medsovetМедицинский СоветMeditsinskiy sovet = Medical Council2079-701X2658-5790REMEDIUM GROUP Ltd.10.21518/2079-701X-2020-7-56-65medsovet-5656Research ArticleОСЛОЖНЕНИЯ САХАРНОГО ДИАБЕТАCOMPLICATIONS OF DIABETESДиагностика и лечение ранних стадий диабетической полинейропатииDiagnosis and treatment of the early stages of diabetic polyneuropathyhttps://orcid.org/0000-0002-5161-7743ХрамилинВ. Н.KhramilinV. N.

 

117997, Россия, Москва, ул. Островитянова, д. 1

Vladimir N. Khramilin, Cand. of Sci. (Med.), Associate Professor, Chair for Endocrinology and Diabetology, Faculty of Additional Professional Education,

1, Ostrovityanov St., Moscow, 117997, Russia

Khramilin_RGMU@mail.ruhttps://orcid.org/0000-0002-4632-6829ЗавьяловА. Н.ZavyalovA. N.

 

117997, Россия, Москва, ул. Островитянова, д. 1

Alexander N. Zavyalov, Cand. of Sci. (Med.), Teaching Assistant, Chair for Endocrinology and Diabetology, Faculty of Additional Professional Education

1, Ostrovityanov St., Moscow, 117997, Russia

https://orcid.org/0000-0001-7214-6795ДемидоваИ. Ю.DemidovaI. Yu.

 

117997, Россия, Москва, ул. Островитянова, д. 1

Irina Yu. Demidova, Dr. of Sci. (Med.), Professor, Head of Chair for Endocrinology and Diabetology, Faculty of Additional Professional Education

1, Ostrovityanov St., Moscow, 117997, Russia

Российский национальный исследовательский медицинский университет им. Н.И. ПироговаРоссияPirogov Russian National Research Medical UniversityRussian Federation202028052020075665Copyright © Храмилин В.Н., Завьялов А.Н., Демидова И.Ю., 20202020Храмилин В.Н., Завьялов А.Н., Демидова И.Ю.Khramilin V.N., Zavyalov A.N., Demidova I.Y.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.med-sovet.pro/jour/article/view/5656

Диабетическая полинейропатия является самым ранним и наиболее частым осложнением сахарного диабета. Диабетическая полинейропатия может развиваться на ранних стадиях нарушения углеводного обмена, более того, дистальная полинейропатия может развиваться и у пациентов с метаболическим синдромом, не имеющих нарушений углеводного обмена. Гипергликемия является важнейшим, но не единственным фактором риска развития и прогрессии диабетической полинейропатии. Поражение периферической нервной системы при преддиабете и на начальных этапах сахарного диабета преимущественно затрагивает тонкие нервные волокна, что обуславливает достаточно частое развитие нарушений со стороны вегетативной нервной системы. Так, уже на момент диагностики сахарного диабета 1-го и 2-го типов кардиальная автономная нейропатия диагностируется у 5–7,7%. Скрининг диабетической полинейропатии рекомендован не только при сахарном диабете 1-го типа длительностью 5 лет и более и сахарном диабете 2-го типа с момента диагноза, но и среди симптомных пациентов с преддиабетом. Для ранней диагностики диабетической полинейропатии могут использоваться как рутинные тесты оценки периферической чувствительности, так и специализированные методики (симпатические кожные реакции, биопсия кожи, конфокальная корнеальная микроскопия, количественные сенсорные тесты) и валидизированные опросники (шкала Юта для диагностики ранних проявлений нейропатии), акцентированные на оценке функции тонких нервных волокон. Для диагностики ранней диабетической полинейропатии могут быть использованы и неэлектрофизиологические исследования: соноэластография периферических нервов, оптическая когерентная томография, МРТ-нейрография, спиральная позитронно-эмиссионная КТ с 123 йод-метайодобензилгуанидином. Ранняя диагностика диабетической полинейропатии крайне важна, т. к. изменение образа жизни, расширение физической активности способно замедлить развитие данного осложнения. Соотношение выраженности оксидативного стресса и активности антиоксидантной защиты рассматривается как потенциальный механизм раннего поражения периферической нервной системы при гипергликемии и как возможная цель терапевтического воздействия. В обзоре обсуждаются вопросы эпидемиологии, диагностики и потенциальные терапевтические стратегии ранней диабетической полинейропатии.

Diabetic polyneuropathy (DPN) is the most common and earliest complication of diabetes mellitus and it may occur much earlier in patients with type-2 diabetes than in patients with type-1. Distal polyneuropathy can develop not only in diabetes mellitus, but also at the stage of prediabetes and even in patients with metabolic syndrome without impaired glycemic state. Hyperglycemia viewed as a major, but not the sole factor, responsible for development and progression DPN. The control of blood glucose as an obligatory step of therapy to delay or reverse DPN is no longer an arguable issue. Damage of peripheral nervous system in prediabetes and in the initial stages of diabetes mainly affects small nerve fibers, which also leads to disorders of the autonomic nervous system. Cardiac autonomic neuropathy diagnosed in 5-7.7% of patients at the time of diagnosis of type 1 and type 2 diabetes mellitus. For the early diagnosis of DPN, both routine assessment of peripheral sensation can be used, as well as specialized methods (sympathetic skin reactions, skin biopsy, confocal corneal microscopy, quantitative sensory tests) and validated questionnaires (Utah Early Neuropathy Scale) focused on assessing the function of small nerve fibers. Non-electrophysiological studies also were tested for early diagnosis of DPN: peripheral nerve sonoelastography, optical coherence tomography, MRI neurography, spiral positron emission CT (SPECT) with 123I-MIBG. DPN diagnosis in the pre-clinical stage very important, because treatment with diet and lifestyle intervention may be successful. The correlation between the severity of oxidative stress and the activity of antioxidant defense is considered as a potential mechanism for early nerves damage with hyperglycemia and as a possible target for therapeutic intervention. In this work, we will review prevalence, diagnostic approaches and potential treatment options for early diabetic polyneuropathy.

