{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,14]],"date-time":"2026-11-14T01:54:53Z","timestamp":1794621293795,"version":"4.9.1"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T00:00:00Z","timestamp":1719878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>This study was undertaken to investigate whether sustained rather than a single measure of corneal nerve loss was associated with the onset of diabetic peripheral neuropathy (DPN) and the progression of neuropathic symptoms and deficits in individuals with type 2 diabetes (T2D).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Participants underwent clinical, metabolic testing and assessment of neuropathic symptoms, vibration perception threshold (VPT), sudomotor function, and corneal confocal microscopy (CCM) at baseline, 1, 2, and 4\u20137\u2009years. Sustained corneal nerve loss was defined as abnormal corneal nerve fiber density (CNFD, &amp;lt;24 fibers\/mm<jats:sup>2<\/jats:sup>), corneal nerve branch density (CNBD, &amp;lt;21 branches\/mm<jats:sup>2<\/jats:sup>), and corneal nerve fiber length (CNFL, &amp;lt;16\u2009mm\/mm<jats:sup>2<\/jats:sup>) persisting for \u226550% of the study duration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 107 participants with a mean duration of T2D of 13.3\u2009\u00b1\u20097.3\u2009years, aged 54.8\u2009\u00b1\u20098.5\u2009years, underwent baseline and follow-up assessments over a median duration of 4\u2009years, ranging from 1 to 7\u2009years. The DPN prevalence at baseline was 18\/107 (16.8%), and of the 89 participants without DPN at baseline, 13 (14.6%) developed DPN during follow-up. Approximately half of the cohort had sustained corneal nerve damage, and corneal nerve measures were significantly lower in this group than those without sustained damage (<jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.0001). Sustained corneal nerve damage was associated with the development of DPN (<jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.0001), a progressive loss of vibration perception (<jats:italic>p<\/jats:italic>\u2009\u2264\u20090.05), an increased incidence of burning pain, numbness, or a combination of both (<jats:italic>p<\/jats:italic>\u2009=\u20090.01\u20130.001), and a borderline association with progressive sudomotor dysfunction (<jats:italic>p<\/jats:italic>\u2009=\u20090.07). Sustained abnormal CNFL effectively distinguished between participants who developed DPN and those who did not (AUC: 76.3, 95% CI: 65.9\u201386.8%, <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.0001), while baseline and other sustained measures did not predict DPN onset.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Sustained abnormal CCM is associated with more severe corneal nerve damage, DPN development, and the progression of neuropathic symptoms and deficits. Regular CCM monitoring may enable the identification of those at greater risk of developing and worsening DPN who may benefit from more aggressive risk factor reduction.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnins.2024.1393105","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T04:44:50Z","timestamp":1719895490000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Sustained corneal nerve loss predicts the development of diabetic neuropathy in type 2 diabetes"],"prefix":"10.3389","volume":"18","author":[{"given":"Georgios","family":"Ponirakis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim","family":"Al-Janahi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Einas","family":"Elgassim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moayad","family":"Homssi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis N.","family":"Petropoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoda","family":"Gad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adnan","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hadeel B.","family":"Zaghloul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamda","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mashhood A.","family":"Siddique","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima F. S.","family":"Mohamed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina H. M.","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youssra","family":"Dakroury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abeer M. M.","family":"El Shewehy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruba","family":"Saeid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadwa","family":"Mahjoub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaikha N.","family":"Al-Thani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farheen","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rawan","family":"Hussein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salah","family":"Mahmoud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nebras H.","family":"Hadid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aisha","family":"Al Obaidan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iuliia","family":"Salivon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyad R.","family":"Mahfoud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud A.","family":"Zirie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yousuf","family":"Al-Ansari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen L.","family":"Atkin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rayaz A.","family":"Malik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,7,2]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"e0180175","DOI":"10.1371\/journal.pone.0180175","article-title":"Diagnostic utility of corneal confocal microscopy and intra-epidermal nerve fibre density in diabetic neuropathy","volume":"12","author":"Alam","year":"2017","journal-title":"PLoS One"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1502","DOI":"10.2337\/dc14-2733","article-title":"Corneal confocal microscopy identifies small-Fiber neuropathy in subjects with impaired glucose tolerance who develop type 2 diabetes","volume":"38","author":"Azmi","year":"2015","journal-title":"Diabetes Care"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1478","DOI":"10.1007\/s00125-019-4897-y","article-title":"Early nerve fibre regeneration in individuals with type 1 diabetes after simultaneous pancreas and kidney transplantation","volume":"62","author":"Azmi","year":"2019","journal-title":"Diabetologia"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.2337\/dc14-2422","article-title":"Small nerve fiber quantification in the diagnosis of diabetic sensorimotor polyneuropathy: comparing corneal confocal microscopy with intraepidermal nerve fiber density","volume":"38","author":"Chen","year":"2015","journal-title":"Diabetes Care"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1016\/j.media.2011.05.016","article-title":"Automatic analysis of diabetic peripheral neuropathy using multi-scale quantitative morphology of nerve fibres in corneal confocal microscopy imaging","volume":"15","author":"Dabbah","year":"2011","journal-title":"Med. Image Anal."