Liraglutide promotes diabetic corneal epithelial and nerve regeneration by suppressing oxidative stress via the PI3K/AKT signalling pathway.

AIMS: Although clinical evidence suggested that glucagon-like peptide-1 (GLP-1) receptor agonists exhibit neuroprotective properties in patients with diabetic peripheral neuropathy, their therapeutic potential in diabetic keratopathy (DK) remains unexplored. This study investigates the neuroprotective and wound-healing effects of liraglutide in DK through PI3K/AKT pathway activation and oxidative stress amelioration.

METHODS

In vitro, we evaluated the effects of liraglutide on migration, oxidative stress, and apoptosis in human corneal epithelial cells (HCECs). Axonal outgrowth was quantified in the primary trigeminal ganglion neurons cultured under high glucose conditions. The role of the PI3K/AKT pathway was confirmed using specific pharmacological inhibitors. In vivo, diabetic mice were treated with liraglutide, and clinical outcomes (corneal fluorescein scores, tear production, sensitivity, goblet cell density) were measured. Corneal tissues were analysed for PI3K/AKT activation, wound healing, and nerve regeneration. Additional experiments using PI3K inhibitors were performed to confirm the pathway's involvement.

RESULTS

Our in vitro experiments demonstrated that liraglutide promoted HCECs migration, reduced oxidative stress, and inhibited apoptosis via activation of the PI3K/AKT pathway. Additionally, liraglutide enhanced axonal outgrowth in high glucose-treated primary trigeminal ganglion neurons through the same mechanism. In vivo, liraglutide treatment significantly improved clinical outcomes in diabetic mice, including reduced corneal fluorescein staining, increased tear production, improved corneal sensitivity, and restoration of conjunctival goblet cell density. Mechanistically, liraglutide activated PI3K/AKT signalling in the diabetic cornea, promoting wound healing and nerve regeneration by mitigating oxidative stress. These beneficial effects were abolished upon PI3K pathway inhibition.

CONCLUSIONS

These findings provide strong preclinical evidence supporting the therapeutic potential of liraglutide for the treatment of DK.