сахарный диабетпреддиабетдиабетическая полинейропатияавтономная нейропатиядиагностика диабетической полинейропатииdiabetes mellitusprediabetesdiabetic polyneuropathyautonomic neuropathydiagnostic tests for early detection diabetic neuropathyReferencesDedov I.I., Kalashnikova M.F., Belousov D.Y., Kolbin A.S., Rafalskiy V.V., Cheberda A.E., Kantemirova M.A., Zakiev V.D., Fadeyev V.V. Cost-of-Illness Analysis of Type 2 Diabetes Mellitus in the Russian Federation: Results from Russian multicenter observational pharmacoepidemiologic study of diabetes care for patients with type 2 diabetes mellitus (FORSIGHT- Т2DM). Sakharni Diabet = Diabetes Mellitus. 2017;20(6):403–419. (In Russ.) doi: 10.14341/DM9278Dedov I.I., Kalashnikova M.F., Belousov D.Y., Kolbin A.S., Rafalskiy V.V., Cheberda A.E., Kantemirova M.A., Zakiev V.D., Fadeyev V.V. Cost-of-Illness Analysis of Type 2 Diabetes Mellitus in the Russian Federation: Results from Russian multicenter observational pharmacoepidemiologic study of diabetes care for patients with type 2 diabetes mellitus (FORSIGHT- Т2DM). Sakharni Diabet = Diabetes Mellitus. 2017;20(6):403–419. (In Russ.) doi: 10.14341/DM9278Malik R.A. Which test for diagnosing early diabetic neuropathy? Diabetes. 2014;63(7):2206–2208. doi: https://doi.org/10.2337/db14-0492.Malik R.A. Which test for diagnosing early diabetic neuropathy? Diabetes. 2014;63(7):2206–2208. doi: https://doi.org/10.2337/db14-0492.Vinik A.I., Casellini C., Nevoret M.L. Alternative quantitative tools in the assessment of diabetic peripheral and autonomic neuropathy. Int Rev Neurobiol. 2016;127:235–285. doi: 10.1016/bs.irn.2016.03.010.Vinik A.I., Casellini C., Nevoret M.L. Alternative quantitative tools in the assessment of diabetic peripheral and autonomic neuropathy. Int Rev Neurobiol. 2016;127:235–285. doi: 10.1016/bs.irn.2016.03.010.Tesfaye S., Boulton A.J.M., Dyck P.J., Freeman R., Horowitz M., Kempler P. et al. Diabetic neuropathies: update on definitions, diagnostic care, estimation of severity, and treatments. Diabetes Care. 2010;33(10):2285–2293. doi: 10.2337/dc10-1303.Tesfaye S., Boulton A.J.M., Dyck P.J., Freeman R., Horowitz M., Kempler P. et al. Diabetic neuropathies: update on definitions, diagnostic care, estimation of severity, and treatments. Diabetes Care. 2010;33(10):2285–2293. doi: 10.2337/dc10-1303.Pop-Busui R., Boulton A.J.M., Feldman E.L., Bril V., Freeman R., Malik R.A., Sosenko J.M., Ziegler D. Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136–154. doi: 10.2337/dc16-2042Pop-Busui R., Boulton A.J.M., Feldman E.L., Bril V., Freeman R., Malik R.A., Sosenko J.M., Ziegler D. Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136–154. doi: 10.2337/dc16-2042Dyck P.J., Albers J.W., Andersen H., Arezzo J.C., Biessels G.J., Bril V. et al. Diabetic polyneuropathies: update on research definition, diagnostic criteria and estimation of severity. Diabetes Metab Res Rev. 2011;27(7):620–628. doi: 10.1002/dmrr.1226.Dyck P.J., Albers J.W., Andersen H., Arezzo J.C., Biessels G.J., Bril V. et al. Diabetic polyneuropathies: update on research definition, diagnostic criteria and estimation of severity. Diabetes Metab Res Rev. 2011;27(7):620–628. doi: 10.1002/dmrr.1226.Won J.C., Park T.S. Recent advances in diagnostic strategies for diabetic peripheral neuropathy. Endocrinol Metab. 2016;31(2):230–238. doi: 10.3803/EnM.2016.31.2.230.Won J.C., Park T.S. Recent advances in diagnostic strategies for diabetic peripheral neuropathy. Endocrinol Metab. 2016;31(2):230–238. doi: 10.3803/EnM.2016.31.2.230.Rajabally Y.A. Neuropathy and impaired glucose tolerance: un updated review of the evidence. Acta Neurol Scand. 2011;124(1):1–8. doi: 10.1111/j.1600-0404.2010.01425.x.Rajabally Y.A. Neuropathy and impaired glucose tolerance: un updated review of the evidence. Acta Neurol Scand. 2011;124(1):1–8. doi: 10.1111/j.1600-0404.2010.01425.x.Celikbilek A., Tank N., Sabah S., Borecki E., Akyol L., Ak H. et al. Elevated neurofilament light chain (NLC) mRNA levels in pre-diabetic peripheral neuropathy. Mol Biol Rep. 2014;41:4017–4022. doi: 10.1007/s11033-014-3270-y.Celikbilek A., Tank N., Sabah S., Borecki E., Akyol L., Ak H. et al. Elevated neurofilament light chain (NLC) mRNA levels in pre-diabetic peripheral neuropathy. Mol Biol Rep. 2014;41:4017–4022. doi: 10.1007/s11033-014-3270-y.Han L., Ji L., Chang J., Wen J., Zhao W., Shi H. et al. Peripheral neuropathy is associated with insulin resistance independent of metabolic syndrome. Diabetol Metab Syndr. 2015;3(7):14. doi: 10.1186/s13098-015-0010-y.Han L., Ji L., Chang J., Wen J., Zhao W., Shi H. et al. Peripheral neuropathy is associated with insulin resistance independent of metabolic syndrome. Diabetol Metab Syndr. 2015;3(7):14. doi: 10.1186/s13098-015-0010-y.Smith A.G., Rose K., Singleton J.R. Idiopathic neuropathy patients are at high risk for metabolic syndrome. J Neurol Sci. 2008;273(1–2):25–28. doi: 10.1016/j.jns.2008.06.005.Smith A.G., Rose K., Singleton J.R. Idiopathic neuropathy patients are at high risk for metabolic syndrome. J Neurol Sci. 2008;273(1–2):25–28. doi: 10.1016/j.jns.2008.06.005.Spijkerman A.M., Dekker J.M., Nijpels G. et al. Microvascular complications at time of diagnosis of type 2 diabetes are similar among diabetic patients detected by targeted screening and patients newly diagnosed in general practice: the hoorn screening study. Diabetes Care. 2003;26(9):2604–2608. doi: 10.2337/diacare.26.9.2604.Spijkerman A.M., Dekker J.M., Nijpels G. et al. Microvascular complications at time of diagnosis of type 2 diabetes are similar among diabetic patients detected by targeted screening and patients newly diagnosed in general practice: the hoorn screening study. Diabetes Care. 2003;26(9):2604–2608. doi: 10.2337/diacare.26.9.2604.England J.D., Gronseth G.S., Franklin G., Miller R.G., Asbury A.K., Carter G.T. et al. Distal symmetric polyneuropathy: a definition for clinical research: Report of the American Academy of Neurology, the American Association of Electrodiagnostic medicine, and the American Academy of Physical medicine and Rehabilitation. Neurology 2005;64(2):199–207. doi: 10.1212/01.WNL.0000149522.32823.EA.England J.D., Gronseth G.S., Franklin G., Miller R.G., Asbury A.K., Carter G.T. et al. Distal symmetric polyneuropathy: a definition for clinical research: Report of the American Academy of Neurology, the American Association of Electrodiagnostic medicine, and the American Academy of Physical medicine and Rehabilitation. Neurology 2005;64(2):199–207. doi: 10.1212/01.WNL.0000149522.32823.EA.American Diabetes Association. Standards of Medical Care in Diabetes. Microvascular complications and foot care. Diabetes Care. 2017;40(1):88–98. doi: 10.2337/dc17-S013.American Diabetes Association. Standards of Medical Care in Diabetes. Microvascular complications and foot care. Diabetes Care. 2017;40(1):88–98. doi: 10.2337/dc17-S013.Alam U. Prevalence of Peripheral Neuropathy in Prediabetes. Diabetes. 2018;67(Suppl. 