Diagnostic Tools, Biomarkers, and Treatments in Diabetic polyneuropathy
and Cardiovascular Autonomic Neuropathy

Gidon    J.    Bönhof; Christian       Herder; Dan       Ziegler
Abstract

The various manifestations of diabetic neuropathy, including distal symmetric sensorimotor polyneuropathy (DSPN) and cardiovascular autonomic neuropathy (CAN), are among the most prevalent chronic complications of diabetes. Major clinical complications of diabetic neuropathies, such as neuropathic pain, chronic foot ulcers, and orthostatic hypotension, are associated with considerable morbidity, increased mortality, and diminished quality of life. Despite the substantial individual and socioeconomic burden, the strategies to diagnose and treat diabetic neuropathies remain insufficient. This review provides an overview of the current clinical aspects and recent advances in exploring local and systemic biomarkers of both DSPN and CAN assessed in human studies (such as biomarkers of inflammation and oxidative stress) for better understanding of the underlying pathophysiology and for improving early detection. Current therapeutic options for DSPN are (I) causal treatment, including lifestyle modification, optimal glycemic control, and multifactorial risk intervention, (II) pharmacotherapy derived from pathogenetic concepts, and (III) analgesic treatment against neuropathic pain. Recent advances in each category are discussed, including non-pharmacological approaches, such as electrical stimulation. Finally, the current therapeutic options for cardiovascular autonomic complications are provided. These insights should contribute to a broader understanding of the various manifestations of diabetic neuropathies from both the research and clinical perspectives.
Keywords: Polyneuropathy, peripheral neuropathy, autonomic neuropathy, CAN, neuropathic pain, inflammation, therapy, exercise.
[1] 
International Diabetes FederationIDF Diabetes Atlas.  9th ed. Brussels, Belgium: International Diabetes Federation 2019.
[2] 
Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes Care  2017; 40(1): 136-54.
[http://dx.doi.org/10.2337/dc16-2042] [PMID: 27999003] 
[3] 
Tesfaye S, Boulton AJM, Dyck PJ, et al. Toronto Diabetic Neuropathy Expert Group. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care  2010; 33(10): 2285-93.
[http://dx.doi.org/10.2337/dc10-1303] [PMID: 20876709] 
[4] 
Bönhof GJ, Herder C, Strom A, Papanas N, Roden M, Ziegler D. Emerging Biomarkers, Tools, and Treatments for Diabetic Polyneuropathy. Endocr Rev  2019; 40(1): 153-92.
[http://dx.doi.org/10.1210/er.2018-00107] [PMID: 30256929] 
[5] 
Hicks CW, Wang D, Matsushita K, Windham BG, Selvin E. Peripheral Neuropathy and All-Cause and Cardiovascular Mortality in U.S. Adults: A Prospective Cohort Study. Ann Intern Med 2020.
[PMID: 33284680] 
[6] 
Lu B, Hu J, Wen J, et al. Determination of peripheral neuropathy prevalence and associated factors in Chinese subjects with diabetes and pre-diabetes - ShangHai Diabetic neuRopathy Epidemiology and Molecular Genetics Study (SH-DREAMS). PLoS One  2013; 8(4): e61053.
[http://dx.doi.org/10.1371/journal.pone.0061053] [PMID: 23613782] 
[7] 
Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A, Group KS. KORA Study Group. 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; 31(3): 464-9.
[http://dx.doi.org/10.2337/dc07-1796] [PMID: 18039804] 
[8] 
Callaghan BC, Gao L, Li Y, et al. Diabetes and obesity are the main metabolic drivers of peripheral neuropathy. Ann Clin Transl Neurol  2018; 5(4): 397-405.
[http://dx.doi.org/10.1002/acn3.531] [PMID: 29687018] 
[9] 
Ziegler D, Papanas N, Vinik AI, Shaw JE. Epidemiology of polyneuropathy in diabetes and prediabetes. Handb Clin Neurol  2014; 126: 3-22.
[http://dx.doi.org/10.1016/B978-0-444-53480-4.00001-1] [PMID: 25410210] 
[10] 
Ziegler D, Landgraf R, Lobmann R, et al. Painful and painless neuropathies are distinct and largely undiagnosed entities in subjects participating in an educational initiative (PROTECT study). Diabetes Res Clin Pract  2018; 139: 147-54.
[http://dx.doi.org/10.1016/j.diabres.2018.02.043] [PMID: 29518491] 
[11] 
Zochodne DW. Clinical features of diabetic polyneuropathy. Handb Clin Neurol  2014; 126: 23-30.
[http://dx.doi.org/10.1016/B978-0-444-53480-4.00002-3] [PMID: 25410211] 
[12] 
Dyck PJ, Albers JW, Andersen H, et al. Toronto Expert Panel on Diabetic Neuropathy. Diabetic polyneuropathies: update on research definition, diagnostic criteria and estimation of severity. Diabetes Metab Res Rev  2011; 27(7): 620-8.
[http://dx.doi.org/10.1002/dmrr.1226] [PMID: 21695763] 
[13] 
Apfel SC, Asbury AK, Bril V, et al. Ad Hoc Panel on Endpoints for Diabetic Neuropathy Trials. Positive neuropathic sensory symptoms as endpoints in diabetic neuropathy trials. J Neurol Sci  2001; 189(1-2): 3-5.
[http://dx.doi.org/10.1016/S0022-510X(01)00584-6] [PMID: 11596565] 
[14] 
Neundorfer B, Thomas P. Symmetric distal polyneuropathy.Textbook of Diabetic Neuropathy.  New York: Thieme 2003; pp. 199-202.
[15] 
Young MJ, Boulton AJ, MacLeod AF, Williams DR, Sonksen PH. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia  1993; 36(2): 150-4.
[http://dx.doi.org/10.1007/BF00400697] [PMID: 8458529] 
[16] 
Ametov AS, Barinov A, Dyck PJ, et al. SYDNEY Trial Study Group. The sensory symptoms of diabetic polyneuropathy are improved with α-lipoic acid: the SYDNEY trial. Diabetes Care  2003; 26(3): 770-6.
[http://dx.doi.org/10.2337/diacare.26.3.770] [PMID: 12610036] 
[17] 
Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Greene DA. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care  1994; 17(11): 1281-9.
[http://dx.doi.org/10.2337/diacare.17.11.1281] [PMID: 7821168] 
[18] 
Bril V, Tomioka S, Buchanan RA, Perkins BA. mTCNS Study Group. Reliability and validity of the modified Toronto Clinical Neuropathy Score in diabetic sensorimotor polyneuropathy. Diabet Med  2009; 26(3): 240-6.
[http://dx.doi.org/10.1111/j.1464-5491.2009.02667.x] [PMID: 19317818] 
[19] 
Singleton JR, Bixby B, Russell JW, et al. The Utah Early Neuropathy Scale: a sensitive clinical scale for early sensory predominant neuropathy. J Peripher Nerv Syst  2008; 13(3): 218-27.
[http://dx.doi.org/10.1111/j.1529-8027.2008.00180.x] [PMID: 18844788] 
[20] 
Tesfaye S, Vileikyte L, Rayman G, et al. Toronto Expert Panel on Diabetic Neuropathy. Painful diabetic peripheral neuropathy: consensus recommendations on diagnosis, assessment and management. Diabetes Metab Res Rev  2011; 27(7): 629-38.
[http://dx.doi.org/10.1002/dmrr.1225] [PMID: 21695762] 
[21] 
Treede RD, Jensen TS, Campbell JN, et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology  2008; 70(18): 1630-5.
[http://dx.doi.org/10.1212/01.wnl.0000282763.29778.59] [PMID: 18003941] 
[22] 
Rosenberger DC, Blechschmidt V, Timmerman H, Wolff A, Treede RD. Challenges of neuropathic pain: focus on diabetic neuropathy. J Neural Transm (Vienna)  2020; 127(4): 589-624. Epub ahead of print
[http://dx.doi.org/10.1007/s00702-020-02145-7] [PMID: 32036431] 
[23] 
Tesfaye S, Boulton AJM, Dickenson AH. Mechanisms and management of diabetic painful distal symmetrical polyneuropathy. Diabetes Care  2013; 36(9): 2456-65.
[http://dx.doi.org/10.2337/dc12-1964] [PMID: 23970715] 
[24] 
Spallone V, Greco C. Painful and painless diabetic neuropathy: one disease or two? Curr Diab Rep  2013; 13(4): 533-49.
[http://dx.doi.org/10.1007/s11892-013-0387-7] [PMID: 23677582] 
[25] 
Gasparotti R, Padua L, Briani C, Lauria G. New technologies for the assessment of neuropathies. Nat Rev Neurol  2017; 13(4): 203-16.
[http://dx.doi.org/10.1038/nrneurol.2017.31] [PMID: 28303912] 
[26] 
Kennedy WR, Wendelschafer-Crabb G, Johnson T. Quantitation of epidermal nerves in diabetic neuropathy. Neurology  1996; 47(4): 1042-8.
[http://dx.doi.org/10.1212/WNL.47.4.1042] [PMID: 8857742] 
[27] 
Lauria G, Cornblath DR, Johansson O, et al. European Federation of Neurological Societies. EFNS guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy. Eur J Neurol  2005; 12(10): 747-58.
[http://dx.doi.org/10.1111/j.1468-1331.2005.01260.x] [PMID: 16190912] 
[28] 
Ziegler D, Papanas N, Zhivov A, et al. German Diabetes Study (GDS) Group. Early detection of nerve fiber loss by corneal confocal microscopy and skin biopsy in recently diagnosed type 2 diabetes. Diabetes  2014; 63(7): 2454-63.
[http://dx.doi.org/10.2337/db13-1819] [PMID: 24574045] 
[29] 
Bönhof GJ, Strom A, Püttgen S, et al. Patterns of cutaneous nerve fibre loss and regeneration in type 2 diabetes with painful and painless polyneuropathy. Diabetologia  2017; 60(12): 2495-503.
[http://dx.doi.org/10.1007/s00125-017-4438-5] [PMID: 28914336] 
[30] 
Zochodne DW. The challenges and beauty of peripheral nerve regrowth. J Peripher Nerv Syst  2012; 17(1): 1-18.
[http://dx.doi.org/10.1111/j.1529-8027.2012.00378.x] [PMID: 22462663] 
[31] 
Terkelsen AJ, Karlsson P, Lauria G, Freeman R, Finnerup NB, Jensen TS. The diagnostic challenge of small fibre neuropathy: clinical presentations, evaluations, and causes. Lancet Neurol  2017; 16(11): 934-44.
