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Egyptian Rheumatology and Rehabilitation
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Tumor necrosis factor-α is a novel biomarker for peripheral neuropathy in type II diabetes mellitus: a clinical and electrophysiological study

Egyptian Rheumatology and Rehabilitation volume 44, pages 83–90 (2017)Cite this article

Abstract

Background

Tumor necrosis factor-α (TNF-α) is an adipocytokine locally produced by Schwann cells and has a role in nerve regeneration and regulation of apoptosis. The role of TNF-α in the development of diabetic peripheral neuropathy (DPN) is controversial.

Objective

The objective of this study was to evaluate TNF-α serum level in a group of type II diabetes mellitus (DM) patients with and without neuropathy in comparison with healthy age-matched control group.

Design

This is a cross-sectional case–control study.

Settings

The study was conducted in outpatient clinics of the diabetes and physical medicine, rheumatology, and rehabilitation departments.

Patients

Ninety patients diagnosed with type II diabetes were included in the study.

Main outcome measures

All patients were assessed for clinical neuropathy using neuropathy symptom score and neuropathy disability score. All patients underwent nerve conduction studies of both upper and lower limbs. They were divided into two groups: group I with confirmed DPN (n=60) and group II with DM but no peripheral neuropathy (n=30). Serum TNF-α level was measured in all previous DM patients (90 patients) in addition to 48 healthy age-matched controls.

Results

A statistically significant difference was detected between serum TNF-α level in controls and diabetic patients. Similarly, a significant difference was detected between its level in non-DPN patients and confirmed DPN patients, being higher in the latter. A positive significant correlation has been detected between TNF-α level and patients’ age, as well as blood cholesterol level. A positive significant correlation has been found between TNF-α level and both neuropathy symptom score and neuropathy disability score. A significant negative correlation had been detected between TNF-α level and motor amplitudes of both tibial nerves.

Conclusion

Serum TNF-α level might be a potential biomarker for peripheral neuropathy in type II DM.

References

  1. Purwata TE. High TNF-alpha plasma levels and macrophages iNOS and TNF-alpha expression as risk factors for painful diabetic neuropathy. J Pain Res 2011; 4:169–175.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Armati PJ, Pollard JD. Immunology of the Schwann cell. Baillieres Clin Neurol 1996; 5:47–64.

    CAS  PubMed  Google Scholar 

  3. Mather KJ, Funahashi T, Matsuzawa Y, Edelstein S, Bray GA, Kahn SE, Goldberg R. Adiponectin, change in adiponectin, and progression to diabetes in the Diabetes Prevention Program. Diabetes 2008; 57:980–986.

    CAS  PubMed  Google Scholar 

  4. Satoh J, Yagihashi S, Toyota T. The possible role of tumor necrosis factor-α in diabetic polyneuropathy. Exp Diabesity Res. 2003; 4:65–71.

    PubMed  PubMed Central  Google Scholar 

  5. Schäfers M, Svensson CI, Sommer C, Sorkin LS. Tumor necrosis factor-α induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J Neurosci 2003; 23:2517–2521.

    PubMed  PubMed Central  Google Scholar 

  6. Dinarello CA. Overview of inflammatory cytokines and their role in pain. In: Watkins LR, Maier SF, editors. Cytokines and pain. Basel, Switzerland: Birkhauser Verlag; 1999. 1–39.

    Google Scholar 

  7. Sharma S, Chopra K, Kulkarni SK. Effect of insulin and its combination with resveratrol or curcumin in attenuation of diabetic neuropathic pain: participation of nitric oxide and TNF-alpha. Phytother Res 2007;21:278–283.

    CAS  PubMed  Google Scholar 

  8. Ferro TJ, Gertzberg N, Selden L, Neumann P, Johnson A. Endothelial barrier dysfunction and p42 oxidation induced by TNF-alpha are mediated by nitric oxide. Am J Physiol 1997; 272:L979–L988.

    CAS  PubMed  Google Scholar 

  9. Samad F, Uysal KT, Wiesbrock SM, Pandey M, Hotamisligil GS, Loskutoff DJ. Tumor necrosis factor α is a key component in the obesity-linked elevation of plasminogen activator inhibitor 1. Proc Natl Acad Sci USA 1999; 96:6902–6907.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2014; 37:S81–S90.

    Google Scholar 

  11. Meijer JW, Smit AJ, Sonderen EV, Groothoff JW, Eisma WH, Links TP. Symptom scoring systems to diagnose distal polyneuropathy in diabetes: the diabetic neuropathy symptom score. Diabetic Med 2002; 19:962–965.

