The Korean Journal of Pain

The Korean Pain Society (대한통증학회)
권호 표지
DOI QR코드

DOI QR Code

Insulin enhances neurite extension and myelination of diabetic neuropathy neurons

  • Pham, Vuong M. (Singapore Institute for Neurotechnology, National University of Singapore) ;
  • Thakor, Nitish (Singapore Institute for Neurotechnology, National University of Singapore)
  • Received : 2022.02.03
  • Accepted : 2022.03.09
  • Published : 2022.04.01
Download PDF
⟨ Previous Next ⟩

Abstract

Background: The authors established an in vitro model of diabetic neuropathy based on the culture system of primary neurons and Schwann cells (SCs) to mimic similar symptoms observed in in vivo models of this complication, such as impaired neurite extension and impaired myelination. The model was then utilized to investigate the effects of insulin on enhancing neurite extension and myelination of diabetic neurons. Methods: SCs and primary neurons were cultured under conditions mimicking hyperglycemia prepared by adding glucose to the basal culture medium. In a single culture, the proliferation and maturation of SCs and the neurite extension of neurons were evaluated. In a co-culture, the percentage of myelination of diabetic neurons was investigated. Insulin at different concentrations was supplemented to culture media to examine its effects on neurite extension and myelination. Results: The cells showed similar symptoms observed in in vivo models of this complication. In a single culture, hyperglycemia attenuated the proliferation and maturation of SCs, induced apoptosis, and impaired neurite extension of both sensory and motor neurons. In a co-culture of SCs and neurons, the percentage of myelinated neurites in the hyperglycemia-treated group was significantly lower than that in the control group. This impaired neurite extension and myelination was reversed by the introduction of insulin to the hyperglycemic culture media. Conclusions: Insulin may be a potential candidate for improving diabetic neuropathy. Insulin can function as a neurotrophic factor to support both neurons and SCs. Further research is needed to discover the potential of insulin in improving diabetic neuropathy.

Keywords

Acknowledgement

The authors would like to thank Dr. Luo Baiwen for helping in the initial set up of isolation of rat embryonic neurons. We also would like to thank Dr. Kazuhiko Nishida and Dr. Shinji Matsumura for a helpful discussion about the method to measure neurite length. We thank Dr. Aishwarya Bandla, Alexis Lowe, and Elizabeth Redmond for reading and giving comments on the manuscript.

