exposure was shown to be associated with higher stages of ROP [15]. In our study, we have shown that the duration of hyperglycemia is a significant risk factor in the develop- ment of ROP, with each day of hyperglycemia increasing the risk by 7% in a population of ELBW infants who did not receive insulin therapy. Studying infants who did not receive insulin therapy allowed us to investigate the role of hyperglycemia in the incidence of ROP independently of insulin exposure. Our study also shows that duration of hyperglycemia is associated with ROP, building on previous studies that chose highest glucose at one time point to define hyperglycemia.
Interestingly, however, we were unable to establish an association between duration of hyperglycemia and severe (Stage III) ROP. Utilizing two different multiple logistic regression models, duration of hyperglycemia was found to not be associated with the development of severe (Stage III) ROP. This is in contrast to Garg et al’s study, where hyperglycemia, as defined by highest measured blood glucose in the first month of life, was found to be associated with the development of Stage III or IV ROP, although they specifically chose to study the impact of glucose on Stages III and IV and included infants with Stage I in the control group of their case–control study. Similar to our results, they also demonstrated a significantly higher number of days with glucose measurements of > 150 mg/ dl among patients with ROP (8.4 days vs. 5.3 days, p = 0.028), but did not include duration of hyperglycemia in multivariable analysis [14].
In adults, hyperglycemia has been shown to play a significant role in the development of proliferative diabetic retinopathy [19]. Like ROP, proliferative diabetic retinopathy is characterized by the development of new blood vessels in the retina that can extend into the vitreous of the eye. Additionally, similar to severe ROP, retinal detachment can occur due to the fibrous contractile tissue that is formed [20].
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
Page 4 of 5
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.
exposure was shown to be associated with higher stages of ROP [15]. In our study, we have shown that the duration of hyperglycemia is a significant risk factor in the develop- ment of ROP, with each day of hyperglycemia increasing the risk by 7% in a population of ELBW infants who did not receive insulin therapy. Studying infants who did not receive insulin therapy allowed us to investigate the role of hyperglycemia in the incidence of ROP independently of insulin exposure. Our study also shows that duration of hyperglycemia is associated with ROP, building on previous studies that chose highest glucose at one time point to define hyperglycemia.Interestingly, however, we were unable to establish an association between duration of hyperglycemia and severe (Stage III) ROP. Utilizing two different multiple logistic regression models, duration of hyperglycemia was found to not be associated with the development of severe (Stage III) ROP. This is in contrast to Garg et al’s study, where hyperglycemia, as defined by highest measured blood glucose in the first month of life, was found to be associated with the development of Stage III or IV ROP, although they specifically chose to study the impact of glucose on Stages III and IV and included infants with Stage I in the control group of their case–control study. Similar to our results, they also demonstrated a significantly higher number of days with glucose measurements of > 150 mg/ dl among patients with ROP (8.4 days vs. 5.3 days, p = 0.028), but did not include duration of hyperglycemia in multivariable analysis [14].In adults, hyperglycemia has been shown to play a significant role in the development of proliferative diabetic retinopathy [19]. Like ROP, proliferative diabetic retinopathy is characterized by the development of new blood vessels in the retina that can extend into the vitreous of the eye. Additionally, similar to severe ROP, retinal detachment can occur due to the fibrous contractile tissue that is formed [20].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 productionPage 4 of 5when 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.
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