Diabetes mellitus is a systemic metabolic disease that exerts profound effects on the eye, including significant alterations of the 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. The 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 of diabetic keratopathy encompass a broad spectrum of corneal changes. Patients frequently exhibit decreased corneal sensitivity, recurrent epithelial erosions, delayed wound healing, corneal edema, punctate keratitis, and in severe cases, neurotrophic ulcers with risk of perforation. The pathophysiological changes are not limited to the epithelium but involve the sub-basal nerve plexus, stroma, and endothelium. Decreased corneal nerve density and function are early indicators of diabetic neuropathy and precede the onset of diabetic retinopathy. In vivo confocal microscopy has demonstrated reduced nerve fiber density, length, and branching, often accompanied by increased tortuosity and reduced epithelial basal cell density.
Reduced corneal sensitivity, also known as hypesthesia or corneal anesthesia, is one of the most significant and early functional alterations observed in diabetic keratopathy. It impairs the eye’s normal protective reflexes, including blinking and reflex tear secretion, thereby exposing the ocular surface to an increased risk of trauma, infection, and desiccation. Clinically, the loss of sensitivity renders the corneal epithelium vulnerable to repeated microtraumas that, under normal conditions, would be rapidly detected and compensated for by enhanced lubrication and cellular turnover. Over time, reduced innervation disrupts the communication between epithelial and nerve cells, compromising the trophic signaling necessary for tissue regeneration. The consequences include the formation of persistent epithelial defects, progression to neurotrophic ulcers, and a higher incidence of postoperative complications. Moreover, the absence of subjective symptoms in patients with advanced hypesthesia often delays the diagnosis and treatment of corneal lesions, further worsening the prognosis. Therefore, routine assessment of corneal sensitivity in diabetic patients serves as a crucial diagnostic and prognostic parameter for the prevention of severe corneal complications.
Dry eye disease is one of the most common early symptoms of diabetic keratopathy. Tear film instability, reduced tear secretion, and increased osmolarity are frequently observed in diabetic patients. These changes are linked to both autonomic dysfunction of the lacrimal gland and reduced blink reflex due to impaired corneal innervation. Chronic tear film abnormalities increase susceptibility to corneal epithelial injury and compromise the regenerative capacity of the ocular surface. The severity of dry eye symptoms correlates with poor glycemic control and disease duration.

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

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

Evidence from both 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 corneal epithelial ultrastructure repair and nerve regeneration, with significant improvements observed in corneal nerve density and dry eye symptoms compared to controls. Similarly, topical insulin has demonstrated efficacy in enhancing corneal wound healing in diabetic models. In streptozotocin-induced diabetic rats, topical insulin (1 U) restored tear production and corneal sensitivity within hours, with effects lasting several days. In a randomized controlled trial in diabetic patients undergoing vitrectomy with epithelial debridement, topical insulin at 0.5 U four times daily significantly accelerated epithelial healing compared to placebo and higher concentrations.

Topical insulin has also shown promise in treating refractory neurotrophic corneal ulcers. In a retrospective series of six patients aged 2 to 73 years with ulcers unresponsive to conventional treatments such as amniotic membrane grafts and tarsorrhaphy, topical insulin (1 U/mL) achieved complete epithelial closure within 7 to 25 days. The formulation was 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 capacity to activate mitogenic and neurotrophic pathways via IGF-1R. These include downstream signaling cascades such as PI3K-Akt, which promote cell survival, migration, and proliferation. IGF binding proteins (IGFBPs), especially IGFBP-2 and IGFBP-3, modulate the availability of IGF ligands and play a role in stromal fibroblast differentiation and myofibroblast proliferation during wound repair.

In conclusion, diabetic keratopathy encompasses a wide spectrum of corneal abnormalities resulting from hyperglycemia-induced metabolic, inflammatory, and neurotrophic changes. Early manifestations include dry eye symptoms and reduced corneal sensitivity, which can progress to persistent epithelial defects and neurotrophic ulcers. The IGF/insulin axis is a critical regulator of corneal integrity and repair. Topical application of IGF-1 or insulin represents a promising therapeutic approach for restoring corneal function in diabetic patients. Integration of these agents into clinical practice may improve outcomes for patients with refractory corneal epithelial disease.

References

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Bikbova, G. et al. Diabetic corneal neuropathy: clinical perspectives. Clin. Ophthalmol. 12, 981–987 (2018). PMCID: PMC5973365.
Leong, C. Y. et al. Usage of topical insulin for the treatment of diabetic keratopathy, including corneal epithelial defects. World J. Diabetes 14(6), 930–938 (2023). PMCID: PMC10294054.
Wang, A. L. et al. Use of Topical Insulin to Treat Refractory Neurotrophic Corneal Ulcers. Cornea 36(11), 1426–1428 (2017). PMCID: PMC5633504.
Stuard, W. L. et al. The IGF/Insulin-IGFBP Axis in Corneal Development, Wound Healing, and Disease. Front. Endocrinol. 11, 24 (2020). PMCID: PMC7062709.