1):552-P. doi: 10.2337/db18-552-P.Alam U. Prevalence of Peripheral Neuropathy in Prediabetes. Diabetes. 2018;67(Suppl. 1):552-P. doi: 10.2337/db18-552-P.Lee C.C., Perkins B.A., Kayaniyil S., Harris S.B., Retnakaran R., Gerstein H.C., Zinman B., Hanley A.J. Peripheral Neuropathy and Nerve Dysfunction in Individuals at High Risk for Type 2 Diabetes: The PROMISE Cohort. Diabetes Care. 2015;38(50):793–800. doi: 10.2337/dc14-2585.Lee C.C., Perkins B.A., Kayaniyil S., Harris S.B., Retnakaran R., Gerstein H.C., Zinman B., Hanley A.J. Peripheral Neuropathy and Nerve Dysfunction in Individuals at High Risk for Type 2 Diabetes: The PROMISE Cohort. Diabetes Care. 2015;38(50):793–800. doi: 10.2337/dc14-2585.Dyck P.J. Detection, characterization and staging of polyneuropathy: assessed in diabetics. Muscle Nerve. 1988;11(1):21–32. doi: 10.1002/mus.880110106.Dyck P.J. Detection, characterization and staging of polyneuropathy: assessed in diabetics. Muscle Nerve. 1988;11(1):21–32. doi: 10.1002/mus.880110106.Russell J.W., Zilliox L.A. Diabetic Neuropathies. Continuum (Minneap Minn). 2014;20(5):1226–140. doi: 10.1212/01.CON.0000455884.29545.d2.Russell J.W., Zilliox L.A. Diabetic Neuropathies. Continuum (Minneap Minn). 2014;20(5):1226–140. doi: 10.1212/01.CON.0000455884.29545.d2.Feng Y., Schossler P.J., Sumpio B.E. The Semmes-Weinstein monofi lament is a signifi cant predictor of the risk of foot ulceration and amputation in patients with diabetes mellitus. J Vasc Surg 2011;53(1):220–226. doi: 10.1016/j.jvs.2010.06.100.Feng Y., Schossler P.J., Sumpio B.E. The Semmes-Weinstein monofi lament is a signifi cant predictor of the risk of foot ulceration and amputation in patients with diabetes mellitus. J Vasc Surg 2011;53(1):220–226. doi: 10.1016/j.jvs.2010.06.100.Bril V., Perkins B., Toth C. Canadian Diabetes Association Clinical Practice Guidelines. Neuropathy. Can J Diabetes. 2013;37(1):142–144. doi: 10.1016/j.jcjd.2013.01.039.Bril V., Perkins B., Toth C. Canadian Diabetes Association Clinical Practice Guidelines. Neuropathy. Can J Diabetes. 2013;37(1):142–144. doi: 10.1016/j.jcjd.2013.01.039.Dros J., Wewerinke A., Bindels P.J., von Weert H.C. Accuracy of monofilament testing to diagnose peripheral neuropathy: a systematic review. Ann Fam Med. 2009;7(6):555–558. doi: 10.1370/afm.1016.Dros J., Wewerinke A., Bindels P.J., von Weert H.C. Accuracy of monofilament testing to diagnose peripheral neuropathy: a systematic review. Ann Fam Med. 2009;7(6):555–558. doi: 10.1370/afm.1016.Feldman E.L., Stevens M.J., Thomas P.K., Brown M.B., Canal M., Greene D.A. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care. 1994;17(11):1281–1289. doi: 10.2337/diacare.17.11.1281.Feldman E.L., Stevens M.J., Thomas P.K., Brown M.B., Canal M., Greene D.A. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care. 1994;17(11):1281–1289. doi: 10.2337/diacare.17.11.1281.Herman W.H., Pop-Busui R., Braffett B.H., Martin C.L., Cleary P.A., Albers J.W., Feldman E.L.; DCCT/EDIC Research Group. Use of the Michigan Neuropathy Screening Instrument as a measure of distal symmetrical peripheral neuropathy in Type 1 diabetes: results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications. Diabet Med. 2012;29(7):937–944. doi: 10.1111/j.1464-5491.2012.03644.x.Herman W.H., Pop-Busui R., Braffett B.H., Martin C.L., Cleary P.A., Albers J.W., Feldman E.L.; DCCT/EDIC Research Group. Use of the Michigan Neuropathy Screening Instrument as a measure of distal symmetrical peripheral neuropathy in Type 1 diabetes: results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications. Diabet Med. 2012;29(7):937–944. doi: 10.1111/j.1464-5491.2012.03644.x.Moghtaderi A., Bakhshipour A, Rashidi H. Validation of Michigan neuropathy screening instrument for diabetic peripheral neuropathy. Clin Neurol Neurosurg. 2006;108(5):477–481. doi: 10.1016/j.clineuro.2005.08.003.Moghtaderi A., Bakhshipour A, Rashidi H. Validation of Michigan neuropathy screening instrument for diabetic peripheral neuropathy. Clin Neurol Neurosurg. 2006;108(5):477–481. doi: 10.1016/j.clineuro.2005.08.003.Singleton J.R., Bixby B., Russell J.W., Feldman E.L., Peltier A., Goldstein J., Howard J., Smith A.G. The Utah Early Neuropathy Scale: a sensitive clinical scale for early sensory predominant neuropathy. J Periph Nerv Syst. 2008;13(3):218–227. doi: 1111/j.1529-8027.2008.00180.x.Singleton J.R., Bixby B., Russell J.W., Feldman E.L., Peltier A., Goldstein J., Howard J., Smith A.G. The Utah Early Neuropathy Scale: a sensitive clinical scale for early sensory predominant neuropathy. J Periph Nerv Syst. 2008;13(3):218–227. doi: 1111/j.1529-8027.2008.00180.x.Vinik E., Hayes R.P., Oglesby A., Bastyr E., Barlow P., Ford-Molvik S.L., Vinik A.I. The development and validation of the Norfolk QOL-DN, a new measure of patients´ perception of the effects of diabetes and diabetic neuropathy. Diabetes Technol Ther. 2008;7(3):497–508. doi: 10.1089/dia.2005.7.497.Vinik E., Hayes R.P., Oglesby A., Bastyr E., Barlow P., Ford-Molvik S.L., Vinik A.I. The development and validation of the Norfolk QOL-DN, a new measure of patients´ perception of the effects of diabetes and diabetic neuropathy. Diabetes Technol Ther. 2008;7(3):497–508. doi: 10.1089/dia.2005.7.497.Hillienmark L., Alstrand N., Jonsson B., Ludvigson J., Cooray G., Wahlberg- Topp J. Early electrophysiological abnormalities and clinical neuropathy. Diabetes Care. 2013;36(10):3187–3194. doi: 10.2337/dc12-2226.Hillienmark L., Alstrand N., Jonsson B., Ludvigson J., Cooray G., Wahlberg- Topp J. Early electrophysiological abnormalities and clinical neuropathy. Diabetes Care. 2013;36(10):3187–3194. doi: 10.2337/dc12-2226.Shin J.B., Seong Y.J., Lee H.J., Kim S.H., Suk H., Lee Y.J. The usefulness of minimal F-wave latency and sural/radial amplitude ratio in diabetic polyneuropathy. Yonsei Med J. 2000;41(3):393–397. doi: 10.3349/ymj.2000.41.3.393.Shin J.B., Seong Y.J., Lee H.J., Kim S.H., Suk H., Lee Y.J. The usefulness of minimal F-wave latency and sural/radial amplitude ratio in diabetic polyneuropathy. Yonsei Med J. 2000;41(3):393–397. doi: 10.3349/ymj.2000.41.3.393.Dyck P.J., Litchy W., Daube J.R., Harper M., Dyck J.B., Davies J., O’Brien P.C. Individual attributes versus composite scores of nerve conduction abnormality: sensitivity, reproducibility and concordance with impairment. Muscle Nerve 2003;27(2):202–210. doi: 10.1002/mus.10320.Dyck P.J., Litchy W., Daube J.R., Harper M., Dyck J.B., Davies J., O’Brien P.C. Individual attributes versus composite scores of nerve conduction abnormality: sensitivity, reproducibility and concordance with impairment. Muscle Nerve 2003;27(2):202–210. doi: 10.1002/mus.10320.Albers J.W., Brown M.B., Sima A.A.F., Greene D.A. Frequency of median nerve mononeuropathy in patients with mild diabetic polyneuropathy in the early diabetes intervention trial (EDIT). Muscle Nerve;1996;19(2):140–146. doi: 10.1002/(SICI)1097-4598(199602)19:2<140::AID-MUS3>3.0.CO;2-E.Albers J.W., Brown M.B., Sima A.A.F., Greene D.A. Frequency of median nerve mononeuropathy in patients with mild diabetic polyneuropathy in the early diabetes intervention trial (EDIT). Muscle Nerve;1996;19(2):140–146. doi: 10.1002/(SICI)1097-4598(199602)19:2<140::AID-MUS3>3.0.CO;2-E.Horinouchi S., Deguchi T., Arimura K., Arimura A., Dochi Y., Uto T. et al. Median neuropathy at the wrist as an early manifestation of diabetic neuropathy. J Diabetes Invest. 