Topical Insulin Improves Corneal Re-Epithelization for Refractory Persistent Epithelial Defects

TRUJILLO, PERU – APRIL 19: Corneal edema aphakia patient Jose, aged 87, (R) undergoes post-operative tests with Dr Maria Montero (C) after the previous days surgery at the IRO (Regional Institute for Ophthalmology) on April 19, 2018 in Trujillo, Peru. Following a clinical screening day, Jose was chosen for a penetrating keratoplasty procedure (cornea transplant) during a programme run by Orbis, the ophthalmic training organisation. Founded in 1982 by ophthalmologist David Paton, Orbis trains eyecare teams across Africa, Asia and Latin America to improve the standard of eyecare in the region. As well as working in local hospitals, the charity also has a self-sufficient surgical unit on the Orbis Flying Eye Hospital, a converted McDonald-Douglas MD10 aircraft. (Photo by Leon Neal/Getty Images)
Researchers show potential treatment against epithelial defects.

Patients with refractory persistent epithelial defects (PEDs) may benefit from topical insulin, according to a new study published in the European Journal of Ophthalmology. The research shows most patients who underwent this treatment achieved re-epithelium in approximately 1 month.

In healthy corneas, epithelial cells are continually regenerated from stem cells at the limbus, with an average lifespan and self-renewal rate of 7 to 10 days. Corneal lesions in healthy corneas usually heal in 7 to 14 days, the researchers say. However, Persistent epithelial defects (PEDs) — defined as corneal defects with a minimum area of 2 mm2 that don’t improve in at least 2 weeks with conventional treatment — can develop due to altered epithelial adhesion, limbal stem cell deficiency, trauma, medications, and infections.

No clear established treatment of PEDs exists in the academic literature. Conventional non-invasive treatment includes aggressive non-preserved lubrication, withdrawal of epitheliotoxic medication, prophylactic antibiotics, or the use of bandage soft contact lenses or punctal plugs. Autologous serum, platelet-rich plasma, surgical debridement, or amniotic membrane grafting are other treatment options.

When the epithelium is damaged, it heals through an activation of stem cells in the corneoscleral junction that is stimulated by growth factors, cytokines, and extracellular matrix signals. Insulin-like growth factors (IGFs) are critical for the growth, differentiation, and proliferation of corneal epithelial cells and act through insulin receptors and IGF receptors. Corneal keratocytes and epithelial cells express IGF-I, its receptors, and insulin receptors.

Insulin is closely related to IGFs, and has been proven safe for topical human ocular use, the investigators say.  Research also shows insulin can enhance the growth of corneal epithelial cells and promote wound healing. With this in mind, researchers evaluated insulin eye drops for PEDs that didn’t respond to conventional treatment.

During the prospective, non-randomized, hospital-based study, patients with refractory PEDs were treated with insulin eye drops four times a day (every 6 hours). Patients’ demographics, PED etiology, concomitant treatments, and comorbidities were reviewed. The rate of PED closure and epithelial healing time (defined as the absence of fluorescein staining) were considered the primary outcome measures.

A total of 21 patients (12 females and 9 males) with a mean age of 72.2 years were treated with insulin drops. The mean PED area before treatment was 17.6 (± 16.5) mm2 (median 13.2 mm2; range 3.9 mm2 – 70.6 mm2). PED comorbidities included 7 eyes with infectious keratitis (33%), 5 eyes with calcium keratopathy (24%), ocular surgery on 3 eyes (14%), 3  eyes with lagophthalmos (14%), 2 eyes with bullous keratopathy (10%), and 1 with herpetic eye disease (5%).

At the conclusion of the study, the eyes of 17 patients treated with insulin drops (81%) with refractory PEDs had re-epithelized and 4 patients (19%) still had an epithelial defect at follow-up, although the affected area had decreased in size. In patients where PED closure was achieved, mean time until re-epithelization was 34.8 (± 29.9) days (median 23; range 7–114). In the remaining patients, a mean area reduction of 91.5% was achieved.

Because the cornea is the outermost layer of the eye, it functions as a barrier and is responsible for most of the eye’s refractive power, the researchers explain. The corneal epithelium is susceptible to abrasions and epithelial defects. If left untreated or if re-epithelization is not achieved, PEDs can lead to infection, perforation, neovascularization, scarring, and a decrease of visual acuity.

How insulin restores epithelization is not fully understood, but investigators conclude that topical insulin can promote and accelerate corneal re-epithelization of refractory PEDs. The treatment also offers other advantages, including excellent tolerance, availability, and cost-effectiveness.

The researchers acknowledge that the study examined a series of cases with a very heterogeneous patient profile in terms of etiology, size of the initial epithelial defect, and accompanying treatment. This study also lacked a control group to compare effectiveness.


Diaz-Valle D, Burgos-Blasco B, Gegundez-Fernandez JA, et al. Topical insulin for refractory persistent corneal epithelial defects. European Journal of Ophthalmology. September 2020. doi:10.1177/1120672120958307