References

  1. Schreiber AK, Nones CF, Reis RC, Chichorro JG, Cunha JM. Diabetic neuropathic pain: physiopathology and treatment. World J Diabetes 2015; 6: 432-44. https://doi.org/10.4239/wjd.v6.i3.432
  2. Hicks CW, Selvin E. Epidemiology of peripheral neuropathy and lower extremity disease in diabetes. Curr Diab Rep 2019; 19: 86. https://doi.org/10.1007/s11892-019-1212-8
  3. Feldman EL, Nave KA, Jensen TS, Bennett DLH. New horizons in diabetic neuropathy: mechanisms, bioenergetics, and pain. Neuron 2017; 93: 1296-313. https://doi.org/10.1016/j.neuron.2017.02.005
  4. Zychowska M, Rojewska E, Przewlocka B, Mika J. Mechanisms and pharmacology of diabetic neuropathy - experimental and clinical studies. Pharmacol Rep 2013; 65: 1601-10. https://doi.org/10.1016/S1734-1140(13)71521-4
  5. Gaesser JM, Fyffe-Maricich SL. Intracellular signaling pathway regulation of myelination and remyelination in the CNS. Exp Neurol 2016; 283(Pt B): 501-11. https://doi.org/10.1016/j.expneurol.2016.03.008
  6. Geuna S, Raimondo S, Fregnan F, Haastert-Talini K, Grothe C. In vitro models for peripheral nerve regeneration. Eur J Neurosci 2016; 43: 287-96. https://doi.org/10.1111/ejn.13054
  7. 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. https://doi.org/10.1046/j.1529-8027.2002.02005.x
  8. Pham VM, Matsumura S, Katano T, Funatsu N, Ito S. Diabetic neuropathy research: from mouse models to targets for treatment. Neural Regen Res 2019; 14: 1870-9. https://doi.org/10.4103/1673-5374.259603
  9. Hao W, Tashiro S, Hasegawa T, Sato Y, Kobayashi T, Tando T, et al. Hyperglycemia promotes Schwann cell de-differentiation and de-myelination via sorbitol accumulation and Igf1 protein down-regulation. J Biol Chem 2015; 290: 17106-15. https://doi.org/10.1074/jbc.M114.631291
  10. Almhanna K, Wilkins PL, Bavis JR, Harwalkar S, BertiMattera LN. Hyperglycemia triggers abnormal signaling and proliferative responses in Schwann cells. Neurochem Res 2002; 27: 1341-7. https://doi.org/10.1023/A:1021671615939
  11. Russell JW, Golovoy D, Vincent AM, Mahendru P, Olzmann JA, Mentzer A, et al. High glucose-induced oxidative stress and mitochondrial dysfunction in neurons. FASEB J 2002; 16: 1738-48. https://doi.org/10.1096/fj.01-1027com
  12. 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. https://doi.org/10.1042/CBI20100523
  13. Vincent AM, Brownlee M, Russell JW. Oxidative stress and programmed cell death in diabetic neuropathy. Ann N Y Acad Sci 2002; 959: 368-83. https://doi.org/10.1111/j.1749-6632.2002.tb02108.x
  14. Kamiya H, Nakamura J, Hamada Y, Nakashima E, Naruse K, Kato K, et al. Polyol pathway and protein kinase C activity of rat Schwannoma cells. Diabetes Metab Res Rev 2003; 19: 131-9. https://doi.org/10.1002/dmrr.354
  15. Sango K, Suzuki T, Yanagisawa H, Takaku S, Hirooka H, Tamura M, et al. High glucose-induced activation of the polyol pathway and changes of gene expression profiles in immortalized adult mouse Schwann cells IMS32. J Neurochem 2006; 98: 446-58. https://doi.org/10.1111/j.1471-4159.2006.03885.x
  16. Russell JW, Cheng HL, Golovoy D. Insulin-like growth factorI promotes myelination of peripheral sensory axons. J Neuropathol Exp Neurol 2000; 59: 575-84. https://doi.org/10.1093/jnen/59.7.575
  17. Shindo H, Thomas TP, Larkin DD, Karihaloo AK, Inada H, Onaya T, et al. Modulation of basal nitric oxide-dependent cyclic-GMP production by ambient glucose, myo-inositol, and protein kinase C in SH-SY5Y human neuroblastoma cells. J Clin Invest 1996; 97: 736-45. https://doi.org/10.1172/JCI118472
  18. Koshimura K, Tanaka J, Murakami Y, Kato Y. Effect of high concentration of glucose on dopamine release from pheochromocytoma-12 cells. Metabolism 2003; 52: 922-6. https://doi.org/10.1016/S0026-0495(03)00059-3
  19. Koshimura K, Tanaka J, Murakami Y, Kato Y. Involvement of nitric oxide in glucose toxicity on differentiated PC12 cells: prevention of glucose toxicity by tetrahydrobiopterin, a cofactor for nitric oxide synthase. Neurosci Res 2002; 43: 31-8. https://doi.org/10.1016/S0168-0102(02)00016-0
  20. Roder PV, Wu B, Liu Y, Han W. Pancreatic regulation of glucose homeostasis. Exp Mol Med 2016; 48: e219. https://doi.org/10.1038/emm.2016.6
  21. Grote CW, Wright DE. A role for insulin in diabetic neuropathy. Front Neurosci 2016; 10: 581. https://doi.org/10.3389/fnins.2016.00581
  22. McCloy RA, Rogers S, Caldon CE, Lorca T, Castro A, Burgess A. Partial inhibition of Cdk1 in G 2 phase overrides the SAC and decouples mitotic events. Cell Cycle 2014; 13: 1400-12. https://doi.org/10.4161/cc.28401
  23. More HL, Chen J, Gibson E, Donelan JM, Beg MF. A semi-automated method for identifying and measuring myelinated nerve fibers in scanning electron microscope images. J Neurosci Methods 2011; 201: 149-58. https://doi.org/10.1016/j.jneumeth.2011.07.026