2014:5(6):709–713. doi: 10.5455/medarh.2014.68.98-101.Horinouchi S., Deguchi T., Arimura K., Arimura A., Dochi Y., Uto T. et al. Median neuropathy at the wrist as an early manifestation of diabetic neuropathy. J Diabetes Invest. 2014:5(6):709–713. doi: 10.5455/medarh.2014.68.98-101.Sung J.-Y., Tani J., Chang T.-S., Lin C.S.-Y. Uncovering sensory axonal dysfunction in asymptomatic type 2 diabetic neuropathy. PLoS ONE. 2017;12(2):e0171223. doi: 10.1371/journal.pone.0171223.Sung J.-Y., Tani J., Chang T.-S., Lin C.S.-Y. Uncovering sensory axonal dysfunction in asymptomatic type 2 diabetic neuropathy. PLoS ONE. 2017;12(2):e0171223. doi: 10.1371/journal.pone.0171223.Van der Heyden J.C., van der Meer P., Birnie E., de Coo F.M. et al. Decreased excitability of the distal motor nerve of young patients with type-1 diabetes mellitus. Pediatr Diabetes. 2013;14(7):519–525. doi: 10.1111/pedi.12048.Van der Heyden J.C., van der Meer P., Birnie E., de Coo F.M. et al. Decreased excitability of the distal motor nerve of young patients with type-1 diabetes mellitus. Pediatr Diabetes. 2013;14(7):519–525. doi: 10.1111/pedi.12048.American Diabetes Association, American Academy of Neurology. Report and recommendations of the San Antonio Conference on Diabetic neuropathy. Diabetes Care. 1988;11(7):592–597. doi: 10.2337/diacare.11.7.592.American Diabetes Association, American Academy of Neurology. Report and recommendations of the San Antonio Conference on Diabetic neuropathy. Diabetes Care. 1988;11(7):592–597. doi: 10.2337/diacare.11.7.592.Andresen H., Stalberg E., Falck B. F-wave latency, the most sensitive nerve conduction parameter in patients with diabetes mellitus. Muscle Nerve. 1997;20(10):1296–1302. doi: 10.1002/(SICI)1097-4598(199710)20:10<1296::AIDMUS12>3.0.CO;2-1.Andresen H., Stalberg E., Falck B. F-wave latency, the most sensitive nerve conduction parameter in patients with diabetes mellitus. Muscle Nerve. 1997;20(10):1296–1302. doi: 10.1002/(SICI)1097-4598(199710)20:10<1296::AIDMUS12>3.0.CO;2-1.Kohara N., Kimura J., Kaji R., Goyo Y., Ishii J., Takiguchi M., Nakai M. F-wave latency serves as the most reproductible measure in nerve conduction studies of diabetic polyneuropathy: multicenter analysis in healthy patients and patients with diabetic polyneuropathy. Diabetologia 2000;43:915–921. doi: 10.1007/s001250051469.Kohara N., Kimura J., Kaji R., Goyo Y., Ishii J., Takiguchi M., Nakai M. F-wave latency serves as the most reproductible measure in nerve conduction studies of diabetic polyneuropathy: multicenter analysis in healthy patients and patients with diabetic polyneuropathy. Diabetologia 2000;43:915–921. doi: 10.1007/s001250051469.Pan H., Jian F., Lin J., Chen N., Zhang C., Zhang Z. et al. F-wave latencies in patients with diabetes mellitus. Muscle Nerve. 2014;49(6):804–808. doi: 10.1002/mus.24127.Pan H., Jian F., Lin J., Chen N., Zhang C., Zhang Z. et al. F-wave latencies in patients with diabetes mellitus. Muscle Nerve. 2014;49(6):804–808. doi: 10.1002/mus.24127.Lachman T., Shahani B.T., Young R.R. Late responses as aids to diagnosis in peripheral neuropathies. J Neurol Neurosurg Psychiatry. 1980;43:156–162. doi: 10.1136/jnnp.43.2.156.Lachman T., Shahani B.T., Young R.R. Late responses as aids to diagnosis in peripheral neuropathies. J Neurol Neurosurg Psychiatry. 1980;43:156–162. doi: 10.1136/jnnp.43.2.156.Toopchizadeh V., Shiva S., Khiabani N.Y., Ghergherechi R. Electrophysiologic pattern and prevalence of subclinical peripheral neuropathy in children and adolescents with type-1 diabetes mellitus in Iran. Saudi Med J. 2016;37(3):299–303. Available at: https://www.pubfacts.com/detail/26905353/Electrophysiologic-pattern-and-prevalence-ofsubclinical-peripheral-neuropathy-in-children-and-adole.Toopchizadeh V., Shiva S., Khiabani N.Y., Ghergherechi R. Electrophysiologic pattern and prevalence of subclinical peripheral neuropathy in children and adolescents with type-1 diabetes mellitus in Iran. Saudi Med J. 2016;37(3):299–303. Available at: https://www.pubfacts.com/detail/26905353/Electrophysiologic-pattern-and-prevalence-ofsubclinical-peripheral-neuropathy-in-children-and-adole.Pozzessere G., Rossi P., Gabriele A., Cipriani R., Morocutti A., Di Mario U., Morano S. Early detection of small fiber neuropathy in Diabetes. Diabetes Care. 2000;25(12):2355–2357. doi: 10.2337/diacare.25.12.2355.Pozzessere G., Rossi P., Gabriele A., Cipriani R., Morocutti A., Di Mario U., Morano S. Early detection of small fiber neuropathy in Diabetes. Diabetes Care. 2000;25(12):2355–2357. doi: 10.2337/diacare.25.12.2355.Sumner C.J., Sheth S., Griffin J.W., Cornblath D.R., Polydefkis M. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology. 2003;60(1):108–111. doi: 10.1212/wnl.60.1.108.Sumner C.J., Sheth S., Griffin J.W., Cornblath D.R., Polydefkis M. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology. 2003;60(1):108–111. doi: 10.1212/wnl.60.1.108.Yaman M., Uluduz D., Yuksel S., Pay G., Kiziltan M.E. The cutaneous silent period in diabetes mellitus. Neurosci Lett. 2007;419(3):258–262. doi: 10.1016/j.neulet.2007.04.018.Yaman M., Uluduz D., Yuksel S., Pay G., Kiziltan M.E. The cutaneous silent period in diabetes mellitus. Neurosci Lett. 2007;419(3):258–262. doi: 10.1016/j.neulet.2007.04.018.Shy M.E., Frohman E.M., So Y.T., Arezzo J.C., Cornblath D.R., Giuliani M.J. et al. Quantitative sensory testing. Report of the therapeutics and technology assessment subcomitee of the American Academy of Neurology. Neurology. 2003;60(6):898–904. doi: 10.1212/01.wnl.0000058546.16985.11.Shy M.E., Frohman E.M., So Y.T., Arezzo J.C., Cornblath D.R., Giuliani M.J. et al. Quantitative sensory testing. Report of the therapeutics and technology assessment subcomitee of the American Academy of Neurology. Neurology. 2003;60(6):898–904. doi: 10.1212/01.wnl.0000058546.16985.11.Tavakoli M., Petroupoulos I.N., Malik R.A. Corneal confocal microscopy to assess diabetic neuropathy. J Diabetes Sci Technol. 2013;7(5):1179–1189. doi: 10.1177/193229681300700509.Tavakoli M., Petroupoulos I.N., Malik R.A. Corneal confocal microscopy to assess diabetic neuropathy. J Diabetes Sci Technol. 