The present study delves into the burgeoning area of topical ocular insulin for managing various ocular pathologies. While insulin's role in systemic glycemic control is well-established, its topical application in the ophthalmic realm remains a relatively recent investigative avenue. This systematic review and meta-analysis comprehensively assesses the available literature, aiming to elucidate the potential of topical ocular insulin as a simple, safe, and cost-effective therapeutic strategy.
Emerging evidence suggests topical ocular insulin as a potent modulator of the wound healing cascade. Historically, insulin administration primarily focused on diabetes mellitus treatment. However, recent research has unveiled its potential therapeutic applications in diverse medical fields, beckoning further exploration. Beyond glycemic control, insulin exhibits pleiotropic effects, demonstrating growth factor-like activity.22 This translates to enhanced cellular processes like keratinocyte migration, fibroblast proliferation, and extracellular matrix deposition, ultimately promoting tissue regeneration. Additionally, topical ocular insulin modulates the inflammatory milieu, influencing the release of pro- and anti-inflammatory cytokines to orchestrate a balanced healing response. While the specific mechanisms remain under active investigation, topical ocular insulin warrants further exploration as a potential therapeutic adjunct in wound management.23
Christie and Hanzal's pioneering work in 1931 explored topical ocular insulin administration for systemic glucose control.24 However, subsequent studies consistently demonstrated the ineffectiveness of such formulations in modulating systemic glucose levels.25 Our findings concur with this established knowledge, revealing no significant impact of topical ocular insulin on serum glucose levels. This lack of systemic effect suggests that the observed improvement in diabetic corneal re-epithelialization rates likely occurs through localized cellular mechanisms, independent of broader systemic influence. This is further supported by the presence of glucose transporter 1 in the corneal epithelium, facilitating glucose uptake independent of insulin.26 While the precise mechanisms of topical ocular insulin in ocular disease remain elusive, compelling evidence points towards its potential involvement in corneal nerve regeneration and enhanced epithelial cell migration.27 In vitro models further support this notion, demonstrating the ability of topical ocular insulin to stimulate cell migration and facilitate wound closure in cultured corneal epithelial sheets.22
Systematic reviews and meta-analyses play a crucial role in advancing medical knowledge by providing a comprehensive and unbiased synthesis of existing research.28 In the dynamic field of ophthalmology, where new information constantly emerges, these methodologies are particularly valuable for informing clinical practice and guiding future research.29 Our work fills a significant knowledge gap by conducting the first-ever systematic review and meta-analysis on the safety and efficacy of topical ocular insulin for ocular disease.
The quality of included articles is paramount in determining the reliability of a systematic review. Assessing the risk of bias is critical for ensuring review quality. The presence of risk of bias and varying quality levels in included studies necessitate cautious interpretation of findings. Studies classified as "high quality" and "low risk of bias" provides more robust evidence, while those with lower quality and higher risk of bias require careful interpretation and potentially corroboration from additional high-quality studies. This review utilized the NIH tool and QUADAS-2 to assess risk of bias.30,21 The NIH tool evaluated observational studies, while QUADAS-2 focused on intervention studies. Evaluating risk of bias allowed for the identification of potentially unreliable studies and contributed to the selection of high-quality studies for data synthesis.
Our review examined ten studies exploring the efficacy of topical ocular insulin for various ocular conditions. The studies employed diverse methodologies, ranging from retrospective case series to double-blind randomized controlled trials. Despite heterogeneities in methodology, a consistent theme emerged: topical ocular insulin demonstrated promising outcomes across diverse indications, including: promoting healing of refractory neurotrophic corneal ulcers, accelerating re-epithelialization in persistent epithelial defects, reducing recurrence of recurrent epithelial erosions, improving symptoms and reducing corneal staining in dry eye disease, enhancing postoperative corneal epithelial wound healing in diabetic patients.
These findings suggest that topical ocular insulin may offer a valuable tool in managing diverse ocular pathologies, particularly those refractory to conventional therapies. Further well-designed studies are warranted to confirm these preliminary findings and establish the optimal therapeutic role of topical ocular insulin in managing various ocular diseases.