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R. J. Walker, Y. Jiang, J. J. Steinle; Beta-Adrenergic Receptor Agonist Prevents Loss of Insulin Signaling in Diabetic Retina in vivo. Invest. Ophthalmol. Vis. Sci. 2009;50(13):22.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the acute and chronic effects of the regulation of insulin signaling by isoproterenol eye drop application in the retina of diabetic rats.
Rats were made diabetic by a single injection of 60mg/kg streptozotocin (STZ) dissolved in citrate buffer. Diabetic animals were characterized as having a glucose level >200mg/dl within 3 days of STZ injection. In the present studies, 3 different groups of rats used. The first group (control group) received citrate buffer only. The second group of animals received only the STZ injection, while the third group consisted of animals that were diabetic and received isoproterenol eye drops for 2months (acute) or 8months (chronic). The eye drop application of isoproterenol, a non-specific beta-adrenergic receptor agonist, was once every 24 hours at a concentration of 50mM doses. Following the conclusion of 2 months and 8 months of eye drop application, the eyes were enucleated and used for Western blot analyses of phosphorylated and total insulin receptor beta (IRB), insulin-like growth factor receptor (IGF-1R), and Akt. ELISA analyses were also done for cleaved caspase 3.
Changes in glucose environments (due to the induction of diabetes through the STZ injection) significantly decreased insulin receptor beta phosphorylation in the retina of diabetic rats, but isoproterenol eye drops were able to negate this loss of insulin receptor activity at both time points. Results suggest that no significant changes in IGF-1R activity occur in any group over the entire time period. In the chronic time period, diabetic animals showed a significant decrease in Akt activity, suggesting loss of an anti-apoptotic signal. With eye drop application, Akt levels were significantly increased versus diabetic rats to levels similar to control animals. At 2 months of diabetes, no significant changes in Akt activity were noted among the groups. Caspase 3 levels showed a significant decrease following application of eye drops in both the acute and chronic time courses.
These results suggest that induction of diabetes results in a loss of insulin receptor beta and Akt phosphorylation, leading to increases in caspase 3 levels in the retina. Eye drop application of isoproterenol, a non-specific beta agonist, in both acute and chronic time courses was able to negate these deleterious changes in phosphorylation of the insulin signaling pathway during diabetes in rats. These studies indicate that use of eye drop therapy is effective in modulating retinal physiology. Furthermore, eye drop therapy of beta-adrenergic receptor agonists can regulate insulin signaling in the diabetic retina, likely preventing retinal pathology.
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