    CAS  PubMed  Google Scholar 

  12. Young MJ, Boulton AJ, Macleod AF, Williams DR, Sonkesn PH. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia 1993; 36:150–154.

    CAS  PubMed  Google Scholar 

  13. Dyck PJ, Albers JW, Andersen H, Arezzo JC, Biessels GJ, Bril V, et al. Diabetic polyneuropathies: up date on research definition, diagnostic criteria and estimation of severity. Diabetes Metab Res Rev 2011; 27:620–628.

    PubMed  Google Scholar 

  14. Martin CL, Albers JW, Pop-Busui R. Neuropathy and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care 2014; 37:31–38.

    CAS  PubMed  Google Scholar 

  15. Kimura J. Electro diagnosis in diseases of nerve and muscle: principles and practice. 198 Madison Avenue, New York: Oxford University Press; 2001.

    Google Scholar 

  16. Harati Y. Diabetic neuropathies: unanswered questions. Neurol Clin 2007; 25:303–317.

    PubMed  Google Scholar 

  17. Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-Tirgoviste C, Fuller JH. Vascular risk factors and diabetic neuropathy. N Engl J Med 2005; 352:341–350.

    CAS  PubMed  Google Scholar 

  18. Tavakkoly-Bazzaz J, Amoli MM, Pravica V, Chandrasecaran R, Boulton AJ, Larijani B, Hutchinson IV. VEGF gene polymorphism association with diabetic neuropathy. Mol Biol Rep 2010; 37:3625–3630.

    CAS  PubMed  Google Scholar 

  19. Said G, Lacroix C, Lozeron P, Ropert A, Planté V, Adams D. Inflammatory vasculopathy in multifocal diabetic neuropathy. Brain 2003; 126:376–385.

    PubMed  Google Scholar 

  20. Gundogdu BM. Diabetic peripheral neuropathy: an update on pathogenesis and management. Curr Neurol Neurosci Rep 2006; 6:1–4.

    PubMed  Google Scholar 

  21. González-Clemente JM, Mauricio D, Richart C, Broch M, Caixas A, Megia A, Vendrell J. Diabetic neuropathy is associated with activation of the TNF-α system in subjects with type 1 diabetes mellitus. Clin Endocrinol (Oxf) 2005; 63:525–529.

    Google Scholar 

  22. Sung JY, Park SB, Liu YT, Kwai N, Arnold R, Krishnan AV, et al. Progressive axonal dysfunction precedes development of neuropathy in type 2 diabetes. Diabetes 2012; 61:1592–1598.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Krishnan AV, Lin CS, Kiernan MC. Activity-dependent excitability changes suggest Na+/K+ pump dysfunction in diabetic neuropathy. Brain 2008; 131 (Pt 5):1209–1216.

    PubMed  Google Scholar 

  24. Misawa S, Kuwabara S, Ogawara K, Kitano Y, Yagui K, Hattori T. Hyperglycemia alters refractory periods in human diabetic neuropathy. Clin Neurophysiol 2004; 115:2525–2529.

    CAS  PubMed  Google Scholar 

  25. Tesfaye S, Selvarajah D. Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy. Diabetes Metab Res Rev 2012; 28(S1):8–14.

    PubMed  Google Scholar 

  26. 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.

    CAS  PubMed  Google Scholar 

  27. Yamakawa I, Kojima H, Terashima T, Katagi M, Oi J, Urabe H, et al. Inactivation of TNF-alpha ameliorates diabetic neuropathy in mice. Am J Physiol Endocrinol Metab 2011; 301:E844–E852.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Matsuda M, Kawasaki F, Inoue H, Kanda Y, Yamada K, Harada Y, et al. Possible contribution of adipocytokines on diabetic neuropathy. Diabetes Res Clin Pract 2004; 66(Suppl 1):S121–S123.

    CAS  PubMed  Google Scholar 

  29. Hussain G, Rizvi SA, Singhal S, Zubair M, Ahmad J. Serum levels of TNF-α in peripheral neuropathy patients and its correlation with nerve conduction velocity in type 2 diabetes mellitus. Diabetes Metab Syndr 2013; 7: 238–242.

    PubMed  Google Scholar 

  30. Duksal T, Tiftikcioglu BI, Bilgin S, Kose S, Zorlu Y. Role of inflammation in sensory neuropathy in prediabetes or diabetes. Acta Neurol Scand 2015; 133:384–390.

