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.