{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T19:40:16Z","timestamp":1780602016474,"version":"3.54.1"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T00:00:00Z","timestamp":1756252800000},"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. Endocrinol."],"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p>The purpose of the study was to investigate the deposition of microdots in corneal stroma in diabetes mellitus (DM) patients and assess the relationship between microdots and corneal nerve damage as well as retinal microvascular perfusion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>127 patients with DM and 36 age and sex-matched controls were included. All subjects were examined by <jats:italic>in vivo<\/jats:italic> confocal microscopy (IVCM) and optical coherence tomography angiography (OCTA). Histochemistry staining was also performed in cadaver corneas from patients with DM or control subjects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The deposition of microdots was significantly increased in corneal stroma in patients with DM than controls (<jats:italic>P<\/jats:italic>&amp;lt;0.0001). Spearman\u2019s rank correlation showed that the deposition of microdots in subepithelial, anterior stromal, mid stromal, posterior stromal, and pre-Descemet stromal layers had positive correlations with corneal nerve fiber density (CNFD) (<jats:italic>q<\/jats:italic>&amp;lt;0.0001, <jats:italic>q<\/jats:italic>&amp;lt;0.0001, <jats:italic>q<\/jats:italic>&amp;lt;0.0001, <jats:italic>q<\/jats:italic>=0.0039, and <jats:italic>q<\/jats:italic>=0.0104), corneal nerve fiber length (CNFL) (<jats:italic>q<\/jats:italic>&amp;lt;0.0001, <jats:italic>q<\/jats:italic>&amp;lt;0.0001, <jats:italic>q<\/jats:italic>&amp;lt;0.0001, <jats:italic>q<\/jats:italic>&amp;lt;0.0001, and <jats:italic>q<\/jats:italic>&amp;lt;0.0001), and corneal tortuosity (<jats:italic>q<\/jats:italic>&amp;lt;0.0001, <jats:italic>q<\/jats:italic>&amp;lt;0.0001, <jats:italic>q<\/jats:italic>&amp;lt;0.0001, <jats:italic>q<\/jats:italic>&amp;lt;0.0001, and <jats:italic>q<\/jats:italic>&amp;lt;0.0001). The subepithelial, anterior stromal, and mid stromal microdots also showed weak correlations with superficial vascular complexes (SVC) vessel density (VD) (<jats:italic>q<\/jats:italic>&amp;lt;0.0001, <jats:italic>q<\/jats:italic>=0.0011, and <jats:italic>q<\/jats:italic>=0.0004) and deep vascular complexes (DVC) VD (<jats:italic>q=<\/jats:italic>0.0001, <jats:italic>q<\/jats:italic>=0.0109, and <jats:italic>q<\/jats:italic>=0.0037). PAS and long Ziehl-Neelsen staining demonstrated lipofuscin deposits in cornea.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Patients with DM demonstrated a significant increase of deposition of microdots in corneal stroma which correlates with corneal nerve loss and retinal microvascular perfusion. Microdots are at least partially composed of lipofuscin which is also observed in corneal basal epithelial layer.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2025.1481018","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T09:48:36Z","timestamp":1756288116000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Corneal stromal microdots accumulation and its association with corneal neurodegeneration and retinal microvascular perfusion in diabetes"],"prefix":"10.3389","volume":"16","author":[{"given":"Jingrao","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/S2213-8587(13)70112-8","article-title":"Diabetes: a 21st century challenge","volume":"2","author":"Zimmet","year":"2014","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2337\/dc13-S067","article-title":"Diagnosis and classification of diabetes mellitus","year":"2013","journal-title":"Diabetes Care"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.14670\/HH-25.1531","article-title":"Evaluation of the corneal endothelium in patients with diabetes mellitus type I and II","volume":"25","author":"M\u00f3dis","year":"2010","journal-title":"Histol Histopathol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcrs.2010.08.027","article-title":"Corneal biomechanical characteristics in patients with diabetes mellitus","volume":"36","author":"Kotecha","year":"2010","journal-title":"J Cataract Refract Surg"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S0161-6420(97)30011-6","article-title":"Long-term contact lens wear induces a corneal degeneration with microdot deposits in the corneal stroma","volume":"104","author":"B\u00f6hnke","year":"1997","journal-title":"Ophthalmology"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1097\/00003226-200305000-00003","article-title":"Confocal microscopy of Thygeson's superficial punctate keratopathy","volume":"22","author":"Watson","year":"2003","journal-title":"Cornea"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1159\/000358805","article-title":"Reis-B\u00fccklers corneal dystrophy: a reappraisal using in vivo and ex vivo imaging techniques","volume":"51","author":"Liang","year":"2014","journal-title":"Ophthalmic Res"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajo.2005.11.053","article-title":"Corneal and conjunctival manifestations in Fabry disease: in vivo confocal microscopy study","volume":"141","author":"Mastropasqua","year":"2006","journal-title":"Am J Ophthalmol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/s00417-008-0962-9","article-title":"The microstructure of cornea verticillata in Fabry disease and amiodarone-induced keratopathy: a confocal laser-scanning microscopy study","volume":"247","author":"Falke","year":"2009","journal-title":"Graefes Arch Clin Exp Ophthalmol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3928\/15428877-20120209-01","article-title":"In vivo confocal microscopic evaluation of corneal wound healing after femtosecond laser-assisted keratoplasty","volume":"43","author":"Shtein","year":"2012","journal-title":"Ophthalmic Surgery Lasers Imaging: Off J Int Soc For Imaging In Eye"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1080\/02713683.2020.1725062","article-title":"Microdot accumulation in the anterior cornea with aging - quantitative analysis with in vivo confocal microscopy","volume":"45","author":"Utheim","year":"2020","journal-title":"Curr Eye Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2011.07.041","article-title":"How normal is the transparent cornea? 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