2013;7(5):1179–1189. doi: 10.1177/193229681300700509.Merita Tiric-Campara, Miro Denislic, Jasminka Djelilovic-Vranic, Azra Alajbegovic, Emir Tupkovic, Refet Gojak, Rok Zorec, Jasem Y. Al-Hashel. Cutaneous Silent Period in the Evaluation of Small Nerve Fibres. Med Arh. 2014 Apr; 68(2):98-101. doi: 10.5455/medarh.2014.68.98-101Merita Tiric-Campara, Miro Denislic, Jasminka Djelilovic-Vranic, Azra Alajbegovic, Emir Tupkovic, Refet Gojak, Rok Zorec, Jasem Y. Al-Hashel. Cutaneous Silent Period in the Evaluation of Small Nerve Fibres. Med Arh. 2014 Apr; 68(2):98-101. doi: 10.5455/medarh.2014.68.98-101Švilpauskaitė J., Truffert A., Vaičienė N., Magistris M.R. Electrophysiology of small peripheral nerve fibers in man. A study using the cutaneous silent period. Medicina (Kaunas). 2006;42(4):300–312. Available at: http://medicina.lsmuni.lt/med/0604/0604-06e.pdf.Švilpauskaitė J., Truffert A., Vaičienė N., Magistris M.R. Electrophysiology of small peripheral nerve fibers in man. A study using the cutaneous silent period. Medicina (Kaunas). 2006;42(4):300–312. Available at: http://medicina.lsmuni.lt/med/0604/0604-06e.pdf.Koytac P.K., Isak B., Borucu D., Uluk K. Assessment of symptomatic diabetic patients with normal nerve conduction studies: utility of cutaneous silent period and autonomic tests. Muscle Nerve. 2011;43(3):317–323. doi: 10.1002/mus.21877.Koytac P.K., Isak B., Borucu D., Uluk K. Assessment of symptomatic diabetic patients with normal nerve conduction studies: utility of cutaneous silent period and autonomic tests. Muscle Nerve. 2011;43(3):317–323. doi: 10.1002/mus.21877.Onal M.R., Ulas U.H., Oz O., Bek V.S., Yucel M., Talispinar A., Odabası Z. Cutaneous silent period changes in type-2 diabetes mellitus patients with small fiber neuropathy. Clin Neurophysiol. 2010;121(5):714–718. doi: 10.1016/j.clinph.2009.12.024.Onal M.R., Ulas U.H., Oz O., Bek V.S., Yucel M., Talispinar A., Odabası Z. Cutaneous silent period changes in type-2 diabetes mellitus patients with small fiber neuropathy. Clin Neurophysiol. 2010;121(5):714–718. doi: 10.1016/j.clinph.2009.12.024.Braune H.J., Horter C. Sympathetic skin responses in diabetic neuropathy: a prospective clinical and neurophysiological trial on 100 patients. J Neurol Sci. 1996;138(1–2):120–124. doi: 10.1016/0022-510x(96)00023-8.Braune H.J., Horter C. Sympathetic skin responses in diabetic neuropathy: a prospective clinical and neurophysiological trial on 100 patients. J Neurol Sci. 1996;138(1–2):120–124. doi: 10.1016/0022-510x(96)00023-8.Isak B., Oflazoglu B., Tanridag T., Yitmen I., Us O. Evaluation of peripheral and autonomic neuropathy among patients with newly diagnosed impaired glucose tolerance. Diabetes Metab Res Rev. 2008;24(7):563–569. doi: 10.1002/dmrr.859.Isak B., Oflazoglu B., Tanridag T., Yitmen I., Us O. Evaluation of peripheral and autonomic neuropathy among patients with newly diagnosed impaired glucose tolerance. Diabetes Metab Res Rev. 2008;24(7):563–569. doi: 10.1002/dmrr.859.Casellini C.M., Parson H.K., Richardson M.S., Nevoret M.L., Vinik A.I. SUDOSCAN, a non-invasive tool for detecting diabetic small fiber neuropathy and autonomic dysfunction. Diabetes Technol Ther. 2013;15(11):948–953. doi: 10.1089/dia.2013.0129.Casellini C.M., Parson H.K., Richardson M.S., Nevoret M.L., Vinik A.I. SUDOSCAN, a non-invasive tool for detecting diabetic small fiber neuropathy and autonomic dysfunction. Diabetes Technol Ther. 2013;15(11):948–953. doi: 10.1089/dia.2013.0129.Mao F., Liu S., Qiao X., Zheng H., Xiong Q., Wen J. et al. Sudoscan is an effective screening method for asymptomatic diabetic neuropathy in chinese type-2 diabetes mellitus patients. J Diabetes Investig. 2017;8(3):363–368. doi: 10.1111/jdi.12575.Mao F., Liu S., Qiao X., Zheng H., Xiong Q., Wen J. et al. Sudoscan is an effective screening method for asymptomatic diabetic neuropathy in chinese type-2 diabetes mellitus patients. J Diabetes Investig. 2017;8(3):363–368. doi: 10.1111/jdi.12575.Mayaudon H., Miloche P.O., Bauduceau B. A new simple method for assessing sudomotor function: Relevance in type-2 diabetes. Diabetes Metab. 2010;(6 Pt 1):450–454. doi: 10.1016/j.diabet.2010.05.004.Mayaudon H., Miloche P.O., Bauduceau B. A new simple method for assessing sudomotor function: Relevance in type-2 diabetes. Diabetes Metab. 2010;(6 Pt 1):450–454. doi: 10.1016/j.diabet.2010.05.004.Selvarajah D., Cash T., Davies J., Sankar A., Rao G., Grieg M. et al. SUDOSCAN: A simple, rapid and objective method with potential for screening for diabetic peripheral neuropathy. PloS ONE. 2015;10(10):e0138224. doi: 10.1371/journal.pone.0138224.Selvarajah D., Cash T., Davies J., Sankar A., Rao G., Grieg M. et al. SUDOSCAN: A simple, rapid and objective method with potential for screening for diabetic peripheral neuropathy. PloS ONE. 2015;10(10):e0138224. doi: 10.1371/journal.pone.0138224.Smith A.G., Lessard M., Singleton J.R. The diagnostic utility of SUDOSCAN for distal symmetric peripheral neuropathy. J Diabetes Complications. 2014;28(4):511–516. doi: 10.1016/j.jdiacomp.2014.02.013.Smith A.G., Lessard M., Singleton J.R. The diagnostic utility of SUDOSCAN for distal symmetric peripheral neuropathy. J Diabetes Complications. 2014;28(4):511–516. doi: 10.1016/j.jdiacomp.2014.02.013.Yajnik C.S., Kantikar V.V., Pande A.J., Deslypere J.P. Quick and simple evaluation of sudomotor function for screening of diabetic neuropathy. ISRN Endocrinol. 2012;2012:103714. doi: 10.5402/2012/103714.Yajnik C.S., Kantikar V.V., Pande A.J., Deslypere J.P. Quick and simple evaluation of sudomotor function for screening of diabetic neuropathy. ISRN Endocrinol. 2012;2012:103714. doi: 10.5402/2012/103714.Papanas N., Papatheodorou K., Papazoglou D., Christakidis D., Monastiriotis C., Maltezos E. The new indicator test: a valuable diagnostic tool for small fiber impairment in patients with type-2 diabetes. Diabetes Educ. 2007;33(2):251–258. doi: 10.1177/0145721707299661Papanas N., Papatheodorou K., Papazoglou D., Christakidis D., Monastiriotis C., Maltezos E. The new indicator test: a valuable diagnostic tool for small fiber impairment in patients with type-2 diabetes. Diabetes Educ. 2007;33(2):251–258. doi: 10.1177/0145721707299661Shimada H., Kihara M., Kosaka S., Ikeda H., Kawabata K., Tsutada T., Miki T. Comparison of SSR and QSART in early diabetic neuropathy – the value of length-dependent pattern in QSART. Auton Neurosci. 2001;92(1–2):72–75. doi: 10.1016/S1566-0702(01)00287-9.Shimada H., Kihara M., Kosaka S., Ikeda H., Kawabata K., Tsutada T., Miki T. Comparison of SSR and QSART in early diabetic neuropathy – the value of length-dependent pattern in QSART. Auton Neurosci. 2001;92(1–2):72–75. doi: 10.1016/S1566-0702(01)00287-9.Sommer P., Kluschina O., Scley M., Namer B., Schmelz M., Rukwied R. Electrically induced quantitative sudomotor axon test in human volunteers. Auton Neurosci. 2011;159(1–2):111–116. doi: 10.1016/j.autneu.2010.09.004.Sommer P., Kluschina O., Scley M., Namer B., Schmelz M., Rukwied R. Electrically induced quantitative sudomotor axon test in human volunteers. Auton Neurosci. 2011;159(1–2):111–116. doi: 10.1016/j.autneu.2010.09.004.Ravits J.M. AAEM minimonograph #48: autonomic nervous system testing. Muscle Nerve. 1997;20(8):919–937. doi: 10.1002/(sici)1097-4598(199708)20:8<919::aid-mus1>3.0.co;2-9.Ravits J.M. AAEM minimonograph #48: autonomic nervous system testing. Muscle Nerve. 