendations