Skip to main content
SpringerLink
Log in

Targeting the Mitochondrion in Diabetic Neuropathy

  • Chapter
  • First Online:
Diabetic Neuropathy

Part of the book series: Contemporary Diabetes ((CDI))

Abstract

Dysfunction of mitochondria and signaling pathways related to their function can lead to diabetic peripheral neuropathy, and understanding these mechanisms is key to developing new therapies. Though the pathophysiology of diabetic neuropathy (DN) is complex, specific pathways that regulate mitochondrial function are potential targets for therapy. Oxidative stress and nitrosative stress trigger several pathways that induce neuroinflammation associated with the pathophysiology of diabetic neuropathy. Mitochondrial dysfunction in neurons and axons is amplified by aberrant glycemic and hyperlipidemic metabolism resulting in abnormal DNA structure and protein generation. Mitochondrial function can be regulated by transcription factors such as SIRT1, PGC-1α, and TFAM upregulation of these transcription factors improves diabetic neuropathy. Nrf2, which facilitates the expression of several antioxidant proteins via antioxidant response element (ARE) binding sites, affects the progression of diabetic neuropathy. Other pathways that modulate injury to the peripheral nerve are TGF-β, AGEs, glyoxalase 1, PKC, and molecular chaperones. Potential mitochondrial-related pathways that can be targeted for treatment are discussed.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
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

References

  1. Vincent AM, Olzmann JA, Brownlee M, Sivitz WI, Russell JW. Uncoupling proteins prevent glucose-induced neuronal oxidative stress and programmed cell death. Diabetes. 2004;53:726–34.

    CAS  PubMed  Google Scholar 

  2. Chandrasekaran K, Anjaneyulu M, Choi J, Kumar P, Salimian M, Ho CY, et al. Role of mitochondria in diabetic peripheral neuropathy: Influencing the NAD(+)-dependent SIRT1-PGC-1alpha-TFAM pathway. Int Rev Neurobiol. 2019;145:177–209.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Chandrasekaran K, Anjaneyulu M, Inoue T, Choi J, Sagi AR, Chen C, et al. Mitochondrial transcription factor A regulation of mitochondrial degeneration in experimental diabetic neuropathy. Am J Physiol Endocrinol Metab. 2015;309(2):E132–E41.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Choi J, Chandrasekaran K, Inoue T, Muragundla A, Russell JW. PGC-1α regulation of mitochondrial degeneration in experimental diabetic neuropathy. Neurobiol Dis. 2014;64:118–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Rumora AE, Savelieff MG, Sakowski SA, Feldman EL. Disorders of mitochondrial dynamics in peripheral neuropathy: clues from hereditary neuropathy and diabetes. Int Rev Neurobiol. 2019;145:127–76.

    CAS  PubMed  Google Scholar 

  6. Fernyhough P. Mitochondrial dysfunction in diabetic neuropathy: a series of unfortunate metabolic events. Curr Diab Rep. 2015;15(11):89–0671.

    PubMed  Google Scholar 

  7. Russell JW, Berent-Spillson A, Vincent AM, Freimann CL, Sullivan KA, Feldman EL. Oxidative injury and neuropathy in diabetes and impaired glucose tolerance. Neurobiol Dis. 2008;30(3):420–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Cowell RM, Kennedy E, Berent-Spillson A, Sundkvist G, Russell JW. Regulation of mitochondrial biogenesis in Schwann cells: implications for diabetic neuropathy. Ann Neurol. 2005;58:S29.

    Google Scholar 

  9. 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. 2002;16(13):1738–48.

    CAS  Google Scholar 

  10. Vincent AM, Calabek B, Roberts L, Feldman EL. Biology of diabetic neuropathy. Handb Clin Neurol. 2013;115:591–606.

    PubMed  Google Scholar 

  11. Puigserver P. Tissue-specific regulation of metabolic pathways through the transcriptional coactivator PGC1-alpha. Int J Obes. 2005;29(1):5–9.

    Google Scholar 

  12. Puigserver P, Spiegelman BM. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev. 2003;24(1):78–90.

    CAS  PubMed  Google Scholar 

  13. St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jager S, et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell. 2006;127(2):397–408.

    CAS  PubMed  Google Scholar 

  14. Johri A, Calingasan NY, Hennessey TM, Sharma A, Yang L, Wille E, et al. Pharmacologic activation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntington’s disease. Hum Mol Genet. 2012;21(5):1124–37.

    CAS  PubMed  Google Scholar 

  15. Scarpulla RC, Vega RB, Kelly DP. Transcriptional integration of mitochondrial biogenesis. Trends Endocrinol Metab. 2012;23(9):459–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell. 1999;98(1):115–24.

    CAS  PubMed  Google Scholar 

  17. Esterbauer H, Oberkofler H, Krempler F, Patsch W. Human peroxisome proliferator activated receptor gamma coactivator 1 (PPARGC1) gene: cDNA sequence, genomic organization, chromosomal localization, and tissue expression. Genomics. 1999;62(1):98–102.

    CAS  PubMed  Google Scholar 

  18. Andrulionyte L, Kuulasmaa T, Chiasson JL, Laakso M. Single nucleotide polymorphisms of the peroxisome proliferator-activated receptor-alpha gene (PPARA) influence the conversion from impaired glucose tolerance to type 2 diabetes: the STOP-NIDDM trial. Diabetes. 2007;56(4):1181–6.

    CAS  PubMed  Google Scholar 

  19. Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003;34(3):267–73.

    CAS  PubMed  Google Scholar 

  20. Roy Chowdhury SK, Smith DR, Saleh A, Schapansky J, Marquez A, Gomes S, et al. Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes. Brain. 2012;135(6):1751–66.

    PubMed  PubMed Central  Google Scholar 

  21. Chowdhury SK, Smith DR, Fernyhough P. The role of aberrant mitochondrial bioenergetics in diabetic neuropathy. Neurobiol Dis. 2013;51:56–65.

    CAS  PubMed  Google Scholar 

  22. Canto C, Auwerx J. Calorie restriction: is AMPK a key sensor and effector? Physiology. 2011;26(4):214–24.

    CAS  PubMed  Google Scholar 

  23. Fernyhough P, Jonathan M. Mechanisms of disease: mitochondrial dysfunction in sensory neuropathy and other complications in diabetes. Handb Clin Neurol. 2014;126:353–77.

    PubMed  Google Scholar 

  24. Callaghan BC, Cheng HT, Stables CL, Smith AL, Feldman EL. Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol. 2012;11(6):521–34.

    PubMed  PubMed Central  Google Scholar 

  25. Vincent AM, Callaghan BC, Smith AL, Feldman EL. Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat Rev Neurol. 2011;7(10):573–83.

    CAS  PubMed  Google Scholar 

  26. Vincent AM, Hinder LM, Pop-Busui R, Feldman EL. Hyperlipidemia: a new therapeutic target for diabetic neuropathy. J Peripher Nerv Syst. 2009;14(4):257–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Vincent AM, Hayes JM, McLean LL, Vivekanandan-Giri A, Pennathur S, Feldman EL. Dyslipidemia-induced neuropathy in mice: the role of oxLDL/LOX-1. Diabetes. 2009;58(10):2376–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Heilbronn LK, Gregersen S, Shirkhedkar D, Hu D, Campbell LV. Impaired fat oxidation after a single high-fat meal in insulin-sensitive nondiabetic individuals with a family history of type 2 diabetes. Diabetes. 2007;56(8):2046–53.

    CAS  PubMed  Google Scholar 

  29. Kleiner S, Mepani RJ, Laznik D, Ye L, Jurczak MJ, Jornayvaz FR, et al. Development of insulin resistance in mice lacking PGC-1alpha in adipose tissues. Proc Natl Acad Sci U S A. 2012;109(24):9635–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Mootha VK, Handschin C, Arlow D, Xie X, St Pierre J, Sihag S, et al. Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proc Natl Acad Sci U S A. 2004;101(17):6570–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S, et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc Natl Acad Sci U S A. 2003;100(14):8466–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR, Boudina S, et al. PGC-1a deficient mice exhibit multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control, and hepatic steatosis. PLoS Biol. 2005;3:e101.

    PubMed  PubMed Central  Google Scholar 

  33. Farge G, Mehmedovic M, Baclayon M, van den Wildenberg SM, Roos WH, Gustafsson CM, et al. In vitro-reconstituted nucleoids can block mitochondrial DNA replication and transcription. Cell Rep. 2014;8(1):66–74.

    CAS  PubMed  Google Scholar 

  34. Alam TI, Kanki T, Muta T, Ukaji K, Abe Y, Nakayama H, et al. Human mitochondrial DNA is packaged with TFAM. Nucleic Acids Res. 2003;31(6):1640–5.

    CAS  PubMed  Google Scholar 

  35. Ohgaki K, Kanki T, Fukuoh A, Kurisaki H, Aoki Y, Ikeuchi M, et al. The C-terminal tail of mitochondrial transcription factor a markedly strengthens its general binding to DNA. J Biochem. 2007;141(2):201–11.

    CAS  PubMed  Google Scholar 

  36. Wang YE, Marinov GK, Wold BJ, Chan DC. Genome-wide analysis reveals coating of the mitochondrial genome by TFAM. PLoS One. 2013;8(8):e74513.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Morimoto N, Miyazaki K, Kurata T, Ikeda Y, Matsuura T, Kang D, et al. Effect of mitochondrial transcription factor a overexpression on motor neurons in amyotrophic lateral sclerosis model mice. J Neurosci Res. 2012;90(6):1200–8.

    CAS  PubMed  Google Scholar 

  38. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417(1):1–13.

    CAS  PubMed  Google Scholar 

  39. Chandrasekaran K, Salimian M, Konduru SR, Choi J, Kumar P, Long A, et al. Overexpression of Sirtuin 1 protein in neurons prevents and reverses experimental diabetic neuropathy. Brain. 2019;142(12):3737–52.

    PubMed  PubMed Central  Google Scholar 

  40. Chandrasekaran K, Chen C, Sagi AR, Russell JW. A nicotinamide adenine nucleotide (NAD+) precursor is a potential therapy for diabetic neuropathy. J Neuromusc Dis. 2016;3(1):S86.

    Google Scholar 

  41. Chandrasekaran K, Najimi N, Kumar P, Russell JW. Nicotinamide riboside is a potential therapy for diabetic neuropathy. Neurodiab; Bucharest, Romania. 2016.

    Google Scholar 

  42. Trammell SA, Weidemann BJ, Chadda A, Yorek MS, Holmes A, Coppey LJ, et al. Nicotinamide riboside opposes type 2 diabetes and neuropathy in mice. Sci Rep. 2016;6:26933. https://doi.org/10.1038/srep26933.:26933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Feldman EL, Callaghan BC, Pop-Busui R, Zochodne DW, Wright DE, Bennett DL, et al. Diabetic neuropathy. Nat Rev Dis Primers. 2019;5(1):41.

    PubMed  Google Scholar 

  44. Sena LA, Chandel NS. Physiological roles of mitochondrial reactive oxygen species. Mol Cell. 2012;48(2):158–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Milenkovic D, Blaza JN, Larsson NG, Hirst J. The enigma of the respiratory chain supercomplex. Cell Metab. 2017;25(4):765–76.

    CAS  PubMed  Google Scholar 

  46. Topf U, Suppanz I, Samluk L, Wrobel L, Boser A, Sakowska P, et al. Quantitative proteomics identifies redox switches for global translation modulation by mitochondrially produced reactive oxygen species. Nat Commun. 2018;9(1):324.

    PubMed  PubMed Central  Google Scholar 

  47. Pfanner N, Warscheid B, Wiedemann N. Mitochondrial proteins: from biogenesis to functional networks. Nat Rev Mol Cell Biol. 2019;20(5):267–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Cowell RM, Russell JW. Peripheral neuropathy and the Schwann cell. In: Kettenmann H, Ransom BR, editors. Neuroglia. 2nd ed. Oxford: Oxford University Press; 2004. p. 573–85.

    Google Scholar 

  49. Vincent AM, Russell JW, Sullivan KA, Backus C, Hayes JM, McLean LL, et al. SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy. Exp Neurol. 2007;208(2):216–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Mendez MM, Folgado J, Tormo C, Artero A, Ascaso M, Martinez-Hervas S, et al. Altered glutathione system is associated with the presence of distal symmetric peripheral polyneuropathy in type 2 diabetic subjects. J Diabetes Complicat. 2015;29(7):923–7.

    Google Scholar 

  51. Kumar A, Mittal R. Nrf2: a potential therapeutic target for diabetic neuropathy. Inflammopharmacology. 2017;25(4):393–402.

    CAS  PubMed  Google Scholar 

  52. Jimenez-Osorio AS, Gonzalez-Reyes S, Pedraza-Chaverri J. Natural Nrf2 activators in diabetes. Clin Chim Acta. 2015;448:182–92.

    CAS  PubMed  Google Scholar 

  53. Agca CA, Tuzcu M, Hayirli A, Sahin K. Taurine ameliorates neuropathy via regulating NF-kappaB and Nrf2/HO-1 signaling cascades in diabetic rats. Food Chem Toxicol. 2014;71:116–21.

    CAS  PubMed  Google Scholar 

  54. Sandireddy R, Yerra VG, Komirishetti P, Areti A, Kumar A. Fisetin imparts neuroprotection in experimental diabetic neuropathy by modulating Nrf2 and NF-kappaB pathways. Cell Mol Neurobiol. 2016;36(6):883–92.

    CAS  PubMed  Google Scholar 

  55. Maiese K. Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR. Neural Regen Res. 2016;11(3):372–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Mazucanti CH, Cabral-Costa JV, Vasconcelos AR, Andreotti DZ, Scavone C, Kawamoto EM. Longevity pathways (mTOR, SIRT, Insulin/IGF-1) as key modulatory targets on aging and neurodegeneration. Curr Top Med Chem. 2015;15(21):2116–38.