[http://dx.doi.org/10.1016/S1474-4422(17)30329-0] [PMID: 29029847] 
[32] 
Galosi E, La Cesa S, Di Stefano G, et al. A pain in the skin. Regenerating nerve sprouts are distinctly associated with ongoing burning pain in patients with diabetes. Eur J Pain  2018; 22(10): 1727-34.
[http://dx.doi.org/10.1002/ejp.1259] [PMID: 29885017] 
[33] 
Scheytt S, Riediger N, Braunsdorf S, Sommer C, Üçeyler N. Increased gene expression of growth associated protein-43 in skin of patients with early-stage peripheral neuropathies. J Neurol Sci  2015; 355(1-2): 131-7.
[http://dx.doi.org/10.1016/j.jns.2015.05.044] [PMID: 26071889] 
[34] 
Lauria G, Morbin M, Lombardi R, et al. Expression of capsaicin receptor immunoreactivity in human peripheral nervous system and in painful neuropathies. J Peripher Nerv Syst  2006; 11(3): 262-71.
[http://dx.doi.org/10.1111/j.1529-8027.2006.0097.x] [PMID: 16930289] 
[35] 
Narayanaswamy H, Facer P, Misra VP, et al. A longitudinal study of sensory biomarkers of progression in patients with diabetic peripheral neuropathy using skin biopsies. J Clin Neurosci  2012; 19(11): 1490-6.
[http://dx.doi.org/10.1016/j.jocn.2011.12.026] [PMID: 22705139] 
[36] 
Atherton DD, Facer P, Roberts KM, et al. Use of the novel Contact Heat Evoked Potential Stimulator (CHEPS) for the assessment of small fibre neuropathy: correlations with skin flare responses and intra-epidermal nerve fibre counts. BMC Neurol  2007; 7: 21.
[http://dx.doi.org/10.1186/1471-2377-7-21] [PMID: 17683543] 
[37] 
Meeker R, Williams K. Dynamic nature of the p75 neurotrophin receptor in response to injury and disease. J Neuroimmune Pharmacol  2014; 9(5): 615-28.
[http://dx.doi.org/10.1007/s11481-014-9566-9] [PMID: 25239528] 
[38] 
Gonçalves NP, Jager SE, Richner M, et al. Schwann cell p75 neurotrophin receptor modulates small fiber degeneration in diabetic neuropathy. Glia  2020; 68(12): 2725-43.
[http://dx.doi.org/10.1002/glia.23881] [PMID: 32658363] 
[39] 
Gonçalves NP, Vægter CB, Andersen H, Østergaard L, Calcutt NA, Jensen TS. Schwann cell interactions with axons and microvessels in diabetic neuropathy. Nat Rev Neurol  2017; 13(3): 135-47.
[http://dx.doi.org/10.1038/nrneurol.2016.201] [PMID: 28134254] 
[40] 
Ebenezer GJ, McArthur JC, Thomas D, et al. Denervation of skin in neuropathies: the sequence of axonal and Schwann cell changes in skin biopsies. Brain  2007; 130(Pt 10): 2703-14.
[http://dx.doi.org/10.1093/brain/awm199] [PMID: 17898011] 
[41] 
Snider WD, McMahon SB. Tackling pain at the source: new ideas about nociceptors. Neuron  1998; 20(4): 629-32.
[http://dx.doi.org/10.1016/S0896-6273(00)81003-X] [PMID: 9581756] 
[42] 
Karlsson P, Provitera V, Caporaso G, Stancanelli A, Saltalamacchia AM, Borreca I, et al. Increased peptidergic fibers as a potential cutaneous marker of pain in diabetic small fiber neuropathy. Pain 2020.
[PMID: 32833793] 
[43] 
Ziegler D, Papanas N, Schnell O, et al. Current concepts in the management of diabetic polyneuropathy. J Diabetes Investig 2020.
[http://dx.doi.org/10.1111/jdi.13401] [PMID: 32918837] 
[44] 
Martinotti G, Lupi M, Sarchione F, et al. The potential of pregabalin in neurology, psychiatry and addiction: a qualitative overview. Curr Pharm Des  2013; 19(35): 6367-74.
[http://dx.doi.org/10.2174/13816128113199990425] [PMID: 23782139] 
[45] 
Adamska A, Pilacinski S, Zozulinska-Ziolkiewicz D, et al. An increased skin microvessel density is associated with neurovascular complications in type 1 diabetes mellitus. Diab Vasc Dis Res  2019; 16(6): 513-22.
[http://dx.doi.org/10.1177/1479164119850831] [PMID: 31144511] 
[46] 
Ziegler D, Strom A, Brüggemann J, et al. GDS Group. Overexpression of cutaneous mitochondrial superoxide dismutase in recent-onset type 2 diabetes. Diabetologia  2015; 58(7): 1621-5.
[http://dx.doi.org/10.1007/s00125-015-3609-5] [PMID: 25933618] 
[47] 
Ebenezer GJ, O’Donnell R, Hauer P, Cimino NP, McArthur JC, Polydefkis M. Impaired neurovascular repair in subjects with diabetes following experimental intracutaneous axotomy. Brain  2011; 134(Pt 6): 1853-63.
[http://dx.doi.org/10.1093/brain/awr086] [PMID: 21616974] 
[48] 
Sohn E, Suh BC, Wang N, Freeman R, Gibbons CH. A novel method to quantify cutaneous vascular innervation. Muscle Nerve  2020; 62(4): 492-501.
[http://dx.doi.org/10.1002/mus.26889] [PMID: 32270499] 
[49] 
Strom A, Brüggemann J, Ziegler I, et al. GDS Group. Pronounced reduction of cutaneous Langerhans cell density in recently diagnosed type 2 diabetes. Diabetes  2014; 63(3): 1148-53.
[http://dx.doi.org/10.2337/db13-1444] [PMID: 24319115] 
[50] 
Casanova-Molla J, Morales M, Planas-Rigol E, et al. Epidermal Langerhans cells in small fiber neuropathies. Pain  2012; 153(5): 982-9.
[http://dx.doi.org/10.1016/j.pain.2012.01.021] [PMID: 22361736] 
[51] 
Papanas N, Ziegler D. Corneal confocal microscopy: Recent progress in the evaluation of diabetic neuropathy. J Diabetes Investig  2015; 6(4): 381-9.
[http://dx.doi.org/10.1111/jdi.12335] [PMID: 26221515] 
[52] 
Püttgen S, Bönhof GJ, Strom A, et al. Augmented Corneal Nerve Fiber Branching in Painful Compared With Painless Diabetic Neuropathy. J Clin Endocrinol Metab  2019; 104(12): 6220-8.
[http://dx.doi.org/10.1210/jc.2019-01072] [PMID: 31390004] 
[53] 
Haque F, Reaz MBI, Ali SHM, Arsad N, Chowdhury MEH. Performance analysis of noninvasive electrophysiological methods for the assessment of diabetic sensorimotor polyneuropathy in clinical research: a systematic review and meta-analysis with trial sequential analysis. Sci Rep  2020; 10(1): 21770.
[http://dx.doi.org/10.1038/s41598-020-78787-0] [PMID: 33303857] 
[54] 
Tavakoli M, Ferdousi M, Petropoulos IN, et al. Normative values for corneal nerve morphology assessed using corneal confocal microscopy: a multinational normative data set. Diabetes Care  2015; 38(5): 838-43.
[http://dx.doi.org/10.2337/dc14-2311] [PMID: 25633665] 
[55] 
Ziegler D, Winter K, Strom A, et al. German Diabetes Study (GDS) Group. Spatial analysis improves the detection of early corneal nerve fiber loss in patients with recently diagnosed type 2 diabetes. PLoS One  2017; 12(3): e0173832.
[http://dx.doi.org/10.1371/journal.pone.0173832] [PMID: 28296936] 
[56] 
Petropoulos IN, Ferdousi M, Marshall A, et al. The Inferior Whorl For Detecting Diabetic Peripheral Neuropathy Using Corneal Confocal Microscopy. Invest Ophthalmol Vis Sci  2015; 56(4): 2498-504.
[http://dx.doi.org/10.1167/iovs.14-15919] [PMID: 25783609] 
[57] 
Backonja MM, Attal N, Baron R, et al. Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus. Pain  2013; 154(9): 1807-19.
[http://dx.doi.org/10.1016/j.pain.2013.05.047] [PMID: 23742795] 
[58] 
Baron R, Maier C, Attal N, et al. German Neuropathic Pain Research Network (DFNS), and the EUROPAIN, and NEUROPAIN consortia. Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles. Pain  2017; 158(2): 261-72.
[http://dx.doi.org/10.1097/j.pain.0000000000000753] [PMID: 27893485] 
[59] 
Raputova J, Srotova I, Vlckova E, et al. Sensory phenotype and risk factors for painful diabetic neuropathy: a cross-sectional observational study. Pain  2017; 158(12): 2340-53.
[http://dx.doi.org/10.1097/j.pain.0000000000001034] [PMID: 28858986] 
[60] 
Themistocleous AC, Ramirez JD, Shillo PR, et al. The Pain in Neuropathy Study (PiNS): a cross-sectional observational study determining the somatosensory phenotype of painful and painless diabetic neuropathy. Pain  2016; 157(5): 1132-45.
[http://dx.doi.org/10.1097/j.pain.0000000000000491] [PMID: 27088890] 
[61] 
Üçeyler N, Vollert J, Broll B, et al. Sensory profiles and skin innervation of patients with painful and painless neuropathies. Pain  2018; 159(9): 1867-76.
[http://dx.doi.org/10.1097/j.pain.0000000000001287] [PMID: 29863528] 
[62] 
Schmelz M. Quantitative sensory test correlates with neuropathy, not with pain. Pain  2018; 159(3): 409-10.
[http://dx.doi.org/10.1097/j.pain.0000000000001142] [PMID: 29369968] 
[63] 
Papanas N, Papatheodorou K, Christakidis D, et al. Evaluation of a new indicator test for sudomotor function (Neuropad) in the diagnosis of peripheral neuropathy in type 2 diabetic patients. Exp Clin Endocrinol Diabetes  2005; 113(4): 195-8.
[http://dx.doi.org/10.1055/s-2005-837735] [PMID: 15891953] 
[64] 
Calvet JH, Dupin J, Winiecki H, Schwarz PE. Assessment of small fiber neuropathy through a quick, simple and non invasive method in a German diabetes outpatient clinic. Exp Clin Endocrinol Diabetes  2013; 121(2): 80-3.
