Corneal nerves warn first: early neurodegeneration predicts retinopathy progression
Aims: Diabetic corneal neuropathy (DCN) and diabetic retinopathy (DR) share common pathophysiological mechanisms; however, the links between them are poorly understood. The aim of the study was to investigate the relationship between DCN and DR through corneal nerve imaging, ocular surface evaluation, and tear biomarker profiling in patients with type 2 diabetes (T2D).
Methods: Cross-sectional study including 1,654 eyes from 822 participants (634 with T2D; 188 controls). Corneal nerves, dendritic cells, and microneuromas were assessed using in vivo confocal microscopy. Ocular surface tests included corneal sensitivity, tear breakup time (TBUT), Schirmer test, and staining scores. Tear levels of substance P, MMP‑9, IGFBP‑3, and TIMP‑1 were quantified. DR severity was graded using ETDRS criteria: no DR, non-proliferative DR (NPDR), and proliferative DR (PDR).
Results: Among the 634 T2D patients, 277 (43.7%) were female, the mean age was 59.9 ± 9.8 years and 427 (67.4%) had no DR, 156 (24.6%) had NPDR, and 51 (8.0%) had PDR. Among the 188 control participants, 87 (46.3%) were female, with a mean age of 59.3 ± 10.2 years. All nerve parameters (CNFL, CNFD, CNBD, CTBD, CNFA, CfracDim) were significantly lower in diabetics vs. controls (P < 0.001), with progressive deterioration across NPDR and PDR. Dendritic cell density and length were significantly higher in all diabetic groups compared with control (P < 0.001). Microneuromas were larger in no‑DR and NPDR patients compared with controls (P < 0.005). PDR patients showed the most severe ocular surface dysfunction (lower corneal sensitivity, TBUT and Schirmer values and higher staining and symptom scores). Tear substance P was consistently reduced across all DR stages, while MMP 9 and IGFBP 3 increased with DR severity. Corneal nerve metrics and corneal sensitivity were strongly associated with DR stage.
Conclusions: DCN precedes the onset of DR and progressively worsens with its severity. Corneal sensitivity and corneal nerve parameters are significantly associated with DR severity. Thus, corneal nerve status could be an early indicator and predictor of DR.
Comments: This study reinforces the already explored concept that DCN is an early and sensitive marker of neural and vascular damage in diabetes. Corneal nerve loss was evident even in patients without DR, supporting the idea that neurodegeneration precedes microvascular retinal changes. The progressive deterioration of nerve metrics across DR stages, together with increased dendritic cell activation and microneuroma enlargement, highlights a combined neuro‑inflammatory process. Tear biomarkers—particularly reduced substance P and elevated MMP‑9 and IGFBP‑3—mirror these alterations and may offer additional noninvasive indicators of disease severity, reflecting parallel neurodegenerative and inflammatory processes. Thus, the authors highlight that structural nerve changes are detectable earlier than functional ocular surface alterations, suggesting that in vivo confocal microscopy is a sensitive tool for early detection. Although the cross‑sectional design limits causal inference, the large cohort and multimodal assessment strengthen the findings. Overall, corneal nerve imaging emerges as a promising tool for early detection and risk stratification in diabetic microvascular complications. Moreover, the integration of imaging and tear biomarkers highlights a promising non-invasive approach for early DR risk stratification and monitoring.
Carla Greco
Reference. Liu C, Lee IXY, Xue CC, Yu M, Anam A, Wong RKT, Cheng CY, Liu YC. Diabetic Corneal Neuropathy Precedes and Is Associated With Diabetic Retinopathy. Diabetes. 2026 Apr 1;75(4):683-695. doi: 10.2337/db25-0590. PMID: 41563729; PMCID: PMC13007213.
