Therapeutic Effects of Insulin-Like Growth Factor-1 in Hyperglycemic Retinopathy of Prematurity

Abstract

Purpose : Retinopathy of Prematurity (ROP) in preterm babies can lead to blindness. The only available therapies for ROP are ablative laser surgery or intravitreal injection anti-VEGF therapy in the second phase of ROP, both with adverse effects. Hyperglycemia in the early postnatal period in preterm infants is associated with ROP, as are reduced levels of serum Insulin-Like Growth Factor 1 (IGF-1). Increasing IGF-1 to in utero levels may help prevent complications of preterm birth including ROP. We assessed the effect of IGF-1 supplementation in a mouse model of neonatal hyperglycemia on retinal vascular development (phase I of ROP) and in hyperglycemic oxygen-induced retinopathy (phase II of ROP).

Methods : Mouse pups were injected with streptozotocin (STZ) to induce hyperglycemia in normoxic mice, and in mice subjected to oxygen-induced retinopathy (OIR). To compare normal vascular development in normoglycemic and hyperglycemic mice treated with IGF-1, normoxic mice were sacrificed on postnatal day 10 (P10) and retinal vascular density quantified. To determine if IGF-1 affected hyperglycemic/ischemic neovascularization characteristic of Phase II ROP, OIR mice were injected with vehicle or STZ ± IGF-1 and neovascularization and vasoobliteration quantified at P17. An electroretinogram (ERG) was used to assess neuroprotective effects of IGF-1. A subgroup analysis was conducted to determine if body weight affected experimental outcomes.

Results : STZ induced hyperglycemia in neonatal pups when administered daily. STZ-injected mice had a substantially less developed deep vascular network at P10 relative to normoglycemic mice (p<0.001), and IGF-1 treatment from P5-9 rescued the phenotype (p<0.05). On P17 in OIR, hyperglycemic mice had more neovascularization relative to normoglycemic mice (p<0.01), and IGF-1 decreased neovascularization (p<0.01). The body weight subgroup analysis suggested that pups with decreased body weight had more severe neovascularization in the hyperglycemic OIR model, and IGF-1 had a more profound therapeutic effect in this subgroup.

Conclusions : Administration of exogenous IGF-1 has beneficial effects on normal vascular development in hyperglycemic conditions, as well as on neovascularization in ischemic and hyperglycemic conditions. Clinically, preterm infants with low body weight and hyperglycemia may benefit most from this treatment.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.