Usage of topical insulin for the treatment of diabetic keratopathy, including corneal epithelial defects

Table 1 Summary of the key characteristics of the included animal studies

Ref.	Country	Aim	Study design	Subject groups (number)	Insulin type and dose	Results
Nakamura et al[13], 2003	Japan	To study the effect of the combination of FGLM-NH2 and IGF-1 on corneal epithelial wound healing in rats with diabetes	Animal	4-wk-old male Sprague-Dawley Streptozocin-induced diabetic rats; 100 g (n = 20)	FGLM-NH2 (1 mmol/L) and IGF-1 (1 μg/mL) 6 times per day	Similar wound healing processes were observed in normal rats and diabetic rats treated with FGLM-NH2 and IGF-1. Wound closure was significantly faster in diabetic rats treated with FGLM-NH2 and IGF-1 than in those treated with vehicle
Zagon et al[14], 2007	United States	To determine TI normalizes delayed corneal wound healing in rats with diabetes	Animal	Male Sprague-Dawley Streptozocin-induced diabetic rats; 165 g (38 diabetic rats; 11 nondiabetic rats)	Bovine insulin 1, 2, or 5 U. Single drop (20 μL)	TI normalizes corneal re-epithelialization in diabetic rats. No difference in efficacy of insulin dose of 1, 2, or 5 U and safe for cornea
Chen et al[15], 2013	United States	To determine corneal nerve depletion in type 1 diabetes rats using corneal confocal microscopy and its relationship with TI	Animal	Female Swiss Webster Streptozocin-induced diabetic mice; 25-30 g (8 diabetic mice; 8 control)	0.1 IU of regular U-100 Humulin (Lilly, Indianapolis, IN, United States) in 10 μL saline	TI prevent depletion of nerve occupancy in the subbasal nerve plexus of the cornea without affecting systemic glycemic control
Yang et al[10], 2020	China	To investigate the relationship between TI and WnT/β-catenin signaling pathway in corneal epithelial healing and corneal nerve repair in diabetic mice	Animal	Streptozocin-induced diabetic mice (6 to 8-year-old-male C57BL/6J mice)	Human neural insulin (Lilly France S.A., Fegersheim, France). 3 μL QID (1 IU/mL)	Insulin contributes to diabetic corneal epithelial wound healing and nerve injury healing via Wnt signaling, making it a potential protective factor for diabetic corneal epithelial wounds and nerve injuries

IGF-1: Insulin-like growth factor-1; FGLM-NH2: Substance P-derived tetrapeptide; TI: Topical insulin; U: Unit.

Table 2 Summary of the key characteristics of the included clinical studies

Ref.	Country	Aim	Study design	Subject groups (number)	Insulin type and dose	Results
Bastion and Ling[16], 2003	Malaysia	To determine whether TI improve healing rate of corneal epithelial erosion during vitreoretinal surgery	Retrospective review	Human (15 eyes of 14 patients underwent corneal debridement during vitreoretinal surgery)	Actrapid HM, Novo Nordisk 1 U QID (50 UI/mL)	Delayed epithelial healing in diabetic eyes compared with normal eyes. Diabetic eyes treated with TI had significantly smaller defect size than diabetic eyes treated with conventional therapy
Fai et al[3], 2017	Malaysia	To investigate the effect of 3 concentration of TI in corneal epithelial wound healing in postoperative patient with diabetes	Double blind randomized controlled	Human (32 eyes of 32 diabetic patient underwent corneal debridement during vitreoretinal surgery)	Actrapid HM, Novonordisk 0.5, 1, 2 U QID	TI 0.5 U QID is most effective for corneal re-epithelialization in patients with diabetes after vitrectomy surgery as compared with placebo and higher concentrations. TI is safe for human ocular use
Aniah Azmi and Bastion[17], 2020	Malaysia	To determine the short-term effects of TI on symptoms and signs of dry eye disease in patients with diabetes	Randomized, double-blind interventional study	Human (320 eyes of 160 patients with diabetes for treatment of dry eyes)	Actrapid HM, Novo Nordisk 1 U QID (25 UL/mL)	Similar improvement in the Ocular Surface Disease Index score for TI 1 U QID and standard artificial tears in the treatment of dry eye in patients with diabetes
Quiroz-Mendoza et al[18], 2021	Mexico	To compare the effect of TI and sodium hyaluronate in epithelial defects postoperative in patients with diabetes	Controlled human clinical trial	Human (36 eyes of 36 patients with diabetes who underwent corneal debridement during vitreoretinal surgery)	Recombinant human insulin (Humulin® R, Eli Lilly and Company, Indiana, United States) 0.5 IU/drop QID (25 IU/mL)	TI 0.5 IU/drops monotherapy and combined treatment with 0.15% sodium hyaluronate is effective in healing corneal epithelial defects after intraoperative corneal debridement in patients with diabetes. Adding sodium hyaluronate to TI did not provide additional benefit

TI: Topical insulin; U: Unit; QID: 4 times a day.