[PMID: 23073917] 
[65] 
Duchesne M, Richard L, Vallat JM, Magy L. Assessing sudomotor impairment in patients with peripheral neuropathy: Comparison between electrochemical skin conductance and skin biopsy. Clin Neurophysiol  2018; 129(7): 1341-8.
[http://dx.doi.org/10.1016/j.clinph.2018.04.608] [PMID: 29729587] 
[66] 
Gin H, Baudoin R, Raffaitin CH, Rigalleau V, Gonzalez C. Non-invasive and quantitative assessment of sudomotor function for peripheral diabetic neuropathy evaluation. Diabetes Metab  2011; 37(6): 527-32.
[http://dx.doi.org/10.1016/j.diabet.2011.05.003] [PMID: 21715211] 
[67] 
Zhu X, Mao F, Liu S, Zheng H, Lu B, Li Y. Association of SUDOSCAN Values with Vibration Perception Threshold in Chinese Patients with Type 2 Diabetes Mellitus. Int J Endocrinol  2017; 2017: 8435252.
[http://dx.doi.org/10.1155/2017/8435252] [PMID: 28808444] 
[68] 
Mao F, Liu S, Qiao X, 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): 363-8.
[http://dx.doi.org/10.1111/jdi.12575] [PMID: 27607763] 
[69] 
Sheshah E, Madanat A, Al-Greesheh F, et al. Electrochemical skin conductance to detect sudomotor dysfunction, peripheral neuropathy and the risk of foot ulceration among Saudi patients with diabetes mellitus. J Diabetes Metab Disord  2016; 15: 29.
[http://dx.doi.org/10.1186/s40200-016-0252-8] [PMID: 27500133] 
[70] 
Casellini CM, Parson HK, Richardson MS, Nevoret ML, Vinik AI. Sudoscan, a noninvasive tool for detecting diabetic small fiber neuropathy and autonomic dysfunction. Diabetes Technol Ther  2013; 15(11): 948-53.
[http://dx.doi.org/10.1089/dia.2013.0129] [PMID: 23889506] 
[71] 
Jin J, Wang W, Gu T, et al. The Application of SUDOSCAN for Screening Diabetic Peripheral Neuropathy in Chinese Population. Exp Clin Endocrinol Diabetes  2018; 126(8): 472-7.
[http://dx.doi.org/10.1055/s-0043-116673] [PMID: 28895640] 
[72] 
Novak P. Electrochemical skin conductance: a systematic review. Clin Auton Res  2019; 29(1): 17-29.
[http://dx.doi.org/10.1007/s10286-017-0467-x] [PMID: 28951985] 
[73] 
Ponirakis G, Abdul-Ghani MA, Jayyousi A, et al. Effect of treatment with exenatide and pioglitazone or basal-bolus insulin on diabetic neuropathy: a substudy of the Qatar Study. BMJ Open Diabetes Res Care  2020; 8(1): e001420.
[http://dx.doi.org/10.1136/bmjdrc-2020-001420] [PMID: 32576561] 
[74] 
Selvarajah D, Cash T, Davies J, et al. SUDOSCAN: A Simple, Rapid, and Objective Method with Potential for Screening for Diabetic Peripheral Neuropathy. PLoS One  2015; 10(10): e0138224.
[http://dx.doi.org/10.1371/journal.pone.0138224] [PMID: 26457582] 
[75] 
Yajnik CS, Kantikar V, Pande A, et al. Screening of cardiovascular autonomic neuropathy in patients with diabetes using non-invasive quick and simple assessment of sudomotor function. Diabetes Metab  2013; 39(2): 126-31.
[http://dx.doi.org/10.1016/j.diabet.2012.09.004] [PMID: 23159130] 
[76] 
Rajan S, Campagnolo M, Callaghan B, Gibbons CH. Sudomotor function testing by electrochemical skin conductance: does it really measure sudomotor function?  Clinical autonomic research : official journal of the Clinical Autonomic Research Society 2018.
[77] 
Vinik AI, Casellini CM, Parson HK. Electrochemical skin conductance to measure sudomotor function: the importance of not misinterpreting the evidence. Clin Auton Res  2019; 29(1): 13-5.
[http://dx.doi.org/10.1007/s10286-018-0562-7] [PMID: 30191428] 
[78] 
Manes C, Papanas N, Exiara T, et al. The indicator test Neuropad in the assessment of small and overall nerve fibre dysfunction in patients with type 2 diabetes: a large multicentre study. Exp Clin Endocrinol Diabetes  2014; 122(3): 195-9.
[http://dx.doi.org/10.1055/s-0034-1367061] [PMID: 24643697] 
[79] 
Tsapas A, Liakos A, Paschos P, et al. A simple plaster for screening for diabetic neuropathy: a diagnostic test accuracy systematic review and meta-analysis. Metabolism  2014; 63(4): 584-92.
[http://dx.doi.org/10.1016/j.metabol.2013.11.019] [PMID: 24405753] 
[80] 
Ponirakis G, Fadavi H, Petropoulos IN, et al. Automated Quantification of Neuropad Improves Its Diagnostic Ability in Patients with Diabetic Neuropathy. J Diabetes Res  2015; 2015: 847854.
[http://dx.doi.org/10.1155/2015/847854] [PMID: 26064991] 
[81] 
Ponirakis G, Petropoulos IN, Fadavi H, et al. The diagnostic accuracy of Neuropad for assessing large and small fibre diabetic neuropathy. Diabet Med  2014; 31(12): 1673-80.
[http://dx.doi.org/10.1111/dme.12536] [PMID: 24975286] 
[82] 
Volmer-Thole M, Lobmann R. Neuropathy and Diabetic Foot Syndrome. Int J Mol Sci  2016; 17(6): E917.
[http://dx.doi.org/10.3390/ijms17060917] [PMID: 27294922] 
[83] 
Panagoulias GS, Eleftheriadou I, Papanas N, et al. Dryness of Foot Skin Assessed by the Visual Indicator Test and Risk of Diabetic Foot Ulceration: A Prospective Observational Study. Front Endocrinol (Lausanne)  2020; 11: 625.
[http://dx.doi.org/10.3389/fendo.2020.00625] [PMID: 33013702] 
[84] 
Herder C, Roden M, Ziegler D. Novel Insights into Sensorimotor and Cardiovascular Autonomic Neuropathy from Recent-Onset Diabetes and Population-Based Cohorts. Trends Endocrinol Metab  2019; 30(5): 286-98.
[http://dx.doi.org/10.1016/j.tem.2019.02.007] [PMID: 30935671] 
[85] 
Cornblath DR, Griffin DE, Welch D, Griffin JW, McArthur JC. Quantitative analysis of endoneurial T-cells in human sural nerve biopsies. J Neuroimmunol  1990; 26(2): 113-8.
[http://dx.doi.org/10.1016/0165-5728(90)90082-X] [PMID: 1688876] 
[86] 
Schrøder HD, Olsson T, Solders G, Kristensson K, Link H. HLA- DR-expressing cells and T-lymphocytes in sural nerve biopsies. Muscle Nerve  1988; 11(8): 864-70.
[http://dx.doi.org/10.1002/mus.880110811] [PMID: 3262825] 
[87] 
Younger DS, Rosoklija G, Hays AP, Trojaborg W, Latov N. Diabetic peripheral neuropathy: a clinicopathologic and immunohistochemical analysis of sural nerve biopsies. Muscle Nerve  1996; 19(6): 722-7.
[http://dx.doi.org/10.1002/(SICI)1097-4598(199606)19:6<722::AID-MUS6>3.0.CO;2-C] [PMID: 8609922] 
[88] 
Christensen DH, Knudsen ST, Gylfadottir SS, et al. Metabolic Factors, Lifestyle Habits, and Possible Polyneuropathy in Early Type 2 Diabetes: A Nationwide Study of 5,249 Patients in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) Cohort. Diabetes Care  2020; 43(6): 1266-75.
[http://dx.doi.org/10.2337/dc19-2277] [PMID: 32295810] 
[89] 
van der Velde JHPM, Koster A, Strotmeyer ES, et al. Cardiometabolic risk factors as determinants of peripheral nerve function: the Maastricht Study. Diabetologia  2020; 63(8): 1648-58.
[http://dx.doi.org/10.1007/s00125-020-05194-5] [PMID: 32537727] 
[90] 
Okdahl T, Brock C, Fløyel T, et al. Increased levels of inflammatory factors are associated with severity of polyneuropathy in type 1 diabetes. Clin Endocrinol (Oxf)  2020; 93(4): 419-28.
[http://dx.doi.org/10.1111/cen.14261] [PMID: 32497255] 
[91] 
Sun Q, Yan B, Yang D, et al. Serum Adiponectin Levels Are Positively Associated With Diabetic Peripheral Neuropathy in Chinese Patients With Type 2 Diabetes. Front Endocrinol (Lausanne)  2020; 11: 567959.
[http://dx.doi.org/10.3389/fendo.2020.567959] [PMID: 33324342] 
[92] 
Schamarek I, Herder C, Nowotny B, et al. German Diabetes Study Group. Adiponectin, markers of subclinical inflammation and nerve conduction in individuals with recently diagnosed type 1 and type 2 diabetes. Eur J Endocrinol  2016; 174(4): 433-43.
[http://dx.doi.org/10.1530/EJE-15-1010] [PMID: 26733478] 
[93] 
Ziegler D, Strom A, Bönhof GJ, et al. Deficits in systemic biomarkers of neuroinflammation and growth factors promoting nerve regeneration in patients with type 2 diabetes and polyneuropathy. BMJ Open Diabetes Res Care  2019; 7(1): e000752.
[PMID: 31803481] 
[94] 
Maalmi H, Wouters K, Savelberg HHCM, et al. Associations of cells from both innate and adaptive immunity with lower nerve conduction velocity: the Maastricht Study. BMJ Open Diabetes Res Care  2021; 9(1): e001698.
[http://dx.doi.org/10.1136/bmjdrc-2020-001698] [PMID: 33431599] 
[95] 
Herder C, Kannenberg JM, Huth C, et al. Proinflammatory Cytokines Predict the Incidence and Progression of Distal Sensorimotor Polyneuropathy: KORA F4/FF4 Study. Diabetes Care  2017; 40(4): 569-76.
