Overall, we found that high plasma glucose levels and signs of insulin insensitivity during early postnatal life were associated with lower postnatal IGF-1 levels and increased risk of ROP. These findings were replicated in a neonatal hyperglycemia OIR mouse model also demonstrating that decreased insulin signaling suppressed liver production of IGF-I resulting in lower serum IGF-I levels and increased neovascularization in mouse OIR. IGF-1 supplementation improved revascularization and decreased pathological angiogenesis. The data further supports the use of IGF-1 supplementation as a potential treatment in hyperglycemic preterm infants to prevent ROP.