Investigating the Potential Effects of Peroxisome Proliferator-Activated Receptor (PPAR)-α Agonists on Corneal Nerve Regeneration in Patients with Type II Diabetes Mellitus

Abstract

Purpose : Diabetic neuropathy is one of the most common microvascular complications in diabetes mellitus (DM). Here, we investigate the effects of peroxisome proliferator-activated receptor (PPAR)-α agonists, fenofibrates, on the prevention of corneal nerve degeneration and the stimulation of corneal nerve regeneration in patients with type II DM.

Methods : A single-arm, open-label, single-center interventional study was conducted in Singapore National Eye Centre. Twenty-six patients (80.8% Chinese; 80.8% males; aged 60.8 ± 9.31 years) were prescribed 100mg/day and 300mg/day oral fenofibrate for 30 days. The patients (52 eyes) underwent comprehensive ocular surface assessment, corneal nerve metrics and wing cells epithelium analysis using in-vivo confocal microscopy scans, before and after treatment. Tear neuromediator analysis included substance P, calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY), and β-nerve growth factor (β-NGF).

Results : Corneal nerve fiber density (CNFD) significantly increased from 9.46 ± 6.20 to 12.6 ± 4.36 number of fibers/mm² (P=0.01; figure 1), while corneal nerve fiber width significantly decreased from 0.0225 ± 0.00118 to 0.0218 ± 0.00128 mm/mm² (P<0.01). Corneal nerve fractal dimension, which measures spatial loss of nerves, also shows a trend of improvement (pre-treatment: 1.39 ± 0.0641; post-treatment: 1.49 ± 0.0371). After treatment, epithelial cells’ circularity significantly improved from 0.726 ± 0.0162 to 0.717 ± 0.0213 (P<0.05; figure 1). Tear breakup time significantly improved, and ocular surface staining evaluated by Oxford scores significantly increased after treatment (both p<0.01). Additionally, tear substance P concentrations significantly increased after treatment (pre-treatment: 1239 ± 712 pg/mL; post-treatment: 1668 ± 948 pg/mL; P=0.02), and the changes of tear substance P concentrations were significantly correlated with the increment of CNFD (r = 0.41; P=0.036).

Conclusions : PPAR-α has protective effect on the ocular surface and corneal nerve degeneration, while stimulating corneal nerve regeneration in diabetic corneal neuropathy. These findings may offer novel treatments for diabetic corneas.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

 

Figure 1: Representative IVCM scans showing the improvement in CNFD and corneal epithelial morphology after fenofibrate treatment.