{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T09:19:36Z","timestamp":1775121576815,"version":"3.50.1"},"reference-count":45,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Allergan S.p.a."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background: Diabetic neuropathy manifests as symmetric distal and autonomic neuropathy, including cardiovagal dysfunction. Small-fiber involvement can occur, leading to neuropathic pain and dysautonomia. The diagnostic gold standard of these two conditions comprehends skin biopsy and cardiovascular autonomic reflex tests (CARTs), respectively. Non-invasive diagnostic tools, such as laser-evoked potentials (LEPs), show promise in detecting small-fiber damage, though correlations between LEP abnormalities and cardiovascular autonomic dysfunction remain poorly investigated. Methods: We retrospectively evaluated LEPs (from hands and feet stimulation) in 33 diabetic patients, comparing them to a cohort of 33 age-matched healthy subjects, to highlight any significant abnormalities in the diabetic cohort. We further analyzed the LEP results in T2DM cohort with clinical, laboratory variables and CARTs to explore potential correlations and to assess whether any association between LEPs and CARTs could be identified. Results: N2\/P2 complex amplitude was significantly reduced in diabetic patients compared to healthy subjects, with greater involvement in the lower limbs. While no association between LEP abnormalities and abnormal CARTs was observed, LEP amplitude reductions were notably associated with elevated glycated hemoglobin levels and longer disease duration, which appeared to be the strongest predictor of LEP reduction. Conclusions: Our findings corroborated literature data regarding length-dependent LEP alterations detectable even in initial diabetic stages. The lack of correlation between LEP abnormalities and autonomic dysfunction may stem from the predominant involvement of C fibers in autonomic neuropathy, which are not adequately assessed by currently used LEPs.<\/jats:p>","DOI":"10.3390\/brainsci16040390","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T08:08:34Z","timestamp":1775030914000},"page":"390","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Laser-Evoked Potentials in the Early Diagnosis of Diabetic Neuropathy and Their Association with Cardiovascular Autonomic Reflex Tests: A Retrospective Observational Study in Patients with Type 2 Diabetes"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6408-3704","authenticated-orcid":false,"given":"Giovanni Umberto","family":"Borin","sequence":"first","affiliation":[{"name":"Neurology Unit, Department of Neuroscience, Biomedicine and Movement Sciences, Azienda Ospedaliera Universitaria Integrata of Verona, 37126 Verona, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Aventaggiato","sequence":"additional","affiliation":[{"name":"Endocrinology and Diabetology, Rivoli Hospital, 10098 Rivoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Bittante","sequence":"additional","affiliation":[{"name":"Division of Metabolic Disease and Diabetology, University Hospital of Padua, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vittorio","family":"Cacciatori","sequence":"additional","affiliation":[{"name":"Endocrinology, Diabetology and Metabolic Disorders, University and Azienda Ospedaliera Universitaria Integrata of Verona, 37126 Verona, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessia","family":"Segatti","sequence":"additional","affiliation":[{"name":"Neurology Unit, Department of Neuroscience, Biomedicine and Movement Sciences, Azienda Ospedaliera Universitaria Integrata of Verona, 37126 Verona, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"Concon","sequence":"additional","affiliation":[{"name":"Neurology Unit, Department of Neuroscience, Biomedicine and Movement Sciences, Azienda Ospedaliera Universitaria Integrata of Verona, 37126 Verona, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grazia","family":"Devigili","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Neurologico \u201cCarlo Besta\u201d, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enzo","family":"Bonora","sequence":"additional","affiliation":[{"name":"Endocrinology, Diabetology and Metabolic Disorders, University and Azienda Ospedaliera Universitaria Integrata of Verona, 37126 Verona, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giacomo","family":"Zoppini","sequence":"additional","affiliation":[{"name":"Endocrinology, Diabetology and Metabolic Disorders, University and Azienda Ospedaliera Universitaria Integrata of Verona, 37126 Verona, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2191-1324","authenticated-orcid":false,"given":"Giovanna Maddalena","family":"Squintani","sequence":"additional","affiliation":[{"name":"Neurology Unit, Department of Neuroscience, Biomedicine and Movement Sciences, Azienda Ospedaliera Universitaria Integrata of Verona, 37126 Verona, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1007\/s11910-014-0473-5","article-title":"Diabetic neuropathy: Mechanisms, emerging treatments, and subtypes","volume":"14","author":"Albers","year":"2014","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_2","first-page":"e97880","article-title":"Early Diagnosis of Diabetic Neuropathy: A Review of Current Diagnostic Tests","volume":"17","author":"Otti","year":"2025","journal-title":"Cureus"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"136","DOI":"10.2337\/dc16-2042","article-title":"Diabetic Neuropathy: A Position Statement by the American Diabetes Association","volume":"40","author":"Boulton","year":"2017","journal-title":"Diabetes Care"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.2337\/dc10-1303","article-title":"Diabetic