    PubMed  Google Scholar 

  31. Navarro JF, Mora C. Diabetes, inflammation, proinflammatory cytokines, and diabetic nephropathy. Scientific World Journal 2006; 6:908–917.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Skundric DS, Lisak RP. Role of neuropoietic cytokines in development and progression of diabetic polyneuropathy: from glucose metabolism to neurodegeneration. Exp Diabesity Res 2003; 4:303–312.

    PubMed  PubMed Central  Google Scholar 

  33. Vlassara H. Chronic diabetic complications and tissue glycosylation: relevant concern for diabetes-prone black population. Diabetes Care 1990; 13:1180–1185.

    CAS  PubMed  Google Scholar 

  34. King GL, Brownlee M. The cellular and molecular mechanisms of diabetic complications. Endocrinol Metab Clin North Am 1996; 25: 255–270.

    CAS  PubMed  Google Scholar 

  35. Shi X, Chen Y, Nadeem L, Xu G. Beneficial effect of TNF-α inhibition on diabetic peripheral neuropathy. J Neuroinflammation 2013; 10:69.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Créange A, Barlovatz-Meimon G, Gherardi RK. Cytokines and peripheral nerve disorders. Eur Cytokine Netw 1997; 8:145–151.

    PubMed  Google Scholar 

  37. Wagner R, Myers RR. Endoneurial injection of TNF-alpha produces neuropathic pain behaviors. Neuroreport 1996; 7:2897–2901.

    CAS  PubMed  Google Scholar 

  38. Sorkin LS, Xiao WH, Wagner R, Myers RR. Tumour necrosis factor-alpha induces ectopic activity in nociceptive primary afferent fibres. Neuroscience 1997; 81:255–262.

    CAS  PubMed  Google Scholar 

  39. Iwata T, Sato S, Jimenez J, McGowan M, Moroni M, Dey A, Carper D. Osmotic response element is required for the induction of aldose reductase by tumor necrosis factor-α. J Biol Chem 1999; 274:7993–8001.

    CAS  PubMed  Google Scholar 

  40. Magnuson DK, Maier RV, Pohlman TH. Protein kinase C: a potential pathway of endothelial cell activation by endotoxin, tumor necrosis factor, and interleukin-1. Surgery 1989; 106:216–222.

    CAS  PubMed  Google Scholar 

  41. Igarashi M, Wakasaki H, Takahara N, Ishii H, Jiang ZY, Yamauchi T, King GL. Glucose or diabetes activates p38 mitogen-activated protein kinase via different pathways. J Clin Invest 1999; 103: 185–195.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Muñoz-Fernández MA, Fresno M. The role of tumor necrosis factor, interleukin 6, interferon-γ and inducible nitric oxide synthase in the development and pathology of the nervous system. Prog Neurobiol 1998; 56:307–340.

    PubMed  Google Scholar 

  43. Sima AA, Sugimoto K. Experimental diabetic neuropathy: an update. Diabetologia. 1999; 42:773–788.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Physical Medicine, Rheumatology and Rehabilitation, Faculty of Medicine, Ain Shams University, 211 Abdel-Hamid Keshk Street, Hadaeq EL-Quba, 11646, Cairo, Egypt

    Mohja A. El-Badawy M. (Assistant Professor), Dina A. B. Farrag & Samia M. R. Abd El-Rehem

  2. Department of Internal Medicine, Allergy and Immunology, Cairo, Egypt

    Amira R. El-Mahdi

  3. Department of Internal Medicine, Endocrinology, Cairo, Egypt

    Alyaa A. El-Sherbeny

  4. Department of Internal Medicine, Hematology, Cairo, Egypt

    Emad A. M. Abdel Hady

  5. Department of Clinical Pathology, Faculty of Medicine, Ain Shams University Hospital, Ain Shams University, Cairo, Egypt

    Hoda A. Abdel-Sattar & Doaa M. Abdelaziz

Authors
  1. Mohja A. El-Badawy M.
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  2. Dina A. B. Farrag
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  3. Samia M. R. Abd El-Rehem
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  4. Amira R. El-Mahdi
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  5. Alyaa A. El-Sherbeny
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  6. Emad A. M. Abdel Hady
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  7. Hoda A. Abdel-Sattar
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  8. Doaa M. Abdelaziz
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Correspondence to Mohja A. El-Badawy M..

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El-Badawy, M.A., Farrag, D.A.B., Abd El-Rehem, S.M.R. et al. Tumor necrosis factor-α is a novel biomarker for peripheral neuropathy in type II diabetes mellitus: a clinical and electrophysiological study. Egypt Rheumatol Rehabil 44, 83–90 (2017). https://doi.org/10.4103/1110-161X.205663

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  • DOI: https://doi.org/10.4103/1110-161X.205663

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