[http://dx.doi.org/10.2337/dc16-2259] [PMID: 28174259] 
[96] 
Zheng H, Sun W, Zhang Q, et al. Proinflammatory cytokines predict the incidence of diabetic peripheral neuropathy over 5 years in Chinese type 2 diabetes patients: A prospective cohort study. EClinicalMedicine  2020; 31: 100649.
[http://dx.doi.org/10.1016/j.eclinm.2020.100649] [PMID: 33385123] 
[97] 
Herder C, Kannenberg JM, Carstensen-Kirberg M, et al. A Systemic Inflammatory Signature Reflecting Cross Talk Between Innate and Adaptive Immunity Is Associated With Incident Polyneuropathy: KORA F4/FF4 Study. Diabetes  2018; 67(11): 2434-42.
[http://dx.doi.org/10.2337/db18-0060] [PMID: 30115651] 
[98] 
Schlesinger S, Herder C, Kannenberg JM, et al. General and Abdominal Obesity and Incident Distal Sensorimotor Polyneuropathy: Insights Into Inflammatory Biomarkers as Potential Mediators in the KORA F4/FF4 Cohort. Diabetes Care  2019; 42(2): 240-7.
[http://dx.doi.org/10.2337/dc18-1842] [PMID: 30523031] 
[99] 
Mallet ML, Hadjivassiliou M, Sarrigiannis PG, Zis P. The Role of Oxidative Stress in Peripheral Neuropathy. J Mol Neurosci  2020; 70(7): 1009-17.
[http://dx.doi.org/10.1007/s12031-020-01495-x] [PMID: 32103400] 
[100] 
Pop-Busui R, Sima A, Stevens M. Diabetic neuropathy and oxidative stress. Diabetes Metab Res Rev  2006; 22(4): 257-73.
[http://dx.doi.org/10.1002/dmrr.625] [PMID: 16506271] 
[101] 
Kasznicki J, Kosmalski M, Sliwinska A, et al. Evaluation of oxidative stress markers in pathogenesis of diabetic neuropathy. Mol Biol Rep  2012; 39(9): 8669-78.
[http://dx.doi.org/10.1007/s11033-012-1722-9] [PMID: 22718504] 
[102] 
Urner S, Ho F, Jha JC, Ziegler D, Jandeleit-Dahm K. NADPH Oxidase Inhibition: Preclinical and Clinical Studies in Diabetic Complications. Antioxid Redox Signal  2020; 33(6): 415-34.
[http://dx.doi.org/10.1089/ars.2020.8047] [PMID: 32008354] 
[103] 
Strom A, Kaul K, Brüggemann J, et al. Lower serum extracellular superoxide dismutase levels are associated with polyneuropathy in recent-onset diabetes. Exp Mol Med  2017; 49(11): e394.
[http://dx.doi.org/10.1038/emm.2017.173] [PMID: 29147011] 
[104] 
Herder C, Kannenberg JM, Huth C, et al. Myeloperoxidase, superoxide dismutase-3, cardiometabolic risk factors, and distal sensorimotor polyneuropathy: The KORA F4/FF4 study. Diabetes Metab Res Rev  2018; 34(5): e3000.
[http://dx.doi.org/10.1002/dmrr.3000] [PMID: 29577557] 
[105] 
Andersen ST, Witte DR, Dalsgaard EM, et al. Risk Factors for Incident Diabetic Polyneuropathy in a Cohort With Screen-Detected Type 2 Diabetes Followed for 13 Years: ADDITION-Denmark. Diabetes Care  2018; 41(5): 1068-75.
[http://dx.doi.org/10.2337/dc17-2062] [PMID: 29487078] 
[106] 
Strom A, Strassburger K, Schmuck M, et al. GDS Group. Interaction between magnesium and methylglyoxal in diabetic polyneuropathy and neuronal models. Mol Metab  2021; 43: 101114.
[http://dx.doi.org/10.1016/j.molmet.2020.101114] [PMID: 33166742] 
[107] 
Rajagopalan S, Al-Kindi SG, Brook RD. Air Pollution and Cardiovascular Disease: JACC State-of-the-Art Review. J Am Coll Cardiol  2018; 72(17): 2054-70.
[http://dx.doi.org/10.1016/j.jacc.2018.07.099] [PMID: 30336830] 
[108] 
Herder C, Schneider A, Zhang S, et al. Association of Long-Term Air Pollution with Prevalence and Incidence of Distal Sensorimotor Polyneuropathy: KORA F4/FF4 Study. Environ Health Perspect  2020; 128(12): 127013.
[http://dx.doi.org/10.1289/EHP7311] [PMID: 33356516] 
[109] 
Vinik AI, Erbas T. Diabetic autonomic neuropathy. Handb Clin Neurol  2013; 117: 279-94.
[http://dx.doi.org/10.1016/B978-0-444-53491-0.00022-5] [PMID: 24095132] 
[110] 
Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation  2007; 115(3): 387-97.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.106.634949] [PMID: 17242296] 
[111] 
Spallone V, Ziegler D, Freeman R, et al. Toronto Consensus Panel on Diabetic Neuropathy. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev  2011; 27(7): 639-53.
[http://dx.doi.org/10.1002/dmrr.1239] [PMID: 21695768] 
[112] 
Ziegler D. Diabetic cardiovascular autonomic neuropathy: prognosis, diagnosis and treatment. Diabetes Metab Rev  1994; 10(4): 339-83.
[http://dx.doi.org/10.1002/dmr.5610100403] [PMID: 7796704] 
[113] 
Neil HA, Thompson AV, John S, McCarthy ST, Mann JI. Diabetic autonomic neuropathy: the prevalence of impaired heart rate variability in a geographically defined population. Diabet Med  1989; 6(1): 20-4.
[http://dx.doi.org/10.1111/j.1464-5491.1989.tb01133.x] [PMID: 2522369] 
[114] 
Ge X, Pan SM, Zeng F, Tang ZH, Wang YW. A simple Chinese risk score model for screening cardiovascular autonomic neuropathy. PLoS One  2014; 9(3): e89623.
[http://dx.doi.org/10.1371/journal.pone.0089623] [PMID: 24621478] 
[115] 
Ziegler D, Voss A, Rathmann W, et al. KORA Study Group. Increased prevalence of cardiac autonomic dysfunction at different degrees of glucose intolerance in the general population: the KORA S4 survey. Diabetologia  2015; 58(5): 1118-28.
[http://dx.doi.org/10.1007/s00125-015-3534-7] [PMID: 25724570] 
[116] 
Dimova R, Tankova T, Chakarova N, Grozeva G, Dakovska L. Cardio-metabolic profile of subjects with early stages of glucose intolerance and cardiovascular autonomic dysfunction. Diabetes Res Clin Pract  2017; 126: 115-21.
[http://dx.doi.org/10.1016/j.diabres.2017.02.004] [PMID: 28242436] 
[117] 
Eleftheriadou A, Williams S, Nevitt S, Brown E, Roylance R, Wilding JPH, et al. The prevalence of cardiac autonomic neuropathy in prediabetes: a systematic review. Diabetologia 2020.
[http://dx.doi.org/10.1007/s00125-020-05316-z] [PMID: 33164108] 
[118] 
Ziegler D, Strom A, Bönhof G, et al. GDS group. Differential associations of lower cardiac vagal tone with insulin resistance and insulin secretion in recently diagnosed type 1 and type 2 diabetes. Metabolism  2018; 79: 1-9.
[http://dx.doi.org/10.1016/j.metabol.2017.10.013] [PMID: 29113812] 
[119] 
Ziegler D, Dannehl K, Volksw D, Mühlen H, Spüler M, Gries FA. Prevalence of cardiovascular autonomic dysfunction assessed by spectral analysis and standard tests of heart-rate variation in newly diagnosed IDDM patients. Diabetes Care  1992; 15(7): 908-11.
[http://dx.doi.org/10.2337/diacare.15.7.908] [PMID: 1516513] 
[120] 
Ratzmann KP, Raschke M, Gander I, Schimke E. Prevalence of peripheral and autonomic neuropathy in newly diagnosed type II (noninsulin-dependent) diabetes. J Diabet Complications  1991; 5(1): 1-5.
[http://dx.doi.org/10.1016/0891-6632(91)90002-7] [PMID: 1830312] 
[121] 
The Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes therapy on measures of autonomic nervous system function in the Diabetes Control and Complications Trial (DCCT). Diabetologia  1998; 41(4): 416-23.
[http://dx.doi.org/10.1007/s001250050924] [PMID: 9562345] 
[122] 
Pop-Busui R, Low PA, Waberski BH, et al. DCCT/EDIC Research Group. Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes mellitus: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study (DCCT/EDIC). Circulation  2009; 119(22): 2886-93.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.108.837369] [PMID: 19470886] 
[123] 
Andersen ST, Witte DR, Fleischer J, et al. Risk Factors for the Presence and Progression of Cardiovascular Autonomic Neuropathy in Type 2 Diabetes: ADDITION-Denmark. Diabetes Care  2018; 41(12): 2586-94.
[http://dx.doi.org/10.2337/dc18-1411] [PMID: 30305347] 
[124] 
O’Brien IA, O’Hare JP, Lewin IG, Corrall RJ. The prevalence of autonomic neuropathy in insulin-dependent diabetes mellitus: a controlled study based on heart rate variability. Q J Med  1986; 61(234): 957-67.
[PMID: 3628708] 
[125] 
Lehtinen JM, Uusitupa M, Siitonen O, Pyörälä K. Prevalence of neuropathy in newly diagnosed NIDDM and nondiabetic control subjects. Diabetes  1989; 38(10): 1307-13.
[http://dx.doi.org/10.2337/diab.38.10.1307] [PMID: 2551761] 
[126] 
Kempler P, Tesfaye S, Chaturvedi N, et al. EURODIAB IDDM Complications Study Group. Autonomic neuropathy is associated with increased cardiovascular risk factors: the EURODIAB IDDM Complications Study. Diabet Med  2002; 19(11): 900-9.
[http://dx.doi.org/10.1046/j.1464-5491.2002.00821.x] [PMID: 12421426] 
[127] 
Ziegler D, Gries FA, Mühlen H, Rathmann W, Spüler M, Lessmann F. The Diacan Multicenter Study Group. Prevalence and clinical correlates of cardiovascular autonomic and peripheral diabetic neuropathy in patients attending diabetes centers. Diabete Metab  1993; 19(1 Pt 2): 143-51.
