The Insulin-Like Growth Factor System and Muller Cells

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DESCRIPTION (provided by applicant): Proliferative diabetic retinopathy and the fibrocontractive processes that cause retinal detachment are, in the end, cellular diseases in that they arise from the varied activities of individual cells. Muller cells, the principal retinal glia, are physically associated with fibrovascular scar and are capable of generating tractional forces of the type that cause retinal detachment. Recent studies from this and other laboratories indicate that two essential Muller cell activities, proliferation and tractional force generation, are stimulated by insulin-like growth factors and more recent studies indicate that vitreous insulin-like growth factor activities are elevated in diabetes. Interestingly, diabetes-associated increases in vitreous insulin-like growth factor activities cannot be explained by increases in growth factor concentration alone, suggesting the involvement of more complex mechanisms. Our studies of insulin-like growth factor binding protein effects on insulin-like growth factor-stimulated Muller cells suggest that vitreous insulin-like growth factor binding proteins can, under normal conditions, function as a growth factor sink and that diabetes-associated changes contribute to net increases in insulin-like growth factor activities. These studies also place increased emphasis on the involvement of insulin-like growth factor binding protein-3, an abundant binding protein in vitreous and the most effective inhibitor of insulin-like growth factor effects. The current study considers vitreous-specific modifications to insulin-like growth factor binding protein-3, the effects of these modifications on biological activities, the ability of insulin-like growth factor binding proteins to regulate fibroproliferative responses and the origins of vitreous growth factor activities in diabetes. Information gained from this study will improve our understanding of fibrocontractive retinal diseases and should represent a significant gain toward control of proliferative complications associated with diabetic retinopathy.