Diabetic Corneal Neuropathy as a Window Into Diabetic Foot Risk: A Large-Scale Association Study

To evaluate the association between diabetic corneal neuropathy and diabetic foot risk by examining corneal nerve features, clinical characteristics, and tear mediators in patients with different diabetic foot risk categories.

In this cross-sectional study, 710 participants underwent diabetic foot examination, in vivo confocal microscopy scans, ocular surface assessments, and tear mediators measurements. Ordinal regression analysis was applied to determine the associations between foot risk categories and corneal nerve metrics. ROC curve analysis assessed the ability of corneal nerve parameters to identify high-risk diabetic foot.

All diabetic foot risk categories exhibited significantly impaired corneal nerve fibre length, density, fractal dimension, and more swollen width compared with controls (all p < 0.001). These patients also demonstrated significantly shorter tear break-up time, more severe ocular symptoms, elevated tear MMP-9, and reduced tear Substance P levels (all p < 0.05). Patients with high-risk diabetic foot showed significantly more pronounced corneal nerve alterations than those in low and moderate-risk groups (all p < 0.05). The more severe diabetic foot risk category was significantly associated with reduced nerve fibre length, density, fractal dimension, and increased width (all p < 0.05). A predictive model incorporating corneal nerve fibre length, width, and serum creatinine achieved an AUC of 0.80 for identifying high-risk diabetic foot. A CNFL < 5.7 mm/mm² was associated with 4.37-fold higher odds of having a high-risk diabetic foot.

Corneal nerve impairment is evident even in low-risk diabetic foot patients and is associated with foot risk severity. Corneal nerve metrics may serve as early indicators for identifying high-risk diabetic foot.