    CAS  PubMed  Google Scholar 

  57. Cowell RM, Russell JW. Nitrosative injury and antioxidant therapy in the management of diabetic neuropathy. J Investig Med. 2004;52(1):33–44.

    CAS  PubMed  Google Scholar 

  58. Stavniichuk R, Shevalye H, Lupachyk S, Obrosov A, Groves JT, Obrosova IG, et al. Peroxynitrite and protein nitration in the pathogenesis of diabetic peripheral neuropathy. Diabetes Metab Res Rev. 2014;30(8):669–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Muller-Stich BP, Billeter AT, Fleming T, Fischer L, Buchler MW, Nawroth PP. Nitrosative stress but not glycemic parameters correlate with improved neuropathy in nonseverely obese diabetic patients after Roux-Y gastric bypass. Surg Obes Relat Dis. 2015;11(4):847–54.

    PubMed  Google Scholar 

  60. Nigro C, Leone A, Fiory F, Prevenzano I, Nicolo A, Mirra P, et al. Dicarbonyl stress at the crossroads of healthy and unhealthy aging. Cell. 2019;8(7):749.

    CAS  Google Scholar 

  61. Jiating L, Buyun J, Yinchang Z. Role of metformin on osteoblast differentiation in type 2 diabetes. Biomed Res Int. 2019;2019:9203934.

    PubMed  PubMed Central  Google Scholar 

  62. Park S, Kang HJ, Jeon JH, Kim MJ, Lee IK. Recent advances in the pathogenesis of microvascular complications in diabetes. Arch Pharm Res. 2019;42(3):252–62.

    CAS  PubMed  Google Scholar 

  63. Toth C, Rong LL, Yang C, Martinez J, Song F, Ramji N, et al. Receptor for advanced glycation end products (RAGEs) and experimental diabetic neuropathy. Diabetes. 2008;57(4):1002–17.

    CAS  PubMed  Google Scholar 

  64. Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006;114(6):597–605.

    CAS  PubMed  Google Scholar 

  65. Vincent AM, Perrone L, Sullivan KA, Backus C, Sastry AM, Lastoskie C, et al. Receptor for advanced glycation end products activation injures primary sensory neurons via oxidative stress. Endocrinology. 2007;148(2):548–58.

    CAS  PubMed  Google Scholar 

  66. Kanwar YS, Sun L, Xie P, Liu FY, Chen S. A glimpse of various pathogenetic mechanisms of diabetic nephropathy. Annu Rev Pathol. 2011;6:395–423. https://doi.org/10.1146/annurev.pathol.4.110807.092150.:395-423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Haslbeck KM, Schleicher E, Bierhaus A, Nawroth P, Haslbeck M, Neundorfer B, 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(5):288–91.

    CAS  PubMed  Google Scholar 

  68. Anjaneyulu M, Berent-Spillson A, Inoue T, Choi J, Cherian K, Russell JW. Transforming growth factor-beta induces cellular injury in experimental diabetic neuropathy. Exp Neurol. 2008;211(2):469–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Toth C, Rong LL, Yang C, Martinez J, Song F, Ramji N, et al. Receptor for advanced glycation end products (RAGEs) and experimental diabetic neuropathy. Diabetes. 2007;57:1002–17.

    PubMed  Google Scholar 

  70. Ray R, Juranek JK, Rai V. RAGE axis in neuroinflammation, neurodegeneration and its emerging role in the pathogenesis of amyotrophic lateral sclerosis. Neurosci Biobehav Rev. 2016;62:48–55.

    CAS  PubMed  Google Scholar 

  71. Morgenstern J, Fleming T, Schumacher D, Eckstein V, Freichel M, Herzig S, et al. Loss of glyoxalase 1 induces compensatory mechanism to achieve dicarbonyl detoxification in mammalian schwann cells. J Biol Chem. 2017;292(8):3224–38.

    CAS  PubMed  Google Scholar 

  72. Jack MM, Ryals JM, Wright DE. Characterisation of glyoxalase I in a streptozocin-induced mouse model of diabetes with painful and insensate neuropathy. Diabetologia. 2011;54(8):2174–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Alderson NL, Chachich ME, Youssef NN, Beattie RJ, Nachtigal M, Thorpe SR, et al. The AGE inhibitor pyridoxamine inhibits lipemia and development of renal and vascular disease in Zucker obese rats. Kidney Int. 2003;63(6):2123–33.

    CAS  PubMed  Google Scholar 

  74. Archer AE, Von Schulze AT, Geiger PC. Exercise, heat shock proteins and insulin resistance. Philos Trans R Soc Lond Ser B Biol Sci. 2018;373:1738.

