Our objective is to elucidate the role of hormones in modulating diabetes-induced increases in vascular permeability and polyol metabolism in the eye. The general hypothesis to be tested by the proposed experiments is that diabetic retinopathy is an aldose reductase-linked phenomenon and the reason it is much less common in pre- than in post-pubertal diabetics is that tissue levels/activity of aldose reductase are increased by sex steroids at the time of puberty. The experiments described are designed to: 1) assess the role of imbalances in sorbitol/inositol metabolism in the pathogenesis of diabetes-induced increases in 125I-albumin permeation of the retina and in selected extraocular vessels with emphasis on a new model of angiogenesis (granulation tissue vessels) in subcutaneous tissues of diabetic rats, and 2) investigate the role of sex steroids, insulin, and selected other hormones in modulating the development of diabetic cataracts as well as diabetes-induced increases in vascular permeability and imbalances in sorbitol/inositol metabolism in various tissues of the eye and in new (granulation tissue) vessels formed in the diabetic milieu. The importance of this research is that the information obtained should provide important new insights regarding the role of hormones in the pathogenesis of diabetes-induced injury to the retinal vasculature and neural elements. This new information could provide the rationale for new therapeutic approaches for implementation of our long range goal of preventing diabetic vascular disease. Delineation of the role of sex steroids, insulin, corticosteroids, and growth hormone in the pathogenesis of diabetic ocular disease will indicate whether future research should be focused on efforts to modulate the production and/or effects of the implicated hormone on target tissues in order to prevent the complications. Demonstration of the utility of this animal model for investigating the pathogenesis of human diabetic retinopathy would greatly expedite the progress of research, not only in elucidating the pathogenesis of diabetic retinopathy but also in developing and testing new therapeutic approaches and pharmacologic agents designed to prevent such complications.
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