[PMID: 8314418] 
[128] 
Jaiswal M, Divers J, Urbina EM, et al. SEARCH for Diabetes in Youth Study Group. Cardiovascular autonomic neuropathy in adolescents and young adults with type 1 and type 2 diabetes: The SEARCH for Diabetes in Youth Cohort Study. Pediatr Diabetes  2018; 19(4): 680-9.
[http://dx.doi.org/10.1111/pedi.12633] [PMID: 29292558] 
[129] 
Vinik AI, Maser RE, Ziegler D. Autonomic imbalance: prophet of doom or scope for hope? Diabet Med  2011; 28(6): 643-51.
[http://dx.doi.org/10.1111/j.1464-5491.2010.03184.x] [PMID: 21569084] 
[130] 
Vinik AI, Erbas T. Cardiovascular autonomic neuropathy: diagnosis and management. Curr Diab Rep  2006; 6(6): 424-30.
[http://dx.doi.org/10.1007/s11892-006-0074-z] [PMID: 17118224] 
[131] 
Kück JL, Bönhof GJ, Strom A, et al. GDS group. Impairment in Baroreflex Sensitivity in Recent-Onset Type 2 Diabetes Without Progression Over 5 Years. Diabetes  2020; 69(5): 1011-9.
[http://dx.doi.org/10.2337/db19-0990] [PMID: 32086289] 
[132] 
Ziegler D, Strom A, Kupriyanova Y, et al. GDS Group. Association of Lower Cardiovagal Tone and Baroreflex Sensitivity With Higher Liver Fat Content Early in Type 2 Diabetes. J Clin Endocrinol Metab  2018; 103(3): 1130-8.
[http://dx.doi.org/10.1210/jc.2017-02294] [PMID: 29267946] 
[133] 
Ziegler D, Strom A, Straßburger K, et al. German Diabetes Study group. Association of cardiac autonomic dysfunction with higher levels of plasma lipid metabolites in recent-onset type 2 diabetes. Diabetologia  2021; 64(2): 458-68.
[http://dx.doi.org/10.1007/s00125-020-05310-5] [PMID: 33084971] 
[134] 
Röhling M, Strom A, Bönhof G, et al. German Diabetes Study Group. Differential Patterns of Impaired Cardiorespiratory Fitness and Cardiac Autonomic Dysfunction in Recently Diagnosed Type 1 and Type 2 Diabetes. Diabetes Care  2017; 40(2): 246-52.
[http://dx.doi.org/10.2337/dc16-1898] [PMID: 27899499] 
[135] 
Liu Y, Peng Y, Jin J, et al. Insulin resistance is independently associated with cardiovascular autonomic neuropathy in type 2 diabetes. J Diabetes Investig 2021.
[http://dx.doi.org/10.1111/jdi.13507] [PMID: 33460512] 
[136] 
Brock C, Jessen N, Brock B, et al. Cardiac vagal tone, a non-invasive measure of parasympathetic tone, is a clinically relevant tool in Type 1 diabetes mellitus. Diabet Med  2017; 34(10): 1428-34.
[http://dx.doi.org/10.1111/dme.13421] [PMID: 28703868] 
[137] 
Wegeberg AM, Lunde ED, Riahi S, et al. Cardiac vagal tone as a novel screening tool to recognize asymptomatic cardiovascular autonomic neuropathy: Aspects of utility in type 1 diabetes. Diabetes Res Clin Pract  2020; 170: 108517.
[http://dx.doi.org/10.1016/j.diabres.2020.108517] [PMID: 33096186] 
[138] 
La Rovere MT, Pinna GD, Maestri R, Sleight P. Clinical value of baroreflex sensitivity. Neth Heart J  2013; 21(2): 61-3.
[http://dx.doi.org/10.1007/s12471-012-0349-8] [PMID: 23184601] 
[139] 
Bernardi L, De Barbieri G, Rosengård-Bärlund M, Mäkinen VP, Porta C, Groop PH. New method to measure and improve consistency of baroreflex sensitivity values. Clin Auton Res  2010; 20(6): 353-61.
[http://dx.doi.org/10.1007/s10286-010-0079-1] [PMID: 20700641] 
[140] 
Tu H, Zhang D, Li YL. Cellular and Molecular Mechanisms Underlying Arterial Baroreceptor Remodeling in Cardiovascular Diseases and Diabetes. Neurosci Bull  2019; 35(1): 98-112.
[http://dx.doi.org/10.1007/s12264-018-0274-y] [PMID: 30146675] 
[141] 
Wu JS, Lu FH, Yang YC, et al. Impaired baroreflex sensitivity in subjects with impaired glucose tolerance, but not isolated impaired fasting glucose. Acta Diabetol  2014; 51(4): 535-41.
[http://dx.doi.org/10.1007/s00592-013-0548-9] [PMID: 24408773] 
[142] 
Michel-Chávez A, Estañol B, Gien-López JA, et al. Heart rate and systolic blood pressure variability on recently diagnosed diabetics. Arq Bras Cardiol  2015; 105(3): 276-84.
[http://dx.doi.org/10.5935/abc.20150073] [PMID: 26176187] 
[143] 
Gerritsen J, Dekker JM, TenVoorde BJ, et al. Glucose tolerance and other determinants of cardiovascular autonomic function: the Hoorn Study. Diabetologia  2000; 43(5): 561-70.
[http://dx.doi.org/10.1007/s001250051344] [PMID: 10855530] 
[144] 
Zanoli L, Empana JP, Estrugo N, et al. The Neural Baroreflex Pathway in Subjects With Metabolic Syndrome: A Sub-Study of the Paris Prospective Study III. Medicine (Baltimore)  2016; 95(2): e2472.
[http://dx.doi.org/10.1097/MD.0000000000002472] [PMID: 26765449] 
[145] 
Ryan JP, Sheu LK, Verstynen TD, Onyewuenyi IC, Gianaros PJ. Cerebral blood flow links insulin resistance and baroreflex sensitivity. PLoS One  2013; 8(12): e83288.
[http://dx.doi.org/10.1371/journal.pone.0083288] [PMID: 24358272] 
[146] 
Indumathy J, Pal GK, Pal P, et al. Decreased baroreflex sensitivity is linked to sympathovagal imbalance, body fat mass and altered cardiometabolic profile in pre-obesity and obesity. Metabolism  2015; 64(12): 1704-14.
[http://dx.doi.org/10.1016/j.metabol.2015.09.009] [PMID: 26454717] 
[147] 
Ziegler D, Laude D, Akila F, Elghozi JL. Time- and frequency-domain estimation of early diabetic cardiovascular autonomic neuropathy. Clin Auton Res  2001; 11(6): 369-76.
[http://dx.doi.org/10.1007/BF02292769] [PMID: 11794718] 
[148] 
Lefrandt JD, Hoogenberg K, van Roon AM, Dullaart RP, Gans RO, Smit AJ. Baroreflex sensitivity is depressed in microalbuminuric Type I diabetic patients at rest and during sympathetic manoeuvres. Diabetologia  1999; 42(11): 1345-9.
[http://dx.doi.org/10.1007/s001250051448] [PMID: 10550419] 
[149] 
Weston PJ, James MA, Panerai RB, McNally PG, Potter JF, Thurston H. Evidence of defective cardiovascular regulation in insulin-dependent diabetic patients without clinical autonomic dysfunction. Diabetes Res Clin Pract  1998; 42(3): 141-8.
[http://dx.doi.org/10.1016/S0168-8227(98)00094-1] [PMID: 9925343] 
[150] 
Rosengård-Bärlund M, Bernardi L, Fagerudd J, et al. FinnDiane Study Group. Early autonomic dysfunction in type 1 diabetes: a reversible disorder? Diabetologia  2009; 52(6): 1164-72.
[http://dx.doi.org/10.1007/s00125-009-1340-9] [PMID: 19340407] 
[151] 
Frattola A, Parati G, Gamba P, et al. Time and frequency domain estimates of spontaneous baroreflex sensitivity provide early detection of autonomic dysfunction in diabetes mellitus. Diabetologia  1997; 40(12): 1470-5.
[http://dx.doi.org/10.1007/s001250050851] [PMID: 9447956] 
[152] 
Cseh D, Climie RE, Offredo L, et al. Type 2 Diabetes Mellitus Is Independently Associated With Decreased Neural Baroreflex Sensitivity: The Paris Prospective Study III. Arterioscler Thromb Vasc Biol  2020; 40(5): 1420-8.
[http://dx.doi.org/10.1161/ATVBAHA.120.314102] [PMID: 32188272] 
[153] 
Petry D, Mirian de Godoy Marques C, Brum Marques JL. Baroreflex sensitivity with different lags and random forests for staging cardiovascular autonomic neuropathy in subjects with diabetes. Comput Biol Med  2020; 127: 104098.
[http://dx.doi.org/10.1016/j.compbiomed.2020.104098] [PMID: 33152669] 
[154] 
Wegeberg AL, Okdahl T, Fløyel T, et al. Circulating Inflammatory Markers Are Inversely Associated with Heart Rate Variability Measures in Type 1 Diabetes. Mediators Inflamm  2020; 2020: 3590389.
[http://dx.doi.org/10.1155/2020/3590389] [PMID: 32908447] 
[155] 
Herder C, Schamarek I, Nowotny B, et al. German Diabetes Study Group. Inflammatory markers are associated with cardiac autonomic dysfunction in recent-onset type 2 diabetes. Heart  2017; 103(1): 63-70.
[http://dx.doi.org/10.1136/heartjnl-2015-309181] [PMID: 27481890] 
[156] 
Bhati P, Alam R, Moiz JA, Hussain ME. Subclinical inflammation and endothelial dysfunction are linked to cardiac autonomic neuropathy in type 2 diabetes. J Diabetes Metab Disord  2019; 18(2): 419-28.
[http://dx.doi.org/10.1007/s40200-019-00435-w] [PMID: 31890667] 
[157] 
Hansen CS, Vistisen D, Jørgensen ME, et al. Adiponectin, biomarkers of inflammation and changes in cardiac autonomic function: Whitehall II study. Cardiovasc Diabetol  2017; 16(1): 153.
[http://dx.doi.org/10.1186/s12933-017-0634-3] [PMID: 29195493] 
[158] 
Spallone V. Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet. Diabetes Metab J  2019; 43(1): 3-30.
[http://dx.doi.org/10.4093/dmj.2018.0259] [PMID: 30793549] 
[159] 
Ziegler D, Buchholz S, Sohr C, Nourooz-Zadeh J, Roden M. Oxidative stress predicts progression of peripheral and cardiac autonomic nerve dysfunction over 6 years in diabetic patients. Acta Diabetol  2015; 52(1): 65-72.
