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R. S. Singh, G. P. Misra, C. E. N. Reiter, H. D. VanGuilder, A. J. Barber, T. L. Lowe, T. W. Gardner; Periocular Insulin Improves Metabolic and Protein Defects of Early Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5807.
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We have previously reported insulin receptor signaling defects in the retina of diabetic rats and mice. Therefore, we tested the hypothesis that periocular delivery of insulin to the retina of diabetic rats, in doses that do not alter blood glucose levels, will prevent or treat early diabetic retinopathy.
Regular human insulin over a dose range of 0.01U to 1U was injected subconjunctivally in control and 1 month diabetic male Sprague Dawley (SD) rats. Insulin-loaded hydrogels were designed for subconjunctival implantation to provide low levels of insulin to the retina for prolonged periods. The hydrogels were engineered to be thermoresponsive and hydrolytically degradable, and their pharmacokinetic and pharmacodynamic properties were studied in vitro and in vivo using R 28 cells in culture and SD rats respectively. The biological effects of subconjunctival insulin on the retina were analyzed using immunoblotting, kinase assays and immunohistochemical analysis.
The optimal dose of subconjunctivally administered insulin that stimulates the pro survival insulin signaling pathway in the retina, without having any effect on the contralateral uninjected eye or systemic blood glucose levels, was determined to be 0.0325 U/100g. This low-dose of subconjunctival insulin reaches the retina where it normalizes synaptic protein and c-Jun N-terminal Kinase expression (p <0.05). Insulin-loaded hydrogels release low amounts of biologically active insulin for over a month and are non-toxic to cells in culture and are well tolerated by rat eyes after subconjunctival implantation, and do not induce inflammatory response.
Subconjunctivally delivered insulin ameliorates degenerative and inflammatory responses in diabetic rat retinas. Insulin-loaded hydrogels with thermoresponsive and biodegradable properties may provide adjunctive therapy to the retina in diabetes.
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