Diabetes mellitus (DM) is one of the foremost medical and social challenges of the 21st century, and diabetic neuropathy (DN) is one of its most common complications, occurring in 50–60% of patients with long-standing disease. The aim of this study is to systematize current data on the pathophysiological mechanisms of DN and to analyze the role of metabolic, vascular, oxidative, inflammatory, and trophic factors in nerve tissue damage. A systematic literature review (2014–2024) was conducted using international and Russian databases (PubMed, Scopus, Web of Science, RSCI, eLIBRARY.RU) with the following keywords: "diabetes mellitus," "diabetic neuropathy," "hyperglycemia," "polyol pathway," "advanced glycation end-products," "oxidative stress," "nerve growth factor," and their Russian equivalents. The pathogenesis of DN involves the activation of the polyol pathway, the accumulation of advanced glycation end products, mitochondrial and endothelial dysfunction, chronic inflammation, and a deficiency of neurotrophic factors, all of which lead to progressive nerve tissue damage. Understanding these mechanisms offers opportunities for early diagnosis, the development of biomarkers, and pathogenetically-based therapy. A comprehensive approach to treatment can slow the progression of this complication and improve patients' quality of life.

Diabetes mellitus, diabetic neuropathy, oxidative stress

International Diabetes Federation. IDF Diabetes Atlas, 10th edition. Brussels, Belgium: International Diabetes Federation; 2021. Available from: https://diabetesatlas.org

Pop-Busui R., Boulton A.J., Feldman E.L. et al. Diabetic neuropathy: a position statement by the American Diabetes Association // Diabetes Care. 2017. Vol. 40, No. 1. P. 136-154. DOI: 10.2337/dc16-2042

Feldman, E. L., Nave, K. A., Jensen, T. S., & Bennett, D. L. H. (2017). New horizons in diabetic neuropathy: mechanisms, bioenergetics, and pain. *Neuron*, *93* (6), 1296–1313. https://doi.org/10.1016/j.neuron.2017.02.005 P. 1296-1313.

Brownlee, M. (2005). The pathobiology of diabetic complications: a unifying mechanism. *Diabetes*, *54* (6), 1615–1625. https://doi.org/10.2337/diabetes.54.6.1615 P. 1615-1625.

Vincent, A. M., Calabek, B., Roberts, L., & Feldman, E. L. (2013). Biology of diabetic neuropathy. In *Handbook of Clinical Neurology* (Vol. 115, pp. 591–606). https://doi.org/10.1016/B978-0-444-52902-2.00034-5

Tomlinson, D. R., & Gardiner, N. J. (2008). Glucose neurotoxicity. *Nature Reviews Neuroscience*, *9* (1), 36–45. https://doi.org/10.1038/nrn2294 P. 36-45.

Giacco, F., & Brownlee, M. (2010). Oxidative stress and diabetic complications. *Circulation Research*, *107* (9), 1058–1070. https://doi.org/10.1161/CIRCRESAHA.110.223545 P. 1058-1070.

Russell, J. W., Golovoy, D., Vincent, A. M., et al. (2002). High glucose-induced oxidative stress and mitochondrial dysfunction in neurons. *FASEB Journal*, *16* (13), 1738–1748. https://doi.org/10.1096/fj.01-1027com 16, No. 13. P. 1738-1748.

Calcutt, N. A., Cooper, M. E., Kern, T. S., & Schmidt, A. M. (2009). Therapies for hyperglycaemia-induced diabetic complications: from animal models to clinical trials. *Nature Reviews Drug Discovery*, *8* (5), 417–429. https://doi.org/10.1038/nrd2476 P. 417-429.

Dedov I.I., Shestakova M.V., Mayorov A.Yu. et al. Algorithms for specialized medical care for patients with diabetes mellitus. Clinical guidelines. 11th Edition. *Sakharnyi Diabet* = Diabetes Mellitus. 2023;26 (S1):1-148. (In Russ.). DOI: 10.14341/DM13042

Strokov I.A., Novosadova M.V., Barinov A.N. Diabetic polyneuropathy. *RMJ* = Russian Medical Journal. 2019;27 (6):72-77. (In Russ.).

Ziegler D., Papanas N., Vinik A.I., Shaw J.E. Epidemiology of polyneuropathy in diabetes and prediabetes. Handbook of Clinical Neurology. 2014;126:3-22. DOI: 10.1016/B978-0-444-53480-4.00001-1

Yagihashi S., Mizukami H., Sugimoto K. Mechanism of diabetic neuropathy: where are we now and where to go? Journal of Diabetes Investigation. 2011;2 (1):18-32. DOI: 10.1111/j.2040-1124.2010.00070.x P. 18-32.