1997;20(8):919–937. doi: 10.1002/(sici)1097-4598(199708)20:8<919::aid-mus1>3.0.co;2-9.Guthoff R.F., Zhivov A., Stachs O. In vivo confocal microscopy, an inner vision of the cornea – a major review. Clin Expermient Ophtalmol. 2009;37(1):100–117. doi: 10.1111/j.1442-9071.2009.02016.x.Guthoff R.F., Zhivov A., Stachs O. In vivo confocal microscopy, an inner vision of the cornea – a major review. Clin Expermient Ophtalmol. 2009;37(1):100–117. doi: 10.1111/j.1442-9071.2009.02016.x.Azmi S., Ferdousi M., Petropoulos I.N., Ponirakis G., Alam U., Fadavi H. et al. Corneal comnfocal microscopy identifies small-fiber neuropathy in subjects with impaired glucose tolerance who develop type-2 diabetes. Diabetes Care. 2015;38(8):1502–1508. doi: 10.2337/dc14-2733.Azmi S., Ferdousi M., Petropoulos I.N., Ponirakis G., Alam U., Fadavi H. et al. Corneal comnfocal microscopy identifies small-fiber neuropathy in subjects with impaired glucose tolerance who develop type-2 diabetes. Diabetes Care. 2015;38(8):1502–1508. doi: 10.2337/dc14-2733.Lauria G., Lombardi R., Camozzi F., Devigli G. Skin biopsy for the diagnosis of peripheral neuropathy. Histopathology. 2009;54(3):273–285. doi: 10.1111/j.1365-2559.2008.03096.x.Lauria G., Lombardi R., Camozzi F., Devigli G. Skin biopsy for the diagnosis of peripheral neuropathy. Histopathology. 2009;54(3):273–285. doi: 10.1111/j.1365-2559.2008.03096.x.Sommer C., Lauria G. Skin biopsy in the management of peripheral neuropathy. Lancet Neurol. 2007;6(7):632–642. doi: 10.1016/S1474-4422(07)70172-2.Sommer C., Lauria G. Skin biopsy in the management of peripheral neuropathy. Lancet Neurol. 2007;6(7):632–642. doi: 10.1016/S1474-4422(07)70172-2.Periquet M.J., Novak V., Collins M.P., Nagaraja H.N., Erdem S., Nash S.M. et al. Painful sensory neuropathy. Prospective evaluation using skin biopsy. Neurology. 1999;53(8):1641–1647. doi: 10.1212/wnl.53.8.1641.Periquet M.J., Novak V., Collins M.P., Nagaraja H.N., Erdem S., Nash S.M. et al. Painful sensory neuropathy. Prospective evaluation using skin biopsy. Neurology. 1999;53(8):1641–1647. doi: 10.1212/wnl.53.8.1641.Saperstein D.S., Levine T.D. Diagnosing small fiber neuropathy through the use of skin biopsy. Pract Neurol. 2009;8:37–40. Available at: https://corinthianreferencelab.com/wp-content/uploads/2018/01/Pract_Neuro.pdf.Saperstein D.S., Levine T.D. Diagnosing small fiber neuropathy through the use of skin biopsy. Pract Neurol. 2009;8:37–40. Available at: https://corinthianreferencelab.com/wp-content/uploads/2018/01/Pract_Neuro.pdf.Herder C., Roden M., Ziegler D. Novel Insights into Sensorimotor and Cardiovascular Autonomic Neuropathy from Recent-Onset Diabetes and Population-Based Cohorts. Trends in Endocrinology and Metabolism. 2019;30(5):286–298. doi: 10.1016/j.tem.2019.02.007.Herder C., Roden M., Ziegler D. Novel Insights into Sensorimotor and Cardiovascular Autonomic Neuropathy from Recent-Onset Diabetes and Population-Based Cohorts. Trends in Endocrinology and Metabolism. 2019;30(5):286–298. doi: 10.1016/j.tem.2019.02.007.Zoppini G., Cacciatori V., Raimondo D., Gemma M., Trombetta M., Dauriz M. et al. The prevalence of cardiovascular autonomic neuropathy in a cohort of patients with newly diagnosed type-2 diabetes. The Verona Newly Diagnosed Type-2 Diabetes Study (VNDS). Diabetes Care. 2015;38(8):1487–1493. doi: 10.2337/dc15-0081.Zoppini G., Cacciatori V., Raimondo D., Gemma M., Trombetta M., Dauriz M. et al. The prevalence of cardiovascular autonomic neuropathy in a cohort of patients with newly diagnosed type-2 diabetes. The Verona Newly Diagnosed Type-2 Diabetes Study (VNDS). Diabetes Care. 2015;38(8):1487–1493. doi: 10.2337/dc15-0081.Rolim L.C., Sa J.R., Chacra A.R., Dib S.A. Diabetic cardiovascular autonomic neuropathy: risk factors, clinical impact and early diagnosis. Arq Bras Cardiol. 2008;90(4):e24–31. doi: 10.1590/s0066-782x2008000400014.Rolim L.C., Sa J.R., Chacra A.R., Dib S.A. Diabetic cardiovascular autonomic neuropathy: risk factors, clinical impact and early diagnosis. Arq Bras Cardiol. 2008;90(4):e24–31. doi: 10.1590/s0066-782x2008000400014.Zilliox L., Peltier A.C., Wren P.A., Anderson A., Smith A.G., Singleton J.R. et al. Assessing autonomioc dysfunction in the early diabetic neuropathy. The Survey of Autonomic Symptom. Neurology. 2011;76(12):1099–1105. doi: 10.1212/WNL.0b013e3182120147.Zilliox L., Peltier A.C., Wren P.A., Anderson A., Smith A.G., Singleton J.R. et al. Assessing autonomioc dysfunction in the early diabetic neuropathy. The Survey of Autonomic Symptom. Neurology. 2011;76(12):1099–1105. doi: 10.1212/WNL.0b013e3182120147.Ishibashi F., Taniguchi M., Kojima R., Awasaki A., Kosaka A., Uetake H. Elasticity of the tibial nerve assessed by sonoelastography was reduced before the development of neuropathy and further deterioration associated with the severity of neuropathy un type-2 diabetes. J Diabetes Investig. 2016;7(3):404–412. doi: 10.1111/jdi.12408.Ishibashi F., Taniguchi M., Kojima R., Awasaki A., Kosaka A., Uetake H. Elasticity of the tibial nerve assessed by sonoelastography was reduced before the development of neuropathy and further deterioration associated with the severity of neuropathy un type-2 diabetes. J Diabetes Investig. 2016;7(3):404–412. doi: 10.1111/jdi.12408.Pitarokopilli K., Kerasnoudis A., Behredt V., Labedi A., Ayzenberg I., Gold R., Yoon M.-S. Facing the diagnostic challenge: Nerve Ultrasound in diabetic patients with neuropathic symptoms. Muscle Nerve. 2016;54(1):18–24. doi: 10.1002/mus.24981.Pitarokopilli K., Kerasnoudis A., Behredt V., Labedi A., Ayzenberg I., Gold R., Yoon M.-S. Facing the diagnostic challenge: Nerve Ultrasound in diabetic patients with neuropathic symptoms. Muscle Nerve. 2016;54(1):18–24. doi: 10.1002/mus.24981.Vaeggemose M., Ringgaard S., Ejskjaer N., Andersen H. Magnetic Resonance Imaging may be used for early evaluation of diabetic peripheral neuropathy. J Diabetes Sci Technol. 2015;9(1):162–163. doi: 10.1177/1932296814559303.Vaeggemose M., Ringgaard S., Ejskjaer N., Andersen H. Magnetic Resonance Imaging may be used for early evaluation of diabetic peripheral neuropathy. J Diabetes Sci Technol. 2015;9(1):162–163. doi: 10.1177/1932296814559303.Pham M., Oikonomou D., Hornung B., Weiler M., Heiland S., Baumer P. et al. Magnetic resonance neurography detects diabetic neuropathy early and with proximal predominance. Ann Neurol. 2015;78(6):939–948. doi: 10.1002/ana.24524.Pham M., Oikonomou D., Hornung B., Weiler M., Heiland S., Baumer P. et al. Magnetic resonance neurography detects diabetic neuropathy early and with proximal predominance. Ann Neurol. 