[http://dx.doi.org/10.1007/s00592-014-0601-3] [PMID: 24898524] 
[160] 
Chen Z, Miao F, Paterson AD, et al. DCCT/EDIC Research Group. Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort. Proc Natl Acad Sci USA  2016; 113(21): E3002-11.
[http://dx.doi.org/10.1073/pnas.1603712113] [PMID: 27162351] 
[161] 
Ziegler D, Behler M, Schroers-Teuber M, Roden M. Near-normoglycaemia and development of neuropathy: a 24-year prospective study from diagnosis of type 1 diabetes. BMJ Open  2015; 5(6): e006559.
[http://dx.doi.org/10.1136/bmjopen-2014-006559] [PMID: 26109108] 
[162] 
Ang L, Dillon B, Mizokami-Stout K, Pop-Busui R. Cardiovascular autonomic neuropathy: A silent killer with long reach. Auton Neurosci  2020; 225: 102646.
[http://dx.doi.org/10.1016/j.autneu.2020.102646] [PMID: 32106052] 
[163] 
Tavakoli M, Kallinikos P, Iqbal A, et al. Corneal confocal microscopy detects improvement in corneal nerve morphology with an improvement in risk factors for diabetic neuropathy. Diabet Med  2011; 28(10): 1261-7.
[http://dx.doi.org/10.1111/j.1464-5491.2011.03372.x] [PMID: 21699561] 
[164] 
Tavakoli M, Mitu-Pretorian M, Petropoulos IN, et al. Corneal confocal microscopy detects early nerve regeneration in diabetic neuropathy after simultaneous pancreas and kidney transplantation. Diabetes  2013; 62(1): 254-60.
[http://dx.doi.org/10.2337/db12-0574] [PMID: 23002037] 
[165] 
Azmi S, Jeziorska M, Ferdousi M, et al. Early nerve fibre regeneration in individuals with type 1 diabetes after simultaneous pancreas and kidney transplantation. Diabetologia  2019; 62(8): 1478-87.
[http://dx.doi.org/10.1007/s00125-019-4897-y] [PMID: 31175373] 
[166] 
Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med  2008; 358(6): 580-91.
[http://dx.doi.org/10.1056/NEJMoa0706245] [PMID: 18256393] 
[167] 
Tang Y, Shah H, Bueno CR Junior, Sun X, Mitri J, Sambataro M, et al. Intensive Risk Factor Management and Cardiovascular Autonomic Neuropathy in Type 2 Diabetes: The ACCORD Trial. Diabetes Care  2021; Jan;44(1): 164-73.
[PMID: 33144354] 
[168] 
Streckmann F, Zopf EM, Lehmann HC, et al. Exercise intervention studies in patients with peripheral neuropathy: a systematic review. Sports Med  2014; 44(9): 1289-304.
[http://dx.doi.org/10.1007/s40279-014-0207-5] [PMID: 24927670] 
[169] 
Gong Q, Gregg EW, Wang J, et al. Long-term effects of a randomised trial of a 6-year lifestyle intervention in impaired glucose tolerance on diabetes-related microvascular complications: the China Da Qing Diabetes Prevention Outcome Study. Diabetologia  2011; 54(2): 300-7.
[http://dx.doi.org/10.1007/s00125-010-1948-9] [PMID: 21046360] 
[170] 
Diabetes Prevention Program Research Group. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol  2015; 3(11): 866-75.
[http://dx.doi.org/10.1016/S2213-8587(15)00291-0] [PMID: 26377054] 
[171] 
Espeland MA, Luchsinger JA, Neiberg RH, et al. Action for Health in Diabetes Brain Magnetic Resonance Imaging Research Group. Long Term Effect of Intensive Lifestyle Intervention on Cerebral Blood Flow. J Am Geriatr Soc  2018; 66(1): 120-6.
[http://dx.doi.org/10.1111/jgs.15159] [PMID: 29082505] 
[172] 
Ryan DH, Espeland MA, Foster GD, et al. Look AHEAD Research Group. Look AHEAD (Action for Health in Diabetes): design and methods for a clinical trial of weight loss for the prevention of cardiovascular disease in type 2 diabetes. Control Clin Trials  2003; 24(5): 610-28.
[http://dx.doi.org/10.1016/S0197-2456(03)00064-3] [PMID: 14500058] 
[173] 
Look AHEAD Research Group. Effects of a long-term lifestyle modification programme on peripheral neuropathy in overweight or obese adults with type 2 diabetes: the Look AHEAD study. Diabetologia  2017; 60(6): 980-8.
[http://dx.doi.org/10.1007/s00125-017-4253-z] [PMID: 28349174] 
[174] 
Dixit S, Maiya AG, Shastry BA. Effect of aerobic exercise on peripheral nerve functions of population with diabetic peripheral neuropathy in type 2 diabetes: a single blind, parallel group randomized controlled trial. J Diabetes Complications  2014; 28(3): 332-9.
[http://dx.doi.org/10.1016/j.jdiacomp.2013.12.006] [PMID: 24507164] 
[175] 
Ahn S, Song R. Effects of Tai Chi Exercise on glucose control, neuropathy scores, balance, and quality of life in patients with type 2 diabetes and neuropathy. J Altern Complement Med  2012; 18(12): 1172-8.
[http://dx.doi.org/10.1089/acm.2011.0690] [PMID: 22985218] 
[176] 
Hung JW, Liou CW, Wang PW, et al. Effect of 12-week tai chi chuan exercise on peripheral nerve modulation in patients with type 2 diabetes mellitus. J Rehabil Med  2009; 41(11): 924-9.
[http://dx.doi.org/10.2340/16501977-0445] [PMID: 19841845] 
[177] 
Kluding PM, Pasnoor M, Singh R, et al. The effect of exercise on neuropathic symptoms, nerve function, and cutaneous innervation in people with diabetic peripheral neuropathy. J Diabetes Complications  2012; 26(5): 424-9.
[http://dx.doi.org/10.1016/j.jdiacomp.2012.05.007] [PMID: 22717465] 
[178] 
Gholami F, Nikookheslat S, Salekzamani Y, Boule N, Jafari A. Effect of aerobic training on nerve conduction in men with type 2 diabetes and peripheral neuropathy: A randomized controlled trial. Neurophysiol Clin  2018; 48(4): 195-202.
[http://dx.doi.org/10.1016/j.neucli.2018.03.001] [PMID: 29606547] 
[179] 
Balducci S, Iacobellis G, Parisi L, et al. Exercise training can modify the natural history of diabetic peripheral neuropathy. J Diabetes Complications  2006; 20(4): 216-23.
[http://dx.doi.org/10.1016/j.jdiacomp.2005.07.005] [PMID: 16798472] 
[180] 
Howorka K, Pumprla J, Haber P, Koller-Strametz J, Mondrzyk J, Schabmann A. Effects of physical training on heart rate variability in diabetic patients with various degrees of cardiovascular autonomic neuropathy. Cardiovasc Res  1997; 34(1): 206-14.
[http://dx.doi.org/10.1016/S0008-6363(97)00040-0] [PMID: 9217892] 
[181] 
Figueroa A, Baynard T, Fernhall B, Carhart R, Kanaley JA. Endurance training improves post-exercise cardiac autonomic modulation in obese women with and without type 2 diabetes. Eur J Appl Physiol  2007; 100(4): 437-44.
[http://dx.doi.org/10.1007/s00421-007-0446-3] [PMID: 17406886] 
[182] 
Zoppini G, Cacciatori V, Gemma ML, et al. Effect of moderate aerobic exercise on sympatho-vagal balance in Type 2 diabetic patients. Diabet Med  2007; 24(4): 370-6.
[http://dx.doi.org/10.1111/j.1464-5491.2007.02076.x] [PMID: 17335467] 
[183] 
Bhagyalakshmi S, Nagaraja H, Anupama B, et al. Effect of supervised integrated exercise on heart rate variability in type 2 diabetes mellitus. Kardiol Pol  2007; 65(4): 363-8.
[PMID: 17530559] 
[184] 
Pagkalos M, Koutlianos N, Kouidi E, Pagkalos E, Mandroukas K, Deligiannis A. Heart rate variability modifications following exercise training in type 2 diabetic patients with definite cardiac autonomic neuropathy. Br J Sports Med  2008; 42(1): 47-54.
[http://dx.doi.org/10.1136/bjsm.2007.035303] [PMID: 17526623] 
[185] 
Kanaley JA, Goulopoulou S, Franklin RM, et al. Plasticity of heart rate signalling and complexity with exercise training in obese individuals with and without type 2 diabetes. Int J Obes  2009; 33(10): 1198-206.
[http://dx.doi.org/10.1038/ijo.2009.145] [PMID: 19652657] 
[186] 
Sridhar B, Haleagrahara N, Bhat R, Kulur AB, Avabratha S, Adhikary P. Increase in the heart rate variability with deep breathing in diabetic patients after 12-month exercise training. Tohoku J Exp Med  2010; 220(2): 107-13.
[http://dx.doi.org/10.1620/tjem.220.107] [PMID: 20139661] 
[187] 
Goulopoulou S, Baynard T, Franklin RM, et al. Exercise training improves cardiovascular autonomic modulation in response to glucose ingestion in obese adults with and without type 2 diabetes mellitus. Metabolism  2010; 59(6): 901-10.
[http://dx.doi.org/10.1016/j.metabol.2009.10.011] [PMID: 20015524] 
[188] 
Earnest CP, Blair SN, Church TS. Heart rate variability and exercise in aging women. J Womens Health (Larchmt)  2012; 21(3): 334-9.
[http://dx.doi.org/10.1089/jwh.2011.2932] [PMID: 21967166] 
[189] 
Röhling M, Strom A, Bönhof GJ, Roden M, Ziegler D. Cardiorespiratory Fitness and Cardiac Autonomic Function in Diabetes. Curr Diab Rep  2017; 17(12): 125.
[http://dx.doi.org/10.1007/s11892-017-0959-z] [PMID: 29063207] 
[190] 
Loimaala A, Huikuri HV, Kööbi T, Rinne M, Nenonen A, Vuori I. Exercise training improves baroreflex sensitivity in type 2 diabetes. Diabetes  2003; 52(7): 1837-42.
