Vascular complications in diabetes mellitus are the result of metabolic and hormonal abnormalities caused by insulin deficiency. The identification of specific factors and the mechanisms by which they can cause vascular cell dysfunction and subsequent pathologies is very important in the treatment of diabetic patients. Several mechanisms by which hyperglycemia can adversely affect vascular cell function have been postulated. We have been investigating the particular effect of hyperglycemia on increasing levels of diacylglycerol (DAG) and protein Kinase C (PKC) in tissue cultured vascular cells, in retinal vascular tissue from the diabetic rat, and the effect of PKC elevations on retinal blood flow. Retinal blood flow was measured using our video fluorescein angiography (VFA) system. We have demonstrated decreased retinal blood flow in the early stages of diabetes in both humans and in different diabetic rat models. More importantly, we have shown a direct relationship between decreased retinal blood flow in the rat and the activation of PKC. These results provide evidence linking biochemical alterations caused by hyperglycemia with functional changes in retinal circulation in early diabetes. The studies proposed here will focus on characterizing the relationship between DAG and PKC levels, assayed from blood samples, and retinal blood flow changes in Type I insulin dependent diabetic patients with different levels of diabetic retinopathy. Diabetic patients will be studied cross- sectionally from onset of diabetes through the development and progression of diabetic retinopathy. The results from these studies will aid in our understanding of the mode of action of PKC, at a cellular and physiological level, in affecting retinal blood flow changes and the development of retinal vascular complications in diabetic patients. The elucidation of the natural history of these changes in early diabetes will aid in possible future inhibition therapies for treating diabetic patients.
| Higashi, S; Clermont, A C; Dhir, V et al. (1998) Reversibility of retinal flow abnormalities is disease-duration dependent in diabetic rats. Diabetes 47:653-9 |
| Bursell, S E; Takagi, C; Clermont, A C et al. (1997) Specific retinal diacylglycerol and protein kinase C beta isoform modulation mimics abnormal retinal hemodynamics in diabetic rats. Invest Ophthalmol Vis Sci 38:2711-20 |
| Clermont, A C; Aiello, L P; Mori, F et al. (1997) Vascular endothelial growth factor and severity of nonproliferative diabetic retinopathy mediate retinal hemodynamics in vivo: a potential role for vascular endothelial growth factor in the progression of nonproliferative diabetic retinopathy. Am J Ophthalmol 124:433-46 |
| Shiba, T; Inoguchi, T; Sportsman, J R et al. (1993) Correlation of diacylglycerol level and protein kinase C activity in rat retina to retinal circulation. Am J Physiol 265:E783-93 |
