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1 Department of Cellular and Molecular Physiology, Penn State University, The Ulerich Ophthalmology Research Center and The JDRF Diabetic Retinopathy Center, Hershey, PA, USA; Penn State Research Group, Penn State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, PA, USA
2 Department of Pharmacology, Penn State University, The Ulerich Ophthalmology Research Center and The JDRF Diabetic Retinopathy Center, Hershey, PA, USA
3 Department of Ophthalmology, Penn State University, The Ulerich Ophthalmology Research Center and The JDRF Diabetic Retinopathy Center, Hershey, PA, USA; Penn State Research Group, Penn State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, PA, USA
4 Department of Neuroscience and Anatomy, Penn State University, The Ulerich Ophthalmology Research Center and The JDRF Diabetic Retinopathy Center, Hershey, PA, USA
5 Department of Cellular and Molecular Physiology, Penn State University, The Ulerich Ophthalmology Research Center and The JDRF Diabetic Retinopathy Center, Hershey, PA, USA; Department of Ophthalmology, Penn State University, The Ulerich Ophthalmology Research Center and The JDRF Diabetic Retinopathy Center, Hershey, PA, USA; Penn State Research Group, Penn State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, PA, USA
* To whom correspondence should be addressed. E-mail: tgardner{at}psu.edu.
Insulin receptor (IR) signaling cascades have been studied in many tissues, but retinal insulin action has received little attention. Retinal IR signaling and activity was investigated in vivo in rats that were freely fed, fasted, or injected with insulin, by phosphotyrosine (PY) 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 remained constant between freely fed and fasted rats. Furthermore, IR signaling increased in the retina following portal vein administration of superphysiological doses of insulin. Ex vivo retinas responded to 10 nM insulin with IR
subunit (IR) and IRS-2 tyrosine phosphorylation and Aktser473 phosphorylation. The retina expresses mRNA for all 3 Akt isoforms as determined by in situ hybridization, and insulin specifically increases Akt-1 kinase activity. Phospho-Aktser473 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 pro-survival pathway. These findings may have implications in understanding normal and dysfunctional retinal physiology.
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