    Google Scholar 

  75. Mayer MP, Bukau B. Hsp70 chaperones: cellular functions and molecular mechanism. Cell Mol Life Sci. 2005;62(6):670–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Peterson LB, Blagg BS. To fold or not to fold: modulation and consequences of Hsp90 inhibition. Future Med Chem. 2009;1(2):267–83.

    CAS  PubMed  Google Scholar 

  77. Henstridge DC, Whitham M, Febbraio MA. Chaperoning to the metabolic party: the emerging therapeutic role of heat-shock proteins in obesity and type 2 diabetes. Mol Metab. 2014;3(8):781–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Farmer KL, Li C, Dobrowsky RT. Diabetic peripheral neuropathy: should a chaperone accompany our therapeutic approach? Pharmacol Rev. 2012;64(4):880–900.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Dobrowsky RT. Targeting the diabetic chaperome to improve peripheral neuropathy. Curr Diab Rep. 2016;16(8):71.

    PubMed  PubMed Central  Google Scholar 

  80. Murphy M, Hickey F, Godson C. IHG-1 amplifies TGF-beta1 signalling and mitochondrial biogenesis and is increased in diabetic kidney disease. Curr Opin Nephrol Hypertens. 2013;22(1):77–84.

    CAS  PubMed  Google Scholar 

  81. Hussain G, Rizvi SA, Singhal S, Zubair M, Ahmad J. Serum levels of TGF-beta1 in patients of diabetic peripheral neuropathy and its correlation with nerve conduction velocity in type 2 diabetes mellitus. Diabetes Metab Syndr. 2016;10(1):135–9.

    Google Scholar 

  82. Tan CK, Chong HC, Tan EH, Tan NS. Getting ‘Smad’ about obesity and diabetes. Nutr Diabetes. 2012;2:e29.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Berent-Spillson A, Robinson A, Golovoy D, Slusher B, Rojas C, Russell JW. Protection against glucose-induced neuronal death by NAAG and GCP II inhibition is regulated by mGluR3. J Neurochem. 2004;89:90–9.

    CAS  PubMed  Google Scholar 

  84. Choi DW. Excitotoxic cell-death. J Neurobiol. 1992;23(9):1261–76.

    CAS  PubMed  Google Scholar 

  85. Miller KE, Richards BA, Kriebel RM. Glutamine-, glutamine synthetase-, glutamate dehydrogenase- and pyruvate carboxylase-immunoreactivities in the rat dorsal root ganglion and peripheral nerve. Brain Res. 2002;945(2):202–11.

    CAS  PubMed  Google Scholar 

  86. Cangro CB, Sweetnam PM, Wrathall JR, Haser WB, Curthoys NP, Neale JH. Localization of elevated glutaminase immunoreactivity in small DRG neurons. Brain Res. 1985;336(1):158–61.

    CAS  PubMed  Google Scholar 

  87. Carozzi VA, Canta A, Oggioni N, Ceresa C, Marmiroli P, Konvalinka J, et al. Expression and distribution of ‘high affinity’ glutamate transporters GLT1, GLAST, EAAC1 and of GCPII in the rat peripheral nervous system. J Anat. 2008;213(5):539–46.

    PubMed  PubMed Central  Google Scholar 

  88. Ohara PT, Vit JP, Bhargava A, Romero M, Sundberg C, Charles AC, et al. Gliopathic pain: when satellite glial cells go bad. Neuroscientist. 2009;15(5):450–63.

    PubMed  PubMed Central  Google Scholar 

  89. Anjaneyulu M, Berent-Spillson A, Russell JW. Metabotropic glutamate receptors (mGluRs) and diabetic neuropathy. Curr Drug Targets. 2008;9(1):85–93.

    CAS  PubMed  Google Scholar 

  90. Berent Spillson A, Russell JW. Metabotropic glutamate receptor regulation of neuronal cell death. Exp Neurol. 2003;184:S97–S105.

    Google Scholar 

  91. Berent-Spillson A, Russell JW. Metabotropic glutamate receptor 3 protects neurons from glucose-induced oxidative injury by increasing intracellular glutathione concentration. J Neurochem. 2007;101(2):342–54.

    CAS  PubMed  Google Scholar 

  92. Howarth C, Gleeson P, Attwell D. Updated energy budgets for neural computation in the neocortex and cerebellum. J Cereb Blood Flow Metab. 2012;32(7):1222–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Rangaraju V, Calloway N, Ryan TA. Activity-driven local ATP synthesis is required for synaptic function. Cell. 2014;156(4):825–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Misgeld T, Schwarz TL. Mitostasis in neurons: maintaining mitochondria in an extended cellular architecture. Neuron. 2017;96(3):651–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Moehlman AT, Youle RJ. Mitochondrial quality control and restraining innate immunity. Annu Rev Cell Dev Biol. 2020;36:265–89.