neuropathies: Update on definitions, diagnostic criteria, estimation of severity, and treatments","volume":"33","author":"Tesfaye","year":"2010","journal-title":"Diabetes Care"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1002\/mus.27080","article-title":"Differential involvement of myelinated and unmyelinated nerve fibers in painful diabetic polyneuropathy","volume":"63","author":"Galosi","year":"2021","journal-title":"Muscle Nerve"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"801","DOI":"10.2337\/dc16-0081","article-title":"Metabolic Syndrome Components Are Associated With Symptomatic Polyneuropathy Independent of Glycemic Status","volume":"39","author":"Callaghan","year":"2016","journal-title":"Diabetes Care"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.2337\/diacare.24.8.1448","article-title":"Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy","volume":"24","author":"Singleton","year":"2001","journal-title":"Diabetes Care"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.clineuro.2005.08.003","article-title":"Validation of Michigan neuropathy screening instrument for diabetic peripheral neuropathy","volume":"108","author":"Moghtaderi","year":"2006","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.pain.2004.12.010","article-title":"Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4)","volume":"114","author":"Bouhassira","year":"2005","journal-title":"Pain"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1002\/dmrr.1222","article-title":"Small fibre neuropathy: Role in the diagnosis of diabetic sensorimotor polyneuropathy","volume":"27","author":"Malik","year":"2011","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1016\/j.clinthera.2021.03.020","article-title":"Novel and Emerging Electrophysiological Biomarkers of Diabetic Neuropathy and Painful Diabetic Neuropathy","volume":"43","author":"Marshall","year":"2021","journal-title":"Clin. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1016\/j.clinph.2008.03.016","article-title":"Recommendations for the clinical use of somatosensory-evoked potentials","volume":"119","author":"Cruccu","year":"2008","journal-title":"Clin. Neurophysiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1097\/j.pain.0000000000000889","article-title":"Diagnostic accuracy of laser-evoked potentials in diabetic neuropathy","volume":"158","author":"Leone","year":"2017","journal-title":"Pain"},{"key":"ref_14","first-page":"403","article-title":"Diabetic Peripheral Neuropathy: Emerging Treatments of Neuropathic Pain and Novel Diagnostic Methods","volume":"20","author":"Borbjerg","year":"2024","journal-title":"J. Diabetes Sci. Technol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3","DOI":"10.4093\/dmj.2018.0259","article-title":"Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet","volume":"43","author":"Spallone","year":"2019","journal-title":"Diabetes Metab. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1007\/s00125-015-3534-7","article-title":"Increased prevalence of cardiac autonomic dysfunction at different degrees of glucose intolerance in the general population: The KORA S4 survey","volume":"58","author":"Ziegler","year":"2015","journal-title":"Diabetologia"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.2337\/dc15-0081","article-title":"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)","volume":"38","author":"Zoppini","year":"2015","journal-title":"Diabetes Care"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1002\/dmrr.1239","article-title":"Cardiovascular autonomic neuropathy in diabetes: Clinical impact, assessment, diagnosis, and management","volume":"27","author":"Spallone","year":"2011","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"835392","DOI":"10.1155\/2014\/835392","article-title":"Relationship between autonomic nervous system function and continuous interstitial glucose measurement in patients with type 2 diabetes","volume":"2014","author":"Kalopita","year":"2014","journal-title":"J. Diabetes Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4239\/wjd.v9.i1.1","article-title":"Cardiac autonomic neuropathy: Risk factors, diagnosis and treatment","volume":"9","author":"Serhiyenko","year":"2018","journal-title":"World J. Diabetes"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e326792","DOI":"10.1161\/CIRCRESAHA.125.326792","article-title":"Control of Blood Pressure Variability Across Behavioral States by Brainstem Adrenergic Neurons","volume":"138","author":"Souza","year":"2026","journal-title":"Circ. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1016\/j.clinph.2005.09.027","article-title":"Assessment of cardiovascular autonomic function","volume":"117","author":"Freeman","year":"2006","journal-title":"Clin. Neurophysiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1002\/mus.20365","article-title":"Quantitative studies of autonomic function","volume":"33","author":"Hilz","year":"2006","journal-title":"Muscle Nerve"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"108802","DOI":"10.1016\/j.jdiacomp.2024.108802","article-title":"The association of diabetic peripheral neuropathy with cardiac autonomic neuropathy in individuals with diabetes mellitus: A systematic review","volume":"38","author":"Dykstra","year":"2024","journal-title":"J. Diabetes Complicat."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1157\/13119325","article-title":"Declaraci\u00f3n de la Iniciativa STROBE (Strengthening the Reporting of Observational studies in Epidemiology): Directrices para la comunicaci\u00f3n de estudios observacionales","volume":"22","author":"Altman","year":"2008","journal-title":"Gac. Sanit."