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"3195","DOI":"10.1167\/iovs.14-13959","article-title":"Morphometric stability of the corneal subbasal nerve plexus in healthy individuals: a 3-year longitudinal study using corneal confocal microscopy","volume":"55","author":"Dehghani","year":"2014","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"150","DOI":"10.2337\/dc20-1482","article-title":"Diagnosis of neuropathy and risk factors for corneal nerve loss in type 1 and type 2 diabetes: a corneal confocal microscopy study","volume":"44","author":"Ferdousi","year":"2021","journal-title":"Diabetes Care"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1111\/jdi.13643","article-title":"Corneal confocal microscopy for the diagnosis of diabetic peripheral neuropathy: a systematic review and meta-analysis","volume":"13","author":"Gad","year":"2022","journal-title":"J. Diab. Investig."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1080\/14737175.2023.2247163","article-title":"Where art thou O treatment for diabetic neuropathy: the sequel","volume":"23","author":"Guldiken","year":"2023","journal-title":"Expert. Rev. Neurother."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"e1680","DOI":"10.1212\/WNL.0000000000206902","article-title":"Assessing corneal confocal microscopy and other small Fiber measures in diabetic polyneuropathy","volume":"100","author":"Gylfadottir","year":"2023","journal-title":"Neurology"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"e0183040","DOI":"10.1371\/journal.pone.0183040","article-title":"Corneal confocal microscopy is a rapid reproducible ophthalmic technique for quantifying corneal nerve abnormalities","volume":"12","author":"Kalteniece","year":"2017","journal-title":"PLoS One"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1111\/ene.15129","article-title":"Corneal nerve loss is related to the severity of painful diabetic neuropathy","volume":"29","author":"Kalteniece","year":"2022","journal-title":"Eur. J. Neurol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1829","DOI":"10.2337\/dc19-0951","article-title":"Rapid corneal nerve fiber loss: a marker of diabetic neuropathy onset and progression","volume":"43","author":"Lewis","year":"2020","journal-title":"Diabetes Care"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"ii23","DOI":"10.1136\/jnnp.2005.069138","article-title":"Nerve conduction studies: essentials and pitfalls in practice","volume":"76","author":"Mallik","year":"2005","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"2107","DOI":"10.2337\/dc21-0476","article-title":"Corneal confocal microscopy predicts the development of diabetic neuropathy: a longitudinal diagnostic multinational consortium study","volume":"44","author":"Perkins","year":"2021","journal-title":"Diabetes Care"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"e83","DOI":"10.1097\/ICO.0b013e3182749419","article-title":"Repeatability of in vivo corneal confocal microscopy to quantify corneal nerve morphology","volume":"32","author":"Petropoulos","year":"2013","journal-title":"Cornea"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"e001420","DOI":"10.1136\/bmjdrc-2020-001420","article-title":"Effect of treatment with exenatide and pioglitazone or basal-bolus insulin on diabetic neuropathy: a substudy of the Qatar study","volume":"8","author":"Ponirakis","year":"2020","journal-title":"BMJ Open Diabetes Res. Care"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1703","DOI":"10.1111\/jdi.13864","article-title":"Progressive loss of corneal nerve fibers is associated with physical inactivity and glucose lowering medication associated with weight gain in type 2 diabetes","volume":"13","author":"Ponirakis","year":"2022","journal-title":"J. Diab. Investig."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1551","DOI":"10.1111\/jdi.13815","article-title":"Prevalence and risk factors for diabetic peripheral neuropathy, neuropathic pain and foot ulceration in the Arabian gulf region","volume":"13","author":"Ponirakis","year":"2022","journal-title":"J. Diab. Investig."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1111\/jdi.13388","article-title":"Prevalence and risk factors for diabetic neuropathy and painful diabetic neuropathy in primary and secondary healthcare in Qatar","volume":"12","author":"Ponirakis","year":"2021","journal-title":"J. Diab. Investig."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1093\/ajh\/hpz058","article-title":"Hypertension contributes to neuropathy in patients with type 1 diabetes","volume":"32","author":"Ponirakis","year":"2019","journal-title":"Am. J. Hypertens."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"136","DOI":"10.2337\/dc16-2042","article-title":"Diabetic neuropathy: a position statement by the American Diabetes Association","volume":"40","author":"Pop-Busui","year":"2017","journal-title":"Diabetes Care"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"671","DOI":"10.2337\/dc14-2114","article-title":"Corneal confocal microscopy predicts 4-year incident peripheral neuropathy in type 1 diabetes","volume":"38","author":"Pritchard","year":"2015","journal-title":"Diabetes Care"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"e0138224","DOI":"10.1371\/journal.pone.0138224","article-title":"SUDOSCAN: a simple, rapid, and objective method with potential for screening for diabetic peripheral neuropathy","volume":"10","author":"Selvarajah","year":"2015","journal-title":"PLoS One"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1111\/j.1464-5491.2011.03500.x","article-title":"Validation of DN4 as a screening tool for neuropathic pain in painful diabetic polyneuropathy","volume":"29","author":"Spallone","year":"2012","journal-title":"Diabet. Med."},{"key":"ref26","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2023.1161077","article-title":"Abnormal intraepidermal nerve fiber density in disease: a scoping review","author":"Thomas","year":"2023","journal-title":"medRxiv"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1111\/aas.12150","article-title":"Test-retest studies in quantitative sensory testing: a critical review","volume":"57","author":"Werner","year":"2013","journal-title":"Acta Anaesthesiol. Scand."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"2454","DOI":"10.2337\/db13-1819","article-title":"Early detection of nerve fiber loss by corneal confocal microscopy and skin biopsy in recently diagnosed type 2 diabetes","volume":"63","author":"Ziegler","year":"2014","journal-title":"Diabetes"}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2024.1393105\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T04:44:53Z","timestamp":1719895493000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2024.1393105\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,2]]},"references-count":28,"alternative-id":["10.3389\/fnins.2024.1393105"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2024.1393105","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,2]]},"article-number":"1393105"}}