    CAS  PubMed  Google Scholar 

  96. 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(4):1082–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Zuchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, et al. Mutations in the mitochondrial GTPase mitofusin 2 cause charcot-marie-tooth neuropathy type 2A. Nat Genet. 2004;36(5):449–51.

    PubMed  Google Scholar 

  98. Kijima K, Numakura C, Izumino H, Umetsu K, Nezu A, Shiiki T, et al. Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A. Hum Genet. 2005;116(1-2):23–7.

    CAS  PubMed  Google Scholar 

  99. Alexander C, Votruba M, Pesch UE, Thiselton DL, Mayer S, Moore A, et al. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet. 2000;26(2):211–5.

    CAS  PubMed  Google Scholar 

  100. Delettre C, Lenaers G, Griffoin JM, Gigarel N, Lorenzo C, Belenguer P, et al. Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet. 2000;26(2):207–10.

    CAS  PubMed  Google Scholar 

  101. Yu-Wai-Man P, Griffiths PG, Gorman GS, Lourenco CM, Wright AF, Auer-Grumbach M, et al. Multi-system neurological disease is common in patients with OPA1 mutations. Brain. 2010;133(3):771–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Dyall SD, Brown MT, Johnson PJ. Ancient invasions: from endosymbionts to organelles. Science. 2004;304(5668):253–7.

    CAS  PubMed  Google Scholar 

  103. Iyer SS, He Q, Janczy JR, Elliott EI, Zhong Z, Olivier AK, et al. Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation. Immunity. 2013;39(2):311–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. West AP, Shadel GS. Mitochondrial DNA in innate immune responses and inflammatory pathology. Nat Rev Immunol. 2017;17(6):363–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Starobova H, Monteleone M, Adolphe C, Batoon L, Sandrock CJ, Tay B, et al. Vincristine-induced peripheral neuropathy is driven by canonical NLRP3 activation and IL-1beta release. J Exp Med. 2021;218(5):e20201452.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Savelieff MG, Feldman EL. Immune-mediated vincristine-induced neuropathy: unlocking therapies. J Exp Med. 2021;218(5):e20210286.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Jia M, Wu C, Gao F, Xiang H, Sun N, Peng P, et al. Activation of NLRP3 inflammasome in peripheral nerve contributes to paclitaxel-induced neuropathic pain. Mol Pain. 2017;13:1744806917719804.

    CAS  PubMed  Google Scholar 

  108. Kumar A, Negi G, Sharma SS. Suppression of NF-kappaB and NF-kappaB regulated oxidative stress and neuroinflammation by BAY 11-7082 (IkappaB phosphorylation inhibitor) in experimental diabetic neuropathy. Biochimie. 2012;94(5):1158–65.

    CAS  PubMed  Google Scholar 

  109. Zilliox LA, Russell JW. Physical activity and dietary interventions in diabetic neuropathy: a systematic review. Clin Auton Res. 2019;4:443–55.

    Google Scholar 

  110. Smith AG, Russell JW, Feldman EL, Goldstein J, Peltier A, Smith S, et al. Lifestyle intervention for prediabetic neuropathy. Diabetes Care. 2006;29:1294–9.

    PubMed  Google Scholar 

  111. Russell JW, Kaminsky AJ. Oxidative injury in diabetic neuropathy. In: Opara E, editor. Nutrition and diabetes: pathophysiology and management. Boca Raton: Taylor & Francis; 2005. p. 381–97.

    Google Scholar 

  112. Kobilo T, Guerrieri D, Zhang Y, Collica SC, Becker KG, van Praag H. AMPK agonist AICAR improves cognition and motor coordination in young and aged mice. Learn Mem. 2014;21(2):119–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Chandrasekaran K, Choi J, Arvas MI, Salimian M, Singh S, Xu S, et al. Nicotinamide mononucleotide administration prevents experimental diabetes-induced cognitive impairment and loss of hippocampal neurons. Int J Mol Sci. 2020;21(11):3756.

    CAS  PubMed Central  Google Scholar 

  114. Hinder LM, O’Brien PD, Hayes JM, Backus C, Solway AP, Sims-Robinson C, et al. Dietary reversal of neuropathy in a murine model of prediabetes and metabolic syndrome. Dis Model Mech. 2017;10(6):717–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Cooper MA, Menta BW, Perez-Sanchez C, Jack MM, Khan ZW, Ryals JM, et al. A ketogenic diet reduces metabolic syndrome-induced allodynia and promotes peripheral nerve growth in mice. Exp Neurol. 2018;306:149–57.

