Insulin insensitivity in very preterm infants is associated with decreased levels of IGF-1 and increased risk for ROP

Abstract

Purpose : Hyperglycemia with insulin insensitivity is a common problem in preterm infants receiving parenteral nutrition. We conducted a prospective longitudinal study in preterm infants and developed an early hyperglycemic murine retinopathy model to investigate the role of insulin insensitivity on ROP.

Methods : 51 preterm infants with a median gestational age at birth of 26 weeks and birth weight of 846g were included. Daily plasma glucose and parenteral glucose intake were recorded from birth to postnatal day 21; blood sampling for IGF-1, insulin and c-peptide quantification was done weekly from birth through postnatal week (PNW) 5. For the murine study mice were injected with STZ or PBS once daily from P2-12 and exposed to 75% oxygen from P7-12. Mice were returned to room air and retinas were isolated at P12 and 17 for quantification of vaso-obliteration (VO) and neovascularization (NV). At P7, 12 and 17 blood and liver samples were collected for glucose, IGF-1, IGFBP-1, IGFBP-3 and FGF21 assessment.

Results : Mean plasma glucose concentrations during the 1st week of life were divided into tertiles; T_low, T_intermediate and T_high . The ratio between mean plasma glucose and parenteral plasma glucose intake during the 1st week of life was higher in the T_high group compared to the T_low group (p=0.0048). Insulin and c-peptide levels were elevated in the T_high group with significant difference to the T_low group at PNW 4 and 5. IGF-1 plasma levels were significantly lower in the T_high group compared to the T_low group during PNW 3-5. The frequency of infants with ROP was higher in the T_high and T_intermediate group compared to the T_low group (n=13 and 4 vs. n=2). In the mouse model STZ treated mice had lower IGF-1 (P7, P12 and P17) and FGF21 (P12) expression. NV and VO at P17 were increased in the STZ group (p=0.04 and p=0.001). VO was unchanged at P12.

Conclusions : Preterm infants with higher plasma glucose levels during early postnatal life show evidence of decreased insulin sensitivity. This was associated with later low IGF-1 levels and increased risk for ROP. The neonatal hyperglycaemic mice model with suppressed insulin production showed decreased hepatic IGF-1 and FGF21 expression with impaired vascular regrowth and increased NV, similar to the clinical findings. Overall this study underlines the importance of insulin-mediated hepatic IGF-1 production and its impact on phase 1 ROP.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.