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"908","DOI":"10.2337\/diacare.15.7.908","article-title":"Prevalence of cardiovascular autonomic dysfunction assessed by spectral analysis and standard tests of heart-rate variation in newly diagnosed IDDM patients","volume":"15","author":"Ziegler","year":"1992","journal-title":"Diabetes Care"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/S0300-595X(86)80078-0","article-title":"Autonomic neuropathy: Its diagnosis and prognosis","volume":"15","author":"Ewing","year":"1986","journal-title":"Clin. Endocrinol. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7","DOI":"10.21037\/apm.2017.10.04","article-title":"Changes in laser-evoked potentials during hypnotic analgesia for chronic pain: A pilot study","volume":"7","author":"Squintani","year":"2018","journal-title":"Ann. Palliat. Med."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Turri, M., Teatini, F., Donato, F., Zanette, G., Tugnoli, V., Deotto, L., Bonetti, B., and Squintani, G. (2018). Pain Modulation after Oromucosal Cannabinoid Spray (SATIVEX\u00ae) in Patients with Multiple Sclerosis: A Study with Quantitative Sensory Testing and Laser-Evoked Potentials. Medicines, 5.","DOI":"10.3390\/medicines5030059"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/0168-5597(96)95625-7","article-title":"Scalp topography and dipolar source modelling of potentials evoked by CO2 laser stimulation of the hand","volume":"100","author":"Valeriani","year":"1996","journal-title":"Electroencephalogr. Clin. Neurophysiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1002\/(SICI)1097-4598(199809)21:9<1228::AID-MUS20>3.0.CO;2-M","article-title":"Conduction velocity versus amplitude analysis: Evidence for demyelination in diabetic neuropathy","volume":"21","author":"Wilson","year":"1998","journal-title":"Muscle Nerve"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1002\/mus.10204","article-title":"Conduction slowing in diabetic distal polyneuropathy","volume":"26","author":"Herrmann","year":"2002","journal-title":"Muscle Nerve"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1136\/jnnp.40.11.1072","article-title":"Nerve biopsy and conduction studies in diabetic neuropathy","volume":"40","author":"Behse","year":"1977","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1007\/s00415-011-6031-z","article-title":"Asymptomatic small fiber neuropathy in diabetes mellitus: Investigations with intraepidermal nerve fiber density, quantitative sensory testing and laser-evoked potentials","volume":"258","author":"Knaapen","year":"2011","journal-title":"J. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2355","DOI":"10.2337\/diacare.25.12.2355","article-title":"Early detection of small-fiber neuropathy in diabetes: A laser-induced pain somatosensory-evoked potentials and pupillometric study","volume":"25","author":"Pozzessere","year":"2002","journal-title":"Diabetes Care"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1097\/00001756-200206120-00005","article-title":"Pre-perceptual pain sensory responses (N1 component) in type 1 diabetes mellitus","volume":"13","author":"Rossi","year":"2002","journal-title":"Neuroreport"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/S1388-2457(99)00247-3","article-title":"Dysfunction of small myelinated afferents in diabetic polyneuropathy, as assessed by laser evoked potentials","volume":"111","author":"Agostino","year":"2000","journal-title":"Clin. Neurophysiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"815","DOI":"10.2337\/diacare.15.7.815","article-title":"Onset of NIDDM occurs at least 4-7 yr before clinical diagnosis","volume":"15","author":"Harris","year":"1992","journal-title":"Diabetes Care"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1055\/s-0044-1791823","article-title":"The Evolving Landscape of Small Fiber Neuropathy","volume":"45","author":"Devigili","year":"2025","journal-title":"Semin. Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.pain.2010.11.012","article-title":"On the relationship between nociceptive evoked potentials and intraepidermal nerve fiber density in painful sensory polyneuropathies","volume":"152","author":"Morales","year":"2011","journal-title":"Pain"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1007\/s10072-019-03871-x","article-title":"Small-fiber neuropathy definition, diagnosis, and treatment","volume":"40","author":"Basantsova","year":"2019","journal-title":"Neurol. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.neucli.2012.05.002","article-title":"Clinical usefulness of laser evoked potentials","volume":"42","author":"Valeriani","year":"2012","journal-title":"Neurophysiol. Clin."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/bs.irn.2016.03.008","article-title":"Wherefore Art Thou, O Treatment for Diabetic Neuropathy?","volume":"127","author":"Malik","year":"2016","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e70476","DOI":"10.14814\/phy2.70476","article-title":"Assessing the impact of supervised interval training on cardiovascular autonomic neuropathy in type 2 diabetes patients","volume":"13","author":"Stirane","year":"2025","journal-title":"Physiol. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1159\/000546015","article-title":"Small Fiber Neuropathy in Long COVID: A Cohort Study with Multimodal Assessment and Follow-Up","volume":"88","author":"Drobinska","year":"2025","journal-title":"Eur. Neurol."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/4\/390\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T08:15:24Z","timestamp":1775117724000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/4\/390"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,31]]},"references-count":45,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["brainsci16040390"],"URL":"https:\/\/doi.org\/10.3390\/brainsci16040390","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,31]]}}}