Progress in Retinal and Eye Research 22 (2003) 545–562 Functions of insulin and insulin receptor signaling in retina: possible implications for diabetic retinopathy Chad E.N. Reiter a,c , Thomas W. Gardner a,b,c, * a Department of Cellular and Molecular Physiology, The Ulerich Ophthalmology Research Center and The JDRF Diabetic Retinopathy Center at The Penn State College of Medicine, M.S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA b Department of Ophthalmology, The Ulerich Ophthalmology Research Center and The JDRF Diabetic Retinopathy Center at The Penn State College of Medicine, M.S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA c The Penn State Retina Research Group, The Ulerich Ophthalmology Research Center and The JDRF Diabetic Retinopathy Center at The Penn State College of Medicine, M.S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA Abstract Insulin action regulates the metabolic functions of the classically insulin-responsive tissues: liver, adipose, and skeletal muscle. Evidence also suggests that insulin acts on neural tissue and can modulate neural metabolism, synapse activity, and feeding behaviors. Insulin receptors are expressed on both the vasculature and neurons of the retina, but their functions are not completely defined. Insulin action stimulates neuronal development, differentiation, growth, and survival, rather than stimulating nutrient metabolism, e.g., glucose uptake as in skeletal muscle. Insulin receptors from retinal neurons and blood vessels share many similar properties with insulin receptors from other peripheral tissues, and retinal neurons express numerous proteins that are attributed to the insulin signaling cascade as in other tissues. However, undefined neuron-specific signals downstream of the insulin receptor are likely to also exist. This review compares retinal insulin action to that of peripheral tissues, and demonstrates that the retina is an insulin-sensitive tissue. The review also addresses the hypothesis that dysfunctional insulin receptor signaling in the retina contributes to cell dysfunction and death in retinal diseases. r 2003 Elsevier Science Ltd. All rights reserved. Keywords: Insulin; Insulin receptor; Retina; Diabetic retinopathy Contents 1. Introduction to the insulin signaling pathway ............................... 546 2. Properties of retinal insulin receptors .................................... 548 3. Insulin in the retina ............................................. 550 3.1. Insulin and the blood–retina barrier ................................. 550 3.2. Retinal insulin production ...................................... 551 3.3. Insulin signaling in Caenorhabditis elegans and Drosophila melanogaster .............. 552 4. Retinal insulin signaling .......................................... 554 5. Insulin and insulin receptors in retinal diseases .............................. 555 6. Conclusions and future directions ..................................... 558 Acknowledgements ............................................... 558 References .................................................... 558 *Corresponding author: Department of Ophthalmology, Penn State University, College of Medicine, 500 University Drive, H097, Hershey, PA 17033, USA. Tel.: +1-717-531-8783; fax: +1-717-531-7667. E-mail address: tgardner@psu.edu (T.W. Gardner). 1350-9462/03/$-see front matter r 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S1350-9462(03)00035-1