  24. Bhatheja K, Field J. Schwann cells: origins and role in axonal maintenance and regeneration. Int J Biochem Cell Biol 2006; 38: 1995-9. https://doi.org/10.1016/j.biocel.2006.05.007
  25. Tian L, Prabhakaran MP, Ramakrishna S. Strategies for regeneration of components of nervous system: scaffolds, cells and biomolecules. Regen Biomater 2015; 2: 31-45. https://doi.org/10.1093/rb/rbu017
  26. Duraikannu A, Krishnan A, Chandrasekhar A, Zochodne DW. Beyond trophic factors: exploiting the intrinsic regenerative properties of adult neurons. Front Cell Neurosci 2019; 13: 128. https://doi.org/10.3389/fncel.2019.00128
  27. Nave KA. Myelination and the trophic support of long axons. Nat Rev Neurosci 2010; 11: 275-83. https://doi.org/10.1038/nrn2797
  28. Veves A, King GL. Can VEGF reverse diabetic neuropathy in human subjects? J Clin Invest 2001; 107: 1215-8. https://doi.org/10.1172/JCI13038
  29. Chklovskii DB. Synaptic connectivity and neuronal morphology: two sides of the same coin. Neuron 2004; 43: 609-17.
  30. Kastellakis G, Cai DJ, Mednick SC, Silva AJ, Poirazi P. Synaptic clustering within dendrites: an emerging theory of memory formation. Prog Neurobiol 2015; 126: 19-35. https://doi.org/10.1016/j.pneurobio.2014.12.002
  31. Pham VM, Tu NH, Katano T, Matsumura S, Saito A, Yamada A, et al. Impaired peripheral nerve regeneration in type-2 diabetic mouse model. Eur J Neurosci 2018; 47: 126-39. https://doi.org/10.1111/ejn.13771
  32. Serafin A, Molin J, Marquez M, Blasco E, Vidal E, Foradada L, et al. Diabetic neuropathy: electrophysiological and morphological study of peripheral nerve degeneration and regeneration in transgenic mice that express IFNbeta in beta cells. Muscle Nerve 2010; 41: 630-41. https://doi.org/10.1002/mus.21564
  33. Muthuraman A, Ramesh M, Sood S. Development of animal model for vasculatic neuropathy: induction by ischemic-reperfusion in the rat femoral artery. J Neurosci Methods 2010; 186: 215-21. https://doi.org/10.1016/j.jneumeth.2009.12.004
  34. Salzer JL, Zalc B. Myelination. Curr Biol 2016; 26: R971-5. https://doi.org/10.1016/j.cub.2016.07.074
  35. Namgung U. The role of Schwann cell-axon interaction in peripheral nerve regeneration. Cells Tissues Organs 2014; 200: 6-12. https://doi.org/10.1159/000370324
  36. Hyung S, Yoon Lee B, Park JC, Kim J, Hur EM, Francis Suh JK. Coculture of primary motor neurons and Schwann cells as a model for in vitro myelination. Sci Rep 2015; 5: 15122. https://doi.org/10.1038/srep15122
  37. 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. https://doi.org/10.1016/j.nbd.2007.07.022
  38. O'Brien PD, Sakowski SA, Feldman EL. Mouse models of diabetic neuropathy. ILAR J 2014; 54: 259-72. https://doi.org/10.1093/ilar/ilt052
  39. Schmidt RE, Green KG, Snipes LL, Feng D. Neuritic dystrophy and neuronopathy in Akita (Ins2(Akita)) diabetic mouse sympathetic ganglia. Exp Neurol 2009; 216: 207-18. https://doi.org/10.1016/j.expneurol.2008.11.019
  40. Murakami T, Iwanaga T, Ogawa Y, Fujita Y, Sato E, Yoshitomi H, et al. Development of sensory neuropathy in streptozotocin-induced diabetic mice. Brain Behav 2013; 3: 35-41. https://doi.org/10.1002/brb3.111
  41. De Gregorio C, Contador D, Campero M, Ezquer M, Ezquer F. Characterization of diabetic neuropathy progression in a mouse model of type 2 diabetes mellitus. Biol Open 2018; 7: bio036830. https://doi.org/10.1242/bio.036830
  42. Tong Z, Segura-Feliu M, Seira O, Homs-Corbera A, Del Rio JA, Samitier J. A microfluidic neuronal platform for neuron axotomy and controlled regenerative studies. RSC Adv 2015; 5: 73457-66. https://doi.org/10.1039/C5RA11522A
  43. Srinivasan S, Stevens M, Wiley JW. Diabetic peripheral neuropathy: evidence for apoptosis and associated mitochondrial dysfunction. Diabetes 2000; 49: 1932-8. https://doi.org/10.2337/diabetes.49.11.1932
  44. Zochodne DW. Mechanisms of diabetic neuron damage: molecular pathways. Handb Clin Neurol 2014; 126: 379-99. https://doi.org/10.1016/B978-0-444-53480-4.00028-X
  45. Ramji N, Toth C, Kennedy J, Zochodne DW. Does diabetes mellitus target motor neurons? Neurobiol Dis 2007; 26: 301-11. https://doi.org/10.1016/j.nbd.2006.11.016
  46. Hameed S. Nav1.7 and Nav1.8: role in the pathophysiology of pain. Mol Pain 2019; 15: 1744806919858801. https://doi.org/10.1177/1744806919858801
  47. Zochodne DW. Diabetes and the plasticity of sensory neurons. Neurosci Lett 2015; 596: 60-5. https://doi.org/10.1016/j.neulet.2014.11.017
  48. Kerner W, Bruckel J; German Diabetes Association. Definition, classification and diagnosis of diabetes mellitus. Exp Clin Endocrinol Diabetes 2014; 122: 384-6. https://doi.org/10.1055/s-0034-1366278
  49. Krishnamurthy M, Li J, Al-Masri M, Wang R. Expression and function of alphabeta1 integrins in pancretic beta (INS-1) cells. J Cell Commun Signal 2008; 2: 67-79. https://doi.org/10.1007/s12079-008-0030-6
  50. 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. https://doi.org/10.1016/j.peptides.2012.04.012