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Characterization of insulin signaling in rat retina in vivo and ex vivo

Departments of ¹Cellular and Molecular Physiology, ²Pharmacology, ³Ophthalmology, ⁴Neuroscience and Anatomy, and ⁵The Penn State Retina Research Group, Ulerich Ophthalmology Research Center and Juvenile Diabetes Research Foundation Diabetic Retinopathy Center at Pennsylvania State University, The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033

Submitted 19 November 2002 ; accepted in final form 8 June 2003

Insulin receptor (IR) signaling cascades have been studied in many tissues, but retinal insulin action has received little attention. Retinal IR signaling and activity were investigated in vivo in rats that were freely fed, fasted, or injected with insulin by phosphotyrosine immunoblotting and by measuring kinase activity. A retina explant system was utilized to investigate the IR signaling cascade, and immunohistochemistry was used to determine which retinal cell layers respond to insulin. Basal IR activity in the retina was equivalent to that in brain and significantly greater than that of liver, and it remained constant between freely fed and fasted rats. Furthermore, IR signaling increased in the retina after portal vein administration of supraphysiological doses of insulin. Ex vivo retinas responded to 10 nM insulin with IR -subunit (IR) and IR substrate-2 (IRS-2) tyrosine phosphorylation and Akt^Ser473 phosphorylation. The retina expresses mRNA for all three Akt isoforms as determined by in situ hybridization, and insulin specifically increases Akt-1 kinase activity. Phospho-Akt^Ser473 immunoreactivity increases in retinal nuclear cell layers with insulin treatment. These results demonstrate that the retinal IR signaling cascade to Akt-1 possesses constitutive activity, and that exogenous insulin further stimulates this prosurvival pathway. These findings may have implications in understanding normal and dysfunctional retinal physiology.

insulin receptor; Akt; diabetic retinopathy

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