Hyperglycemia may influence ROP through its signifi- cant effect on retinal blood flow [21]. In diabetic rats, reduction of glucose levels resulted in an improvement in retinal blood flow when compared to diabetic rats who remained hyperglycemic [22]. Additionally, hyperglycemia has been shown to increase the formation of diacylglycerol, which in turn increases activation of protein kinase C. Protein kinase C has been shown to have an effect on many different growth factors, such as vascular endothelial growth factor (VEGF), which impacts angiogenesis and vascular permeability [23]. Hyperglycemia, in hypoxic culture conditions, has also been shown to increase VEGF production in retinal Müller cells [24]. Additionally, in an in vitro assay of VEGF production in cultured bovine retinal pigmented epithelial cells, it was shown that those cells that were exposed to a prolonged period of hypergly- cemia had significantly elevated level of VEGF production
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when compared to controls [25]. While the factors that lead to the progression of ROP are not well understood, it is possible that the duration of hyperglycemia is a factor in the initiation of ROP, but other factors such as oxygen exposure and genetics have a more critical role in influencing the factors that are involved in the progression of the disease. As such, duration of hyperglycemia could potentially be more of a risk factor for the development of mild (Stage I) or moderate (Stage II) ROP rather than severe (Stage III) ROP.
Our study is limited due to its retrospective nature. Although we have shown an association between hyper- glycemia and the development of ROP, we have not presented evidence that is suggestive of causation. The question remains whether hyperglycemia itself is a definitive risk factor, or is a marker of significant illness. We did adjust for other known risk factors which are markers for more severe illness, but the possibility of residual confounders is likely. However, using proliferative diabetic retinopathy as a model of a proliferative vascular retinal disease, it has been shown that hyperglycemia has a significant impact on the development and progression of the disease.