Impact of Diabetes on the Cornea

Diabetes mellitus is a systemic metabolic disease that exerts profound effects on the eye, including significant alterations in corneal structure and function. These corneal complications, often grouped under the term “diabetic keratopathy,” range from mild symptoms such as dry eye to severe neurotrophic ulcers and stromal opacification. While diabetic retinopathy is widely recognized, diabetic keratopathy remains underdiagnosed despite being present in 47–64% of patients during the course of the disease. Its pathogenesis involves multiple corneal layers and is driven by complex metabolic and neurotrophic mechanisms. Among these, the insulin-like growth factor (IGF) axis plays a central role in maintaining corneal homeostasis and promoting wound healing.

Clinical Manifestations and Pathophysiology

The clinical manifestations of diabetic keratopathy include a broad spectrum of corneal alterations. Patients often present with reduced corneal sensitivity, recurrent epithelial erosions, delayed wound healing, corneal edema, punctate keratitis, and, in severe cases, neurotrophic ulcers with risk of perforation. Pathophysiological changes extend beyond the epithelium, involving the sub-basal nerve plexus, stroma, and endothelium.

The reduction in corneal nerve density and function represents an early indicator of diabetic neuropathy, preceding the onset of retinopathy.

Confocal Microscopy and Sensitivity Loss

In vivo confocal microscopy has demonstrated a decrease in nerve fiber density, length, and branching, often accompanied by increased tortuosity and reduced basal epithelial cell density.

Reduced corneal sensitivity—known as hypesthesia or corneal anesthesia—is one of the most significant and early functional changes in diabetic keratopathy. It compromises the eye’s natural protective reflexes, such as blinking and reflex tear secretion, increasing vulnerability to trauma, infection, and dehydration.

Clinically, the loss of sensitivity makes the corneal epithelium more susceptible to microtrauma that would normally trigger lubrication and cellular turnover responses. Over time, decreased innervation disrupts the communication between epithelial and neural cells, impairing trophic signaling necessary for tissue regeneration. This leads to persistent epithelial defects, neurotrophic ulcers, and a higher rate of postoperative complications.

Moreover, the lack of symptoms in advanced hypesthesia often delays diagnosis and treatment, worsening prognosis. Therefore, routine assessment of corneal sensitivity in diabetic patients is a key diagnostic and prognostic tool for preventing severe corneal complications.

Dry Eye and Tear Film

Dry eye syndrome is one of the earliest and most common manifestations of diabetic keratopathy. Tear film instability, reduced tear secretion, and increased osmolarity are frequently observed. These changes are linked to autonomic dysfunction of the lacrimal gland and a reduced blink reflex due to impaired corneal innervation. Chronic tear film alterations heighten susceptibility to epithelial injury and impair ocular surface regeneration.

The severity of dry eye symptoms correlates with glycemic control and disease duration.

Molecular Mechanisms and the IGF Axis

At the molecular level, several metabolic pathways contribute to the pathogenesis of diabetic keratopathy. Chronic hyperglycemia induces advanced glycation end products (AGEs), polyol pathway activation through aldose reductase, oxidative stress, and protein kinase C (PKC) dysfunction. These metabolic disturbances impair mitochondrial function, reduce cellular energy availability, and lead to neuronal apoptosis and epithelial dysfunction.

The insulin-like growth factor (IGF) system is crucial in regulating corneal cell proliferation, differentiation, metabolism, and neuroprotection. IGF-1 and IGF-2 bind to receptors IGF-1R, IGF-2R, and hybrid receptors composed of IGF-1R and insulin receptor (INSR) subunits. In the cornea, IGF-1R is expressed in all epithelial layers and regulates wound healing. Unlike other tissues, glucose uptake in the corneal epithelium is insulin-independent due to constitutive GLUT1 expression; however, insulin remains essential for regulating circadian rhythm, metabolism, and cellular repair.

IGF-1 and Insulin: Therapeutic Potential

Evidence from animal and human studies highlights the therapeutic potential of IGF-1 and insulin in corneal healing. In a rabbit LASIK model, topical IGF-1 accelerated epithelial ultrastructural repair and nerve regeneration, significantly improving nerve density and dry eye symptoms compared to controls. Similarly, topical insulin has shown efficacy in promoting corneal healing in diabetic models.

In streptozotocin-induced diabetic rats, topical insulin (1U) restored tear production and corneal sensitivity within hours, with effects lasting several days. In a randomized clinical trial on diabetic patients undergoing vitrectomy with epithelial debridement, topical insulin (0.5U, four times daily) significantly accelerated epithelial healing compared to placebo and higher doses.

Topical insulin has also shown promise in treating refractory neurotrophic corneal ulcers. In a retrospective series of six patients (aged 2–73) unresponsive to conventional treatments such as amniotic membrane grafts and tarsorrhaphy, topical insulin (1U/mL) achieved complete re-epithelialization within 7–25 days. The formulation proved simple, stable for one month, and well tolerated, with no reported adverse effects.

The therapeutic effects of insulin and IGF-1 are attributed to their shared ability to activate mitogenic and neurotrophic signaling pathways via IGF-1R, including downstream cascades such as PI3K-Akt, which promote cell survival, migration, and proliferation. IGF-binding proteins (IGFBPs), particularly IGFBP-2 and IGFBP-3, modulate IGF ligand availability and play a role in stromal fibroblast differentiation and myofibroblast proliferation during wound repair.

Conclusions and Clinical Outlook

In conclusion, diabetic keratopathy encompasses a wide range of corneal alterations arising from metabolic, inflammatory, and neurotrophic changes induced by hyperglycemia. Early manifestations include dry eye symptoms and reduced corneal sensitivity, which may progress to persistent epithelial defects and neurotrophic ulcers.

The IGF/insulin axis serves as a critical regulator of corneal integrity and repair. Topical application of IGF-1 or insulin represents a promising therapeutic strategy for restoring corneal function in diabetic patients. Integrating these agents into clinical practice could significantly improve outcomes for individuals with refractory corneal epithelial disorders.