    PubMed  PubMed Central  Google Scholar 

  116. Coppey L, Davidson E, Shevalye H, Torres ME, Yorek MA. Effect of dietary oils on peripheral neuropathy-related endpoints in dietary obese rats. Diabetes Metab Syndr Obes. 2018;11:117–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Lewis EJH, Perkins BA, Lovblom LE, Bazinet RP, Wolever TMS, Bril V. Effect of omega-3 supplementation on neuropathy in type 1 diabetes: a 12-month pilot trial. Neurology. 2017;88(24):2294–301.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Teodoro JS, Gomes AP, Varela AT, Duarte FV, Rolo AP, Palmeira CM. Uncovering the beginning of diabetes: the cellular redox status and oxidative stress as starting players in hyperglycemic damage. Mol Cell Biochem. 2013;376(1-2):103–10.

    CAS  PubMed  Google Scholar 

  119. Ang L, Jaiswal M, Martin C, Pop-Busui R. Glucose control and diabetic neuropathy: lessons from recent large clinical trials. Curr Diab Rep. 2014;14(9):528.

    PubMed  PubMed Central  Google Scholar 

  120. UK Prospective Diabetes Study (UKPDS). Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837–53.

    Google Scholar 

  121. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(2):129–39.

    CAS  PubMed  Google Scholar 

  122. Azad N, Emanuele NV, Abraira C, Henderson WG, Colwell J, Levin SR, et al. The effects of intensive glycemic control on neuropathy in the VA cooperative study on type II diabetes mellitus (VA CSDM). J Diabetes Complicat. 1999;13:307–13.

    CAS  Google Scholar 

  123. Albers JW, Herman WH, Pop-Busui R, Feldman EL, Martin CL, Cleary PA, et al. Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. Diabetes Care. 2010;33(5):1090–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393–403.

    CAS  PubMed  Google Scholar 

  125. Diabetes Prevention Program Research Group. The 10-year cost-effectiveness of lifestyle intervention or metformin for diabetes prevention: an intent-to-treat analysis of the DPP/DPPOS. Diabetes Care. 2012;35(4):723–30.

    Google Scholar 

  126. Singleton JR, Smith AG, Russell JW, Feldman EL. Microvascular complications of impaired glucose tolerance. Diabetes. 2003;52:2867–76.

    CAS  PubMed  Google Scholar 

  127. Balducci S, Iacobellis G, Parisi L, Di Biase N, Calandriello E, Leonetti F, et al. Exercise training can modify the natural history of diabetic peripheral neuropathy. J Diabetes Complicat. 2006;20(4):216–23.

    Google Scholar 

  128. Singleton JR, Marcus RL, Jackson JE, Lessard K, Graham TE, Smith AG. Exercise increases cutaneous nerve density in diabetic patients without neuropathy. Ann Clin Transl Neurol. 2014;1(10):844–9.

    PubMed  PubMed Central  Google Scholar 

  129. Singleton JR, Marcus RL, Lessard MK, Jackson JE, Smith AG. Supervised exercise improves cutaneous reinnervation capacity in metabolic syndrome patients. Ann Neurol. 2015;77(1):146–53.

    PubMed  Google Scholar 

  130. Kluding PM, Pasnoor M, Singh R, D'Silva LJ, Yoo M, Billinger SA, et al. Safety of aerobic exercise in people with diabetic peripheral neuropathy: single-group clinical trial. Phys Ther. 2015;95(2):223–34.

    PubMed  Google Scholar 

  131. Kluding PM, Pasnoor M, Singh R, Jernigan S, Farmer K, Rucker J, et al. The effect of exercise on neuropathic symptoms, nerve function, and cutaneous innervation in people with diabetic peripheral neuropathy. J Diabetes Complicat. 2012;26(5):424–9.

    Google Scholar 

  132. Ikuta N, Chikamoto K, Asano Y, Yasui Y, Yokokawa H, Terao K, et al. Time course effect of r-alpha-lipoic acid on cellular metabolomics in cultured hepatoma cells. J Med Food. 2017;20(3):211–22.

    CAS  PubMed  Google Scholar 

  133. Karalis DT, Karalis T, Karalis S, Kleisiari AS, Malakoudi F, Maimari KEV. The effect of alpha-lipoic acid on diabetic peripheral neuropathy and the upcoming depressive disorders of type II diabetics. Cureus. 2021;13(1):e12773.

    PubMed  PubMed Central  Google Scholar 

  134. Papanas N, Ziegler D. Efficacy of alpha-lipoic acid in diabetic neuropathy. Expert Opin Pharmacother. 2014;15(18):2721–31.