2015;78(6):939–948. doi: 10.1002/ana.24524.Choi A., Kim H.W., Kwon J.W., Shim Y.S., Jee D.H., Yun J.S. et al. Early inner retinal thinning and cardiovascular autonomic dysfunction in type-2 diabetes. PloS ONE. 2017;12(3):e0174377. doi: 10.1371/journal.pone.0174377.Choi A., Kim H.W., Kwon J.W., Shim Y.S., Jee D.H., Yun J.S. et al. Early inner retinal thinning and cardiovascular autonomic dysfunction in type-2 diabetes. PloS ONE. 2017;12(3):e0174377. doi: 10.1371/journal.pone.0174377.Akbar M., Bhandari U., Habib A., Ahmad R. Potential association of triglyceride glucose index with cardiac autonomic neuropathy in type-2 diabetes mellitus patients. J Korean Sci. 2017;32(7):1131–1138. doi: 10.3346/jkms.2017.32.7.1131.Akbar M., Bhandari U., Habib A., Ahmad R. Potential association of triglyceride glucose index with cardiac autonomic neuropathy in type-2 diabetes mellitus patients. J Korean Sci. 2017;32(7):1131–1138. doi: 10.3346/jkms.2017.32.7.1131.Scott L.A., Kench P.L. Cardiac autonomic neuropathy in the diabetic patient. Does 123I-MIBG imaging have a role to play in early diagnosis? Nucl Med Technol. 2004;32(2):66–71. Available at: http://tech.snmjournals.org/content/32/2/66.Scott L.A., Kench P.L. Cardiac autonomic neuropathy in the diabetic patient. Does 123I-MIBG imaging have a role to play in early diagnosis? Nucl Med Technol. 2004;32(2):66–71. Available at: http://tech.snmjournals.org/content/32/2/66.Hattori N., Tamaki N., Hayashi T., Masuda I., Kudoh T., Tateno M. et al. Regional abnormality of Iodine-123-MIBG in diabetic hearts. J Nucl Med. 1996;37(12):1985–1990. Available at: https://www.ncbi.nlm.nih.gov/pubmed/8970519.Hattori N., Tamaki N., Hayashi T., Masuda I., Kudoh T., Tateno M. et al. Regional abnormality of Iodine-123-MIBG in diabetic hearts. J Nucl Med. 1996;37(12):1985–1990. Available at: https://www.ncbi.nlm.nih.gov/pubmed/8970519.Schnell O., Hammer K., Muhr-Becker D., Ziegler AG, Weiss M., Tatsch K., Standl E. Cardiac sympathetic dysinnervation in type-2 diabetes mellitus with and without ECG-based cardiac autonomic neuropathy. J Diabetes Complications. 2006;16(3):220–227. doi: 10.1016/s1056-8727(01)00180-5.Schnell O., Hammer K., Muhr-Becker D., Ziegler AG, Weiss M., Tatsch K., Standl E. Cardiac sympathetic dysinnervation in type-2 diabetes mellitus with and without ECG-based cardiac autonomic neuropathy. J Diabetes Complications. 2006;16(3):220–227. doi: 10.1016/s1056-8727(01)00180-5.Scholte A.J.H.A., Schvijf J.D., Delgado V., Kok J.A., Bus M.T.J., Maan A.C. et al. Cardiac autonomic neuropathy in patients with diabetes and no symptoms of coronary artery disease: comparison of 123I-metaiodobenzylguanidine myocardial scintigraphy and heart rate variability. Eur J Nucl Med Mol Imaging. 2010;37:1698–1705. doi: 10.1007/s00259-010-1442-0.Scholte A.J.H.A., Schvijf J.D., Delgado V., Kok J.A., Bus M.T.J., Maan A.C. et al. Cardiac autonomic neuropathy in patients with diabetes and no symptoms of coronary artery disease: comparison of 123I-metaiodobenzylguanidine myocardial scintigraphy and heart rate variability. Eur J Nucl Med Mol Imaging. 2010;37:1698–1705. doi: 10.1007/s00259-010-1442-0.Shakher J., Stevens M.J. Update on the management of diabetic polyneuropathies. Diabetes Metab Syndr Obes.2011;4:289–305. doi: 10.2147/DMSO.S11324.Shakher J., Stevens M.J. Update on the management of diabetic polyneuropathies. Diabetes Metab Syndr Obes.2011;4:289–305. doi: 10.2147/DMSO.S11324.The Diabetes Control and Complications Trial research group: the effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med. 1995;122(8):561–568. doi: 10.7326/0003-4819-122-8-199504150-00001.The Diabetes Control and Complications Trial research group: the effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med. 1995;122(8):561–568. doi: 10.7326/0003-4819-122-8-199504150-00001.Callaghan B.C., Little A.A., Feldman E.L., Hughes R.A.C. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev. 2012;(6):CD007543. doi: 10.1002/14651858.CD007543.pub2.Callaghan B.C., Little A.A., Feldman E.L., Hughes R.A.C. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev. 2012;(6):CD007543. doi: 10.1002/14651858.CD007543.pub2.Zhoungas S., Arima H., Gerstein H.C., Holman R.R., Woodward M., Reaven P. et al. Effect of intensive glucose control on microvascular outcomes in patients with type-2 diabetes: a meta-analysis of individual participant data from randomised controlled trials. Lancet Diabetes Endocrinol. 2017;5(6):431–437. doi: 10.1016/S2213-8587(17)30104-3.Zhoungas S., Arima H., Gerstein H.C., Holman R.R., Woodward M., Reaven P. et al. Effect of intensive glucose control on microvascular outcomes in patients with type-2 diabetes: a meta-analysis of individual participant data from randomised controlled trials. Lancet Diabetes Endocrinol. 2017;5(6):431–437. doi: 10.1016/S2213-8587(17)30104-3.Stino A.M., Smith A.G. Peripheral neuropathy in the prediabetes and the metabolic syndrome. J Diabetes Investig. 2017;8(5):646–655. doi: 10.1111/jdi.12650. 86. Smith A.G., Russell J., Feldman E.L., Goldstein J., Peltier A. et al. Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care. 2006;29(6):1294–1299. doi: 10.2337/dc06-0224.Stino A.M., Smith A.G. Peripheral neuropathy in the prediabetes and the metabolic syndrome. J Diabetes Investig. 2017;8(5):646–655. doi: 10.1111/jdi.12650. 86. Smith A.G., Russell J., Feldman E.L., Goldstein J., Peltier A. et al. Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care. 2006;29(6):1294–1299. doi: 10.2337/dc06-0224.Singleton J.R., Marcus R.L., Jackson J.E., Lessard M.K., Graham T.E., Smith A.G. Exercise increases cutaneous nerve density in diabetic patients without neuropathy. Ann Clin Trans Neurol. 2014;1(10):844–849. doi: 10.1002/acn3.125.Singleton J.R., Marcus R.L., Jackson J.E., Lessard M.K., Graham T.E., Smith A.G. Exercise increases cutaneous nerve density in diabetic patients without neuropathy. Ann Clin Trans Neurol. 2014;1(10):844–849. doi: 10.1002/acn3.125.Singleton J.R., Marcus R.L., Lessard M., Jackson J.E., Gordon Smith A. Supervised exercise improves cutaneous reinnervation capacity in metabolic syndrome patients. Ann Neurol. 2015;77(1):146–153. doi: 10.1002/ana.24310.Singleton J.R., Marcus R.L., Lessard M., Jackson J.E., Gordon Smith A. Supervised exercise improves cutaneous reinnervation capacity in metabolic syndrome patients. Ann Neurol. 2015;77(1):146–153. doi: 10.1002/ana.24310.Khang S.J., Ko K.J., Baek U.H. Effect of 12 weeks combined aerobic and resistance exercise on heart-rate variability in type-2 diabetes mellitus patients. J Phys Ther Sci. 2016;28(7):2088–2093. doi: 10.1589/jpts.28.2088.Khang S.J., Ko K.J., Baek U.H. Effect of 12 weeks combined aerobic and resistance exercise on heart-rate variability in type-2 diabetes mellitus patients. J Phys Ther Sci. 2016;28(7):2088–2093. doi: 10.1589/jpts.28.2088.Pennathur S., Jaiswal M., White E.A., Ang L., Raffel D.M., Rubenfire M., Pop- Busui R. Structured lifestyle intervention in patients with the metabolic syndrome mitigates oxidative stress but fails to improve measures of cardiovascular autonomic neuropathy. J Diabet Compl. 2017;31(9):1437–1443. doi: 10.1016/j.jdiacomp.2017.03.008.Pennathur S., Jaiswal M., White E.A., Ang L., Raffel D.M., Rubenfire M., Pop- Busui R. Structured lifestyle intervention in patients with the metabolic syndrome mitigates oxidative stress but fails to improve measures of cardiovascular autonomic neuropathy. J Diabet Compl. 