[http://dx.doi.org/10.2337/diabetes.52.7.1837] [PMID: 12829654] 
[191] 
Madden KM, Lockhart C, Potter TF, Cuff D. Aerobic training restores arterial baroreflex sensitivity in older adults with type 2 diabetes, hypertension, and hypercholesterolemia. Clin J Sport Med  2010; 20(4): 312-7.
[http://dx.doi.org/10.1097/JSM.0b013e3181ea8454] [PMID: 20606518] 
[192] 
Bellia A, Iellamo F, De Carli E, et al. Exercise individualized by TRIMPi method reduces arterial stiffness in early onset type 2 diabetic patients: A randomized controlled trial with aerobic interval training. Int J Cardiol  2017; 248: 314-9.
[http://dx.doi.org/10.1016/j.ijcard.2017.06.065] [PMID: 28716522] 
[193] 
Kang SJ, Ko KJ, Baek UH. Effects 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): 2088-93.
[http://dx.doi.org/10.1589/jpts.28.2088] [PMID: 27512271] 
[194] 
Shin KO, Moritani T, Woo J, et al. Exercise training improves cardiac autonomic nervous system activity in type 1 diabetic children. J Phys Ther Sci  2014; 26(1): 111-5.
[http://dx.doi.org/10.1589/jpts.26.111] [PMID: 24567687] 
[195] 
Chalk C, Benstead TJ, Moore F. Aldose reductase inhibitors for the treatment of diabetic polyneuropathy. Cochrane Database Syst Rev  2007; (4): CD004572.
[http://dx.doi.org/10.1002/14651858.CD004572.pub2] [PMID: 17943821] 
[196] 
Hotta N, Akanuma Y, Kawamori R, et al. Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: the 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial. Diabetes Care  2006; 29(7): 1538-44.
[http://dx.doi.org/10.2337/dc05-2370] [PMID: 16801576] 
[197] 
Polydefkis M, Arezzo J, Nash M, et al. Ranirestat Study Group. Safety and efficacy of ranirestat in patients with mild-to-moderate diabetic sensorimotor polyneuropathy. J Peripher Nerv Syst  2015; 20(4): 363-71.
[http://dx.doi.org/10.1111/jns.12138] [PMID: 26313450] 
[198] 
Papanas N, Ziegler D. Efficacy of α-lipoic acid in diabetic neuropathy. Expert Opin Pharmacother  2014; 15(18): 2721-31.
[http://dx.doi.org/10.1517/14656566.2014.972935] [PMID: 25381809] 
[199] 
Ziegler D, Low PA, Litchy WJ, et al. Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care  2011; 34(9): 2054-60.
[http://dx.doi.org/10.2337/dc11-0503] [PMID: 21775755] 
[200] 
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.
[http://dx.doi.org/10.2337/diacare.20.3.369] [PMID: 9051389] 
[201] 
Hor CP, Fung WY, Ang HA, et al. Vitamin E in Neuroprotection Study (VENUS) Investigators. Efficacy of Oral Mixed Tocotrienols in Diabetic Peripheral Neuropathy: A Randomized Clinical Trial. JAMA Neurol  2018; 75(4): 444-52.
[http://dx.doi.org/10.1001/jamaneurol.2017.4609] [PMID: 29379943] 
[202] 
Xie F, Cheng Z, Li S, et al. Pharmacokinetic study of benfotiamine and the bioavailability assessment compared to thiamine hydrochloride. J Clin Pharmacol  2014; 54(6): 688-95.
[http://dx.doi.org/10.1002/jcph.261] [PMID: 24399744] 
[203] 
Thornalley PJ, Babaei-Jadidi R, Al Ali H, et al. High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease. Diabetologia  2007; 50(10): 2164-70.
[http://dx.doi.org/10.1007/s00125-007-0771-4] [PMID: 17676306] 
[204] 
Anwar A, Ahmed Azmi M, Siddiqui JA, Panhwar G, Shaikh F, Ariff M. Thiamine Level in Type I and Type II Diabetes Mellitus Patients: A Comparative Study Focusing on Hematological and Biochemical Evaluations. Cureus  2020; 12(5): e8027.
[PMID: 32528766] 
[205] 
Haupt E, Ledermann H, Köpcke W. Benfotiamine in the treatment of diabetic polyneuropathy-a three-week randomized, controlled pilot study (BEDIP study). Int J Clin Pharmacol Ther  2005; 43(2): 71-7.
[http://dx.doi.org/10.5414/CPP43071] [PMID: 15726875] 
[206] 
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.
[http://dx.doi.org/10.1055/s-2008-1065351] [PMID: 18473286] 
[207] 
Stirban OA, Zeller-Stefan H, Schumacher J, et al. Treatment with benfotiamine in patients with diabetic sensorimotor polyneuropathy: A double-blind, randomized, placebo-controlled, parallel group pilot study over 12 months. J Diabetes Complications  2020; 34(12): 107757.
[http://dx.doi.org/10.1016/j.jdiacomp.2020.107757] [PMID: 33069584] 
[208] 
Ziegler D, Schleicher E, Strom A, et al. GDS Group. Association of transketolase polymorphisms with measures of polyneuropathy in patients with recently diagnosed diabetes. Diabetes Metab Res Rev  2017; 33(4)
[http://dx.doi.org/10.1002/dmrr.2811] [PMID: 27103086] 
[209] 
Fonseca VA, Lavery LA, Thethi TK, et al. Metanx in type 2 diabetes with peripheral neuropathy: a randomized trial. Am J Med  2013; 126(2): 141-9.
[http://dx.doi.org/10.1016/j.amjmed.2012.06.022] [PMID: 23218892] 
[210] 
Zhang B, Zhao W, Tu J, et al. The relationship between serum 25-hydroxyvitamin D concentration and type 2 diabetic peripheral neuropathy: A systematic review and a meta-analysis. Medicine (Baltimore)  2019; 98(48): e18118.
[http://dx.doi.org/10.1097/MD.0000000000018118] [PMID: 31770239] 
[211] 
Fitri A, Sjahrir H, Bachtiar A, Ichwan M, Fitri FI, Rambe AS. Predictive Model of Diabetic Polyneuropathy Severity Based on Vitamin D Level. Open Access Maced J Med Sci  2019; 7(16): 2626-9.
[http://dx.doi.org/10.3889/oamjms.2019.454] [PMID: 31777620] 
[212] 
Yammine K, Wehbe R, Assi C. A systematic review on the efficacy of vitamin D supplementation on diabetic peripheral neuropathy. Clin Nutr  2020; 39(10): 2970-4.
[http://dx.doi.org/10.1016/j.clnu.2020.01.022] [PMID: 32089370] 
[213] 
Abdelsadek SE, El Saghier EO, Abdel Raheem SI. Serum 25(OH) vitamin D level and its relation to diabetic peripheral neuropathy in Egyptian patients with type 2 diabetes mellitus. Egypt J Neurol Psychiat Neurosurg  2018; 54(1): 36.
[http://dx.doi.org/10.1186/s41983-018-0036-9] [PMID: 30532515] 
[214] 
Shehab D, Al-Jarallah K, Mojiminiyi OA, Al Mohamedy H, Abdella NA. Does Vitamin D deficiency play a role in peripheral neuropathy in Type 2 diabetes? Diabet Med  2012; 29(1): 43-9.
[http://dx.doi.org/10.1111/j.1464-5491.2011.03510.x] [PMID: 22050401] 
[215] 
Alam U, Petropoulos IN, Ponirakis G, et al. Vitamin D deficiency is associated with painful diabetic neuropathy. Diabetes Metab Res Rev  2021; 37(1): e3361.
[http://dx.doi.org/10.1002/dmrr.3361] [PMID: 32506740] 
[216] 
Long W, Fatehi M, Soni S, et al. Vitamin D is an endogenous partial agonist of the transient receptor potential vanilloid 1 channel. J Physiol  2020; 598(19): 4321-38.
[http://dx.doi.org/10.1113/JP279961] [PMID: 32721035] 
[217] 
Fitri A, Sjahrir H, Bachtiar A, Ichwan M. Modulation of Interleukin-8 Production by Vitamin D Supplementation in Indonesian Patients with Diabetic Polyneuropathy: A Randomized Clinical Trial. Oman Med J  2020; 35(5): e168.
[http://dx.doi.org/10.5001/omj.2020.110] [PMID: 33093965] 
[218] 
Ziegler D, Movsesyan L, Mankovsky B, Gurieva I, Abylaiuly Z, Strokov I. Treatment of symptomatic polyneuropathy with actovegin in type 2 diabetic patients. Diabetes Care  2009; 32(8): 1479-84.
[http://dx.doi.org/10.2337/dc09-0545] [PMID: 19470838] 
[219] 
Ziegler D. Diabetic Peripheral and Autonomic Neuropathy. Textbook of Diabetes.  5th ed.  2017; pp. 580-608.
[http://dx.doi.org/10.1002/9781118924853.ch40] 
[220] 
Spallone V, Valensi P. SGLT2 inhibitors and the autonomic nervous system in diabetes: A promising challenge to better understand multiple target improvement. Diabetes Metab  2021; 47(4): 101224.
[http://dx.doi.org/10.1016/j.diabet.2021.101224] [PMID: 33454436] 
[221] 
Kumarathurai P, Anholm C, Larsen BS, et al. Effects of Liraglutide on Heart Rate and Heart Rate Variability: A Randomized, Double-Blind, Placebo-Controlled Crossover Study. Diabetes Care  2017; 40(1): 117-24.
[http://dx.doi.org/10.2337/dc16-1580] [PMID: 27797930] 
[222] 
Nyström T, Santos-Pardo I, Fang X, Cao Y, Hedberg F, Jendle J. Heart rate variability in type 2 diabetic subjects randomized to liraglutide or glimepiride treatment, both in combination with metformin: A randomized, open, parallel-group study.  Endocrinology, diabetes & metabolism  2019; 2(2): e00058.
[http://dx.doi.org/10.1002/edm2.58] 
[223] 
Brock C, Hansen CS, Karmisholt J, et al. Liraglutide treatment reduced interleukin-6 in adults with type 1 diabetes but did not improve established autonomic or polyneuropathy. Br J Clin Pharmacol  2019; 85(11): 2512-23.
[http://dx.doi.org/10.1111/bcp.14063] [PMID: 31338868] 
[224] 
Hansen CS, Frandsen CS, Fleischer J, et al. Liraglutide-Induced Weight Loss May be Affected by Autonomic Regulation in Type 1 Diabetes. Front Endocrinol (Lausanne)  2019; 10: 242.
