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Thomas W. Gardner, William Freeman, Steven F. Abcouwer, Patrice E. Fort; Local Ocular Insulin And Systemic Phloridzin Treatments Indicate That Hypoinsulinemia And Hyperglycemia Have Distinct Effects On Retinal Gene Expression In Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3588.
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© ARVO (1962-2015); The Authors (2016-present)
To determine the mechanisms by which subconjunctival insulin and systemic glucose reduction with phloridzin, a sodium-linked glucose transporter inhibitor, influence a validated mRNA biomarker panel and immunohistochemical markers for diabetic retinopathy.
Diabetic and non-diabetic control male Sprague-Dawley rats received systemic insulin by subcutaneous implants, subconjunctival injections of insulin (0.03 U/100 g body weight), or intraperitoneal injections of phloridzin (0.2 mg/100 g body weight) twice daily for the last 4 days of a 3-month experiment. Retinas were analyzed for expression mRNAs belonging to a 15-gene biomarker panel we previously demonstrated to be altered in experimental diabetic retinopathy. Assay-On-Demand gene specific primers and probes and the 2-ΔΔCt analysis method was used to quantify relative mRNA contents using ß-actin as an endogenous control. Immunohistochemistry with a GFAP-specific antibody was used to determine the effect of both treatments on diabetic-induced retinal gliosis.
Nine of 15 diabetes-induced biomarker changes were reversed after systemic insulin treatment. Subconjunctival insulin administration reversed these same changes, plus that of one additional gene in the biomarker panel. Lowering systemic glucose by phloridzin treatment reversed 8 biomarker changes. Only 5 biomarker reversals were common to both local insulin and phloridzin treatment sets. Surprisingly, combined treatment with local insulin and phloridzin reversed the responses of all 15 genes. Whereas local insulin partially reduced glial cell activation, phloridzin fully blocked this response to diabetes.
These data indicate that ocular insulin administration and systemic glucose reduction each have direct and distinct effects on retinal gene expression, and suggest that manipulating both hormone and nutrient levels may influence the development of early diabetic retinopathy.
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