2017;31(9):1437–1443. doi: 10.1016/j.jdiacomp.2017.03.008.Golbidi S., Badran M., Laher I. Diabetes and alpha lipoic acid. Front Pharmacol. 2011;2:69. doi: 10.3389/fphar.2011.00069.Golbidi S., Badran M., Laher I. Diabetes and alpha lipoic acid. Front Pharmacol. 2011;2:69. doi: 10.3389/fphar.2011.00069.Manning P.J., Sutherland W.H.F., Williams S.M., Walker R.J., Berry E.A., De Jong S.A., Ryalls A.R. The effect of lipoic acid and the vitamin E therapies in individuals with the metabolic syndrome. Nutr Metab Cardiovasc Dis. 2013;23(6):543–549. doi: 10.1016/j.numecd.2011.11.006.Manning P.J., Sutherland W.H.F., Williams S.M., Walker R.J., Berry E.A., De Jong S.A., Ryalls A.R. The effect of lipoic acid and the vitamin E therapies in individuals with the metabolic syndrome. Nutr Metab Cardiovasc Dis. 2013;23(6):543–549. doi: 10.1016/j.numecd.2011.11.006.Namazi N., Larijani B., Azadbakht L. Alpha-lipoic acid supplement in obesity treatment: A systematic review and meta-analysis of clinical trials. Clin Nutr. 2018;37(2):419–428. doi: 10.1016/j.clnu.2017.06.002.Namazi N., Larijani B., Azadbakht L. Alpha-lipoic acid supplement in obesity treatment: A systematic review and meta-analysis of clinical trials. Clin Nutr. 2018;37(2):419–428. doi: 10.1016/j.clnu.2017.06.002.Sun H., Yao W., Tang Y., Zhuang W., Wu D., Huang S., Sheng H. Urinary exosomes as a novel biomarker for the evaluation of a-lipoic acid´s protective effect in early diabetic nephropathy. J Clin Lab Anal. 2017;31(6):e22129. doi: 10.1002/jcla.22129.Sun H., Yao W., Tang Y., Zhuang W., Wu D., Huang S., Sheng H. Urinary exosomes as a novel biomarker for the evaluation of a-lipoic acid´s protective effect in early diabetic nephropathy. J Clin Lab Anal. 2017;31(6):e22129. doi: 10.1002/jcla.22129.Han T., Bai J., Liu W., Hu Y. A systematic review and meta-analysis of α-lipoic acid in the treatment of diabetic peripheral neuropathy. Eur J Endocrinol. 2012;167(4):465–471. doi: 10.1530/EJE-12-0555.Han T., Bai J., Liu W., Hu Y. A systematic review and meta-analysis of α-lipoic acid in the treatment of diabetic peripheral neuropathy. Eur J Endocrinol. 2012;167(4):465–471. doi: 10.1530/EJE-12-0555.Mijnhout G.S., Kollen B.J., Alkhalaf A., Kleefstra N., Bilo H.J. Alpha Lipoic Acid for symptomatic peripheral neuropathy in patients with diabetes: a metaanalysis of randomized controlled trials. Int J Endocrinol. 2012;2012:456279. doi: 10.1155/2012/456279.Mijnhout G.S., Kollen B.J., Alkhalaf A., Kleefstra N., Bilo H.J. Alpha Lipoic Acid for symptomatic peripheral neuropathy in patients with diabetes: a metaanalysis of randomized controlled trials. Int J Endocrinol. 2012;2012:456279. doi: 10.1155/2012/456279.Tankova T., Koev D., Dakovska L. Alpha-lipoic acid in the treatment of autonomic diabetic neuropathy (controlled, randomized, open-label study). Rom J Intern Med. 2004;42(2):457–464. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15529636.Tankova T., Koev D., Dakovska L. Alpha-lipoic acid in the treatment of autonomic diabetic neuropathy (controlled, randomized, open-label study). Rom J Intern Med. 2004;42(2):457–464. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15529636.Ziegler D., Ametov A., Barinov A., Dyck P.J., Gurieva I., Low P.A. et al. Oral treatment with α-lipoic acid improves symptomatic diabetic polyneuropathy. Diabetes Care. 2006;29(11):2365–2370. doi: 10.2337/dc06-1216.Ziegler D., Ametov A., Barinov A., Dyck P.J., Gurieva I., Low P.A. et al. Oral treatment with α-lipoic acid improves symptomatic diabetic polyneuropathy. Diabetes Care. 2006;29(11):2365–2370. doi: 10.2337/dc06-1216.Ziegler D,, Schatz H,, Conrad F,, Gries F,A,, 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 multicentre trial (DEKAN Study). Diabetes Care. 1997;20(3);369–373. doi: 10.2337/diacare.20.3.369.Ziegler D,, Schatz H,, Conrad F,, Gries F,A,, 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 multicentre trial (DEKAN Study). Diabetes Care. 1997;20(3);369–373. doi: 10.2337/diacare.20.3.369.Grewal A.S., Bhardwaj S., Pandita D., Lather V., Sekhon B.S. Updates on Aldose Reductase Inhibitors for management of diabetic complications and non-diabetic diseases. Mini Rev Med Chem. 2016;16(2):120–162. doi: 10.2174/1389557515666150909143737.Grewal A.S., Bhardwaj S., Pandita D., Lather V., Sekhon B.S. Updates on Aldose Reductase Inhibitors for management of diabetic complications and non-diabetic diseases. Mini Rev Med Chem. 2016;16(2):120–162. doi: 10.2174/1389557515666150909143737.Stacke H., Gaus W., Achenbach U., Federlin K., Bretzel R.G. Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised doubleblind, placebo-controlled clinical study. Exp Clin Endocrinol Diabetes. 2008;116(10):600–605. doi: 10.1055/s-2008-1065351.Stacke H., Gaus W., Achenbach U., Federlin K., Bretzel R.G. Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised doubleblind, placebo-controlled clinical study. Exp Clin Endocrinol Diabetes. 2008;116(10):600–605. doi: 10.1055/s-2008-1065351.Won J.C., Kwon H.S., Moon S.S., Chun S.W., Kim C.H. et al. γ-Linolenic Acid versus α-Lipoic Acid for Treating Painful Diabetic Neuropathy in Adults: A 12-Week, Double-Placebo, Randomized, Noninferiority Trial. Diabetes Metab J. 2019;43:e60. doi: 10.4093/dmj.2019.0099.Won J.C., Kwon H.S., Moon S.S., Chun S.W., Kim C.H. et al. γ-Linolenic Acid versus α-Lipoic Acid for Treating Painful Diabetic Neuropathy in Adults: A 12-Week, Double-Placebo, Randomized, Noninferiority Trial. Diabetes Metab J. 2019;43:e60. doi: 10.4093/dmj.2019.0099.Keen H., Payan J., Allawi J. et al. Treatment of Diabetic Neuropathy With γ-Linolenic Acid. Diabetes Care 1993;16(1):8–15. doi: 10.2337/diacare.16.1.8.Keen H., Payan J., Allawi J. et al. Treatment of Diabetic Neuropathy With γ-Linolenic Acid. Diabetes Care 1993;16(1):8–15. doi: 10.2337/diacare.16.1.8.Rolim L.C., da Silva E.M.K., Flumignan R.L.G., Abreu M.M., Dib S.A. Acetyl- L-carnitine for the treatment of diabetic peripheral neuropathy. Cochrane Database of Systematic Reviews. 2019;(6):CD011265. doi: 10.1002/14651858.CD011265.pub2.Rolim L.C., da Silva E.M.K., Flumignan R.L.G., Abreu M.M., Dib S.A. Acetyl- L-carnitine for the treatment of diabetic peripheral neuropathy. Cochrane Database of Systematic Reviews. 2019;(6):CD011265. doi: 10.1002/14651858.CD011265.pub2.Ziegler D., Movsesyan L., Mankovsky B., Gurieva I., Abylaiuly Zh., Strokov I. Treatment of Symptomatic Polyneuropathy With Actovegin in Type 2 Diabetic Patients. Diabetes Care. 2009;32(8):1479–1484. doi: 10.2337/dc09-0545.Ziegler D., Movsesyan L., Mankovsky B., Gurieva I., Abylaiuly Zh., Strokov I. Treatment of Symptomatic Polyneuropathy With Actovegin in Type 2 Diabetic Patients. Diabetes Care. 2009;32(8):1479–1484. doi: 10.2337/dc09-0545.

The authors declare that there are no conflicts of interest present.