Embryonic hyperglycemia perturbs the development of specific retinal cell types, including photoreceptors

Abstract

Chronic hyperglycemia has been linked to various long-term metabolic disruptions in adults, such as neuropathy, nephropathy, and diabetic retinopathy. According to the 2020 National Diabetes Statistics Report, 10.5% of the US population has diabetes and may be susceptible to long-term complications if blood glucose is not tightly regulated. Further, in 2018, 7.6% of US pregnancies were affected by gestational diabetes, with an average of 1-14% annually. During pregnancy, glucose can pass through the placental barrier, and plays an important role in fetal development and survival. However, excess maternal glucose can also result in diabetic embryopathy. While many studies have examined the teratogenic effects of maternal diabetes on fetal heart development, little is known about the consequences of maternal hyperglycemia on the development of the embryonic retina. To address this question, we investigated retinal cell type differentiation and survival in both a genetic and nutritional model of embryonic hyperglycemia in zebrafish. Strikingly, we found that hyperglycemic larvae displayed a significant reduction in rod and cone photoreceptors and horizontal cells, whereas other retinal neurons were not affected. We also observed signs of reactive gliosis in the retinal Müller cells, as well as increased reactive oxygen species (ROS) production in hyperglycemic retinas. Hyperglycemic larvae displayed altered expression of metabolism related genes and had a slower optokinetic response than normoglycemic larvae, indicating altered visual function. Further analysis of early events in retinogenesis revealed a delay in retinal cell differentiation at 48 hpf in hyperglycemic embryos, that coincided with an increase in reactive oxygen species. Taken together, our results suggest that embryonic hyperglycemia results in abnormal retinal cell development via altered timing of retinal cell differentiation and ROS production, which is accompanied by visual defects. As the population with diabetes continues to grow, it is imperative to pinpoint the effects of embryonic hyperglycemia on retinal development. Further studies using zebrafish models of hyperglycemia will allow us to understand the molecular mechanisms underlying these effects, which could aid in the development of therapeutic strategies.