[http://dx.doi.org/10.3389/fendo.2019.00242] [PMID: 31031712] 
[225] 
Shimizu W, Kubota Y, Hoshika Y, et al. EMBODY trial investigators. Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial. Cardiovasc Diabetol  2020; 19(1): 148.
[http://dx.doi.org/10.1186/s12933-020-01127-z] [PMID: 32977831] 
[226] 
Garg V, Verma S, Connelly KA, Yan AT, Sikand A, Garg A, et al. Does empagliflozin modulate the autonomic nervous system among individuals with type 2 diabetes and coronary artery disease? The EMPA-HEART CardioLink-6 Holter analysis.  Metabolism open  2020; 7: 100039.
[http://dx.doi.org/10.1016/j.metop.2020.100039] 
[227] 
Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol  2015; 14(2): 162-73.
[http://dx.doi.org/10.1016/S1474-4422(14)70251-0] [PMID: 25575710] 
[228] 
Wiffen PJ, Derry S, Bell RF, et al. Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev  2017; 6(6): CD007938.
[http://dx.doi.org/10.1002/14651858.CD007938.pub4] [PMID: 28597471] 
[229] 
Derry S, Bell RF, Straube S, Wiffen PJ, Aldington D, Moore RA. Pregabalin for neuropathic pain in adults. Cochrane Database Syst Rev  2019; 1(1): CD007076.
[PMID: 30673120] 
[230] 
Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev  2014; (1): CD007115.
[http://dx.doi.org/10.1002/14651858.CD007115.pub3] [PMID: 24385423] 
[231] 
Waldfogel JM, Nesbit SA, Dy SM, et al. Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: A systematic review. Neurology  2017; 88(20): 1958-67.
[http://dx.doi.org/10.1212/WNL.0000000000003882] [PMID: 28341643] 
[232] 
Dy SM, Bennett WL, Sharma R, Zhang A, Waldfogel JM, Nesbit SA, et al. AHRQ Comparative Effectiveness Reviews. Preventing Complications and Treating Symptoms of Diabetic Peripheral Neuropathy. Rockville (MD): Agency for Healthcare Research and Quality (US) 2017.
[233] 
Ziegler D, Schneider E, Boess FG, Berggren L, Birklein F. Impact of comorbidities on pharmacotherapy of painful diabetic neuropathy in clinical practice. J Diabetes Complications  2014; 28(5): 698-704.
[http://dx.doi.org/10.1016/j.jdiacomp.2014.04.004] [PMID: 24862108] 
[234] 
Chaparro LE, Wiffen PJ, Moore RA, Gilron I. Combination pharmacotherapy for the treatment of neuropathic pain in adults. Cochrane Database Syst Rev  2012; 2012(7): CD008943.
[PMID: 22786518] 
[235] 
Tesfaye S, Wilhelm S, Lledo A, et al. Duloxetine and pregabalin: high-dose monotherapy or their combination? The “COMBO-DN study”-a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain. Pain  2013; 154(12): 2616-25.
[http://dx.doi.org/10.1016/j.pain.2013.05.043] [PMID: 23732189] 
[236] 
Ziegler D, Fonseca V. From guideline to patient: a review of recent recommendations for pharmacotherapy of painful diabetic neuropathy. J Diabetes Complications  2015; 29(1): 146-56.
[http://dx.doi.org/10.1016/j.jdiacomp.2014.08.008] [PMID: 25239450] 
[237] 
Bramson C, Herrmann DN, Carey W, et al. Exploring the role of tanezumab as a novel treatment for the relief of neuropathic pain. Pain Med  2015; 16(6): 1163-76.
[http://dx.doi.org/10.1111/pme.12677] [PMID: 25594611] 
[238] 
Wang H, Romano G, Frustaci ME, et al. Fulranumab for treatment of diabetic peripheral neuropathic pain: A randomized controlled trial. Neurology  2014; 83(7): 628-37.
[http://dx.doi.org/10.1212/WNL.0000000000000686] [PMID: 25008392] 
[239] 
Kessler JA, Smith AG, Cha BS, et al. VM202 DPN-II Study Group. Double-blind, placebo-controlled study of HGF gene therapy in diabetic neuropathy. Ann Clin Transl Neurol  2015; 2(5): 465-78.
[http://dx.doi.org/10.1002/acn3.186] [PMID: 26000320] 
[240] 
Kessler JA, Shaibani A, Sang CN, et al. VM202 study group. Gene therapy for diabetic peripheral neuropathy: A randomized, placebo-controlled phase III study of VM202, a plasmid DNA encoding human hepatocyte growth factor. Clin Transl Sci 2021.
[http://dx.doi.org/10.1111/cts.12977] [PMID: 33465273] 
[241] 
Bonezzi C, Costantini A, Cruccu G, et al. Capsaicin 8% dermal patch in clinical practice: an expert opinion. Expert Opin Pharmacother  2020; 21(11): 1377-87.
[http://dx.doi.org/10.1080/14656566.2020.1759550] [PMID: 32511032] 
[242] 
Vinik AI, Perrot S, Vinik EJ, et al. Capsaicin 8% patch repeat treatment plus standard of care (SOC) versus SOC alone in painful diabetic peripheral neuropathy: a randomised, 52-week, open-label, safety study. BMC Neurol  2016; 16(1): 251.
[http://dx.doi.org/10.1186/s12883-016-0752-7] [PMID: 27919222] 
[243] 
Staudt MD, Prabhala T, Sheldon BL, et al. Current Strategies for the Management of Painful Diabetic Neuropathy. J Diabetes Sci Technol  2022; Mar;16(2): 341-52.
[http://dx.doi.org/10.1177/1932296820951829] [PMID: 32856490] 
[244] 
Amato Nesbit S, Sharma R, Waldfogel JM, et al. Non-pharmacologic treatments for symptoms of diabetic peripheral neuropathy: a systematic review. Curr Med Res Opin  2019; 35(1): 15-25.
[http://dx.doi.org/10.1080/03007995.2018.1497958] [PMID: 30114983] 
[245] 
Abdelkader AA, El Gohary AM, Mourad HS, El Salmawy DA. Repetitive TMS in treatment of resistant diabetic neuropathic pain. Egypt J Neurol Psychiat Neurosurg  2019; 55(1): 30.
[http://dx.doi.org/10.1186/s41983-019-0075-x] 
[246] 
Xu X, Xu DS. Prospects for the application of transcranial magnetic stimulation in diabetic neuropathy. Neural Regen Res  2021; 16(5): 955-62.
[http://dx.doi.org/10.4103/1673-5374.297062] [PMID: 33229735] 
[247] 
Le Forestier N, Lescs MC, Gherardi RK. Anti-NKH-1 antibody specifically stains unmyelinated fibres and non-myelinating Schwann cell columns in humans. Neuropathol Appl Neurobiol  1993; 19(6): 500-6.
[http://dx.doi.org/10.1111/j.1365-2990.1993.tb00478.x] [PMID: 7510048] 
[248] 
Tesfaye S, Watt J, Benbow SJ, Pang KA, Miles J, MacFarlane IA. Electrical spinal-cord stimulation for painful diabetic peripheral neuropathy. Lancet  1996; 348(9043): 1698-701.
[http://dx.doi.org/10.1016/S0140-6736(96)02467-1] [PMID: 8973433] 
[249] 
de Vos CC, Meier K, Zaalberg PB, et al. Spinal cord stimulation in patients with painful diabetic neuropathy: a multicentre randomized clinical trial. Pain  2014; 155(11): 2426-31.
[http://dx.doi.org/10.1016/j.pain.2014.08.031] [PMID: 25180016] 
[250] 
Slangen R, Schaper NC, Faber CG, et al. Spinal cord stimulation and pain relief in painful diabetic peripheral neuropathy: a prospective two-center randomized controlled trial. Diabetes Care  2014; 37(11): 3016-24.
[http://dx.doi.org/10.2337/dc14-0684] [PMID: 25216508] 
[251] 
Raghu ALB, Parker T, Aziz TZ, et al. Invasive Electrical Neuromodulation for the Treatment of Painful Diabetic Neuropathy: Systematic Review and Meta-Analysis. Neuromodulation  2021; 24(1): 13-21.
[http://dx.doi.org/10.1111/ner.13216] [PMID: 32588933] 
[252] 
Kaur M, Michael JA, Hoy KE, et al. Investigating high- and low-frequency neuro-cardiac-guided TMS for probing the frontal vagal pathway. Brain Stimul  2020; 13(3): 931-8.
[http://dx.doi.org/10.1016/j.brs.2020.03.002] [PMID: 32205066] 
[253] 
Gancheva S, Bierwagen A, Markgraf DF, et al. Constant hepatic ATP concentrations during prolonged fasting and absence of effects of Cerbomed Nemos® on parasympathetic tone and hepatic energy metabolism. Mol Metab  2018; 7: 71-9.
[http://dx.doi.org/10.1016/j.molmet.2017.10.002] [PMID: 29122559] 
[254] 
Abraham WT, Zile MR, Weaver FA, et al. Baroreflex Activation Therapy for the Treatment of Heart Failure With a Reduced Ejection Fraction. JACC Heart Fail  2015; 3(6): 487-96.
[http://dx.doi.org/10.1016/j.jchf.2015.02.006] [PMID: 25982108] 
[255] 
Rafanelli M, Walsh K, Hamdan MH, Buyan-Dent L. Autonomic dysfunction: Diagnosis and management. Handb Clin Neurol  2019; 167: 123-37.
[http://dx.doi.org/10.1016/B978-0-12-804766-8.00008-X] [PMID: 31753129] 
[256] 
Freeman R, Abuzinadah AR, Gibbons C, Jones P, Miglis MG, Sinn DI. Orthostatic Hypotension: JACC State-of-the-Art Review. J Am Coll Cardiol  2018; 72(11): 1294-309.
[http://dx.doi.org/10.1016/j.jacc.2018.05.079] [PMID: 30190008] 
[257] 
Kaufmann H, Norcliffe-Kaufmann L, Palma JA. Droxidopa in neurogenic orthostatic hypotension. Expert Rev Cardiovasc Ther  2015; 13(8): 875-91.
[http://dx.doi.org/10.1586/14779072.2015.1057504] [PMID: 26092297] 
Cite As
Current Diabetes Reviews

Diagnostic Tools, Biomarkers, and Treatments in Diabetic polyneuropathy and Cardiovascular Autonomic Neuropathy

Abstract