Obrosova I.G. Diabetic painful and insensate neuropathy: pathogenesis and potential treatments. Neurotherapeutics. 2009;6 (4):638-647. DOI: 10.1016/j.nurt.2009.07.004

Shevalye H., Stavniichuk R., Xu W. et al. Poly (ADP-ribose) polymerase (PARP) inhibition counteracts multiple manifestations of kidney disease in long-term streptozotocin-diabetic rat model. Biochemical Pharmacology. 2010;79 (7):1007-1014. DOI: 10.1016/j.bcp.2009.11.018

Cameron N.E., Cotter M.A. Pro-inflammatory mechanisms in diabetic neuropathy: focus on the nuclear factor kappa B pathway. Current Drug Targets. 2008;9 (1):60-67. DOI: 10.2174/138945008783431718

Rumora A.E., LoGrasso G., Haidar J.A. et al. Chain length of saturated fatty acids regulates mitochondrial trafficking and function in sensory neurons // Journal of Lipid Research. 2019. Vol. 60, No. 1. P. 58-70. DOI: 10.1194/jlr.M086843

Dedov I.I., Shestakova M.V., Galstyan G.R. The prevalence of type 2 diabetes mellitus in the adult population of Russia (NATION study). Sakharnyi diabet. 2016;19 (2):104-112. (In Russ.). DOI: 10.14341/DM2004116-17

Ametov A.S., Kamynina L.L. Diabetic polyneuropathy: present and future. RMJ. Medical Review. 2018;2 (8 (I)):44-50. (In Russ.).

Sima A.A., Kamiya H. Diabetic neuropathy differs in type 1 and type 2 diabetes // Annals of the New York Academy of Sciences. 2006. Vol. 1084. P. 235-249. DOI: 10.1196/annals.1372.004

Zochodne D.W. Diabetes mellitus and the peripheral nervous system: manifestations and mechanisms // Muscle & Nerve. 2007. Vol. 36, No. 2. P. 144-166. DOI: 10.1002/mus.20785

Sorensen L., Molyneaux L., Yue D.K. The relationship among pain, sensory loss, and small nerve fibers in diabetes // Diabetes Care. 2006. Vol. 29, No. 4. P. 883-887. DOI: 10.2337/diacare.29.04.06.dc05-2180

Boulton A.J., Vinik A.I., Arezzo J.C. et al. Diabetic neuropathies: a statement by the American Diabetes Association // Diabetes Care. 2005. Vol. 28, No. 4. P. 956-962. DOI: 10.2337/diacare.28.4.956

Tesfaye S., Selvarajah D., Gandhi R. et al. Diabetic peripheral neuropathy may not be as its name suggests evidence from magnetic resonance imaging // Pain. 2016. Vol. 157, Suppl 1. P. S72-80. DOI: 10.1097/j.pain.0000000000000465

Ziegler D., Rathmann W., Dickhaus T. et al. Prevalence of polyneuropathy in pre-diabetes and diabetes is associated with abdominal obesity and macroangiopathy: the MONICA/KORA Augsburg Surveys S2 and S3 // Diabetes Care. 2008. Vol. 31, No. 3. P. 464-469. DOI: 10.2337/dc07-1796

Callaghan B.C., Cheng H.T., Stables C.L. et al. Diabetic neuropathy: clinical manifestations and current treatments // Lancet Neurology. 2012. Vol. 11, No. 6. P. 521-534. DOI: 10.1016/S1474-4422 (12) 70065-0

Edwards J.L., Vincent A.M., Cheng H.T., Feldman E.L. Diabetic neuropathy: mechanisms to management // Pharmacology & Therapeutics. 2008. Vol. 120, No. 1. P. 1-34. DOI: 10.1016/j.pharmthera.2008.05.005

Figueroa-Romero C., Sadidi M., Feldman E.L. Mechanisms of disease: the oxidative stress theory of diabetic neuropathy // Reviews in Endocrine and Metabolic Disorders. 2008. Vol. 9, No. 4. P. 301-314. DOI: 10.1007/s11154-008-9104-2

Zilov A.V., Misnikova I.V., Kovaleva Yu.A. et al. Modern approaches to the treatment of diabetic polyneuropathy. Effective Pharmacotherapy. 2020, vol. 16, no. 2, pp. 50-58. (in Russ.). DOI: 10.33978/2307-3586-2020-16-2-50-58

Kaminsky A.V., Vorobyov S.V. Pathogenetic therapy of diabetic polyneuropathy. *Consilium Medicum*. 2019;21 (4):31-37. (In Russ.) DOI: 10.26442/20751753.2019.4.190316

Papanas N., Ziegler D. Risk factors and comorbidities in diabetic neuropathy: an update 2015. *Review of Diabetic Studies*. 2015;12 (1-2):48-62. DOI: 10.1900/RDS.2015.12.48

Dyck P.J., Kratz K.M., Karnes J.L. et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. *Neurology*. 1993;43 (4):817-824. DOI: 10.1212/wnl.43.4.817