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Originally published In Press as doi:10.1074/jbc.M104738200 on July 6, 2001

J. Biol. Chem., Vol. 276, Issue 35, 32814-32821, August 31, 2001
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Insulin Rescues Retinal Neurons from Apoptosis by a Phosphatidylinositol 3-Kinase/Akt-mediated Mechanism That Reduces the Activation of Caspase-3*

Alistair J. BarberDagger §, Makoto NakamuraDagger §, Ellen B. WolpertDagger , Chad E. N. Reiter, Gail M. Seigel||, David A. AntonettiDagger , and Thomas W. GardnerDagger **

From the Departments of Dagger  Ophthalmology and  Cellular and Molecular Physiology, Penn State Retina Research Group, Penn State University College of Medicine, Hershey, Pennsylvania 17033 and the || Department of Neurobiology/Anatomy, University of Rochester, Rochester, New York 14642

The ability of insulin to protect neurons from apoptosis was examined in differentiated R28 cells, a neural cell line derived from the neonatal rat retina. Apoptosis was induced by serum deprivation, and the number of pyknotic cells was counted. p53 and Akt were examined by immunoblotting after serum deprivation and insulin treatment, and caspase-3 activation was examined by immunocytochemistry. Serum deprivation for 24 h caused ~20% of R28 cells to undergo apoptosis, detected by both pyknosis and activation of caspase-3. 10 nM insulin maximally reduced the amount of apoptosis with a similar potency as 1.3 nM (10 ng/ml) insulin-like growth factor 1, which acted as a positive control. Insulin induced serine phosphorylation of Akt, through the phosphatidylinositol (PI) 3-kinase pathway. Inhibition of PI 3-kinase with wortmannin or LY294002 blocked the ability of insulin to rescue the cells from apoptosis. SN50, a peptide inhibitor of NF-kappa B nuclear translocation, blocked the rescue effect of insulin, but neither insulin or serum deprivation induced phosphorylation of Ikappa B. These results suggest that insulin is a survival factor for retinal neurons by activating the PI 3-kinase/Akt pathway and by reducing caspase-3 activation. The rescue effect of insulin does not appear to be mediated by NF-kappa B or p53. These data suggest that insulin provides trophic support for retinal neurons through a PI 3-kinase/Akt-dependent pathway.

* This work was supported by National Institutes of Health Grant EY12021 (to T. W. G), the Juvenile Diabetes Foundation International (to T. W. G. and D. A. A.), the American Diabetes Association (to T. W. G.), The Pennsylvania Lions (to A. J. B. and D. A. A), and Mr. and Mrs. Jack Turner of Athens, GA.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors made equal contributions to the work.

** To whom correspondence should be addressed: Ulerich Ophthalmology Research Center, Department of Ophthalmology, H166, Penn State University College of Medicine, Hershey Medical Center, 500 University Dr., Hershey, PA 17033. Tel.: 717-531-5542; Fax: 717-531-7667; E-mail: tgardner@psu.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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