    CAS  PubMed  Google Scholar 

  135. Reljanovic M, Reichel G, Rett K, Lobisch M, Schuette K, Moller W, et al. Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): a two year multicenter randomized double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic Acid in Diabetic Neuropathy. Free Radic Res. 1999;31(3):171–9.

    CAS  PubMed  Google Scholar 

  136. Ziegler D, Hanefeld M, Ruhnau KJ, Hasche H, Lobisch M, Schutte K, et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic Acid in Diabetic Neuropathy. Diabetes Care. 1999;22:1296–301.

    CAS  PubMed  Google Scholar 

  137. Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, Low PA, et al. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care. 2006;29(11):2365–70.

    CAS  PubMed  Google Scholar 

  138. Ziegler D, Low PA, Litchy WJ, Boulton AJ, Vinik AI, Freeman R, et al. Efficacy and safety of antioxidant treatment with alpha-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care. 2011;34(9):2054–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Ziegler D, Schatz H, Conrad F, Gries FA, Ulrich H, Reichel G. Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients. A 4-month randomized controlled multicenter trial (DEKAN Study). Deutsche Kardiale Autonome Neuropathie. Diabetes Care. 1997;20(3):369–73.

    CAS  PubMed  Google Scholar 

  140. Ziegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med. 2004;21(2):114–21.

    CAS  PubMed  Google Scholar 

  141. Didangelos T, Karlafti E, Kotzakioulafi E, Kontoninas Z, Margaritidis C, Giannoulaki P, et al. Efficacy and safety of the combination of superoxide dismutase, alpha lipoic acid, vitamin B12, and carnitine for 12 months in patients with diabetic neuropathy. Nutrients. 2020;12(11):3254.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Didangelos T, Karlafti E, Kotzakioulafi E, Margariti E, Giannoulaki P, Batanis G, et al. Vitamin B12 supplementation in diabetic neuropathy: a 1-year, randomized, double-blind, placebo-controlled trial. Nutrients. 2021;13(2):395.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Balakumar P, Rohilla A, Krishan P, Solairaj P, Thangathirupathi A. The multifaceted therapeutic potential of benfotiamine. Pharmacol Res. 2010;61(6):482–8.

    CAS  PubMed  Google Scholar 

  144. Thornalley PJ. The potential role of thiamine (vitamin B1) in diabetic complications. Curr Diabetes Rev. 2005;1(3):287–98.

    CAS  PubMed  Google Scholar 

  145. Stracke H, Gaus W, Achenbach U, Federlin K, Bretzel RG. Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study. Exp Clin Endocrinol Diabetes. 2008;116(10):600–5.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health 1R01DK107007-01A1, Office of Research Development, Department of Veterans Affairs (Biomedical and Laboratory Research Service and Rehabilitation Research and Development, 101RX001030), Diabetes Action Research and Education Foundation, University of Maryland Institute for Clinical & Translational Research (ICTR), and the Baltimore GRECC (JWR), 1K2RX001651 (LAZ).

Author information

Authors and Affiliations

  1. Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA

    Ahmad Hedayat, Krish Chandrasekaran, Lindsay A. Zilliox & James W. Russell

  2. Maryland VA Healthcare System, Baltimore, MD, USA

    Lindsay A. Zilliox & James W. Russell

  3. CAMC Institute for Academic Medicine, Charleston, WV, USA

    James W. Russell

Authors
  1. Ahmad Hedayat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Krish Chandrasekaran
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lindsay A. Zilliox
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. James W. Russell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James W. Russell .

Editor information

Editors and Affiliations

  1. Royal Hallamshire Hospital, Sheffield Teaching Hospitals and the University of Sheffield Director of Diabetes Research, Sheffield, UK

    Solomon Tesfaye

  2. Beth Israel Deaconess Medical Center, Boston, MA, USA

    Christopher H. Gibbons

  3. Weill Cornell Medicine, Cornell University, Doha, Qatar

    Rayaz Ahmed Malik

  4. Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Aristidis Veves

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Hedayat, A., Chandrasekaran, K., Zilliox, L.A., Russell, J.W. (2023). Targeting the Mitochondrion in Diabetic Neuropathy. In: Tesfaye, S., Gibbons, C.H., Malik, R.A., Veves, A. (eds) Diabetic Neuropathy. Contemporary Diabetes. Humana, Cham. https://doi.org/10.1007/978-3-031-15613-7_17

Download citation

  • DOI: https://doi.org/10.1007/978-3-031-15613-7_17

  • Published:

  • Publisher Name: Humana, Cham

  • Print ISBN: 978-3-031-15612-0

  • Online ISBN: 978-3-031-15613-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation