|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 276, Issue 47, 43748-43755, November 23, 2001
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the Pennsylvania State Retina Research Group, The Ulerich
Ophthalmology Research Center, the Departments of
In addition to microvascular
abnormalities, neuronal apoptosis occurs early in diabetic retinopathy,
but the mechanism is unknown. Insulin may act as a neurotrophic factor
in the retina via the phosphoinositide 3-kinase/Akt pathway. Excessive
glucose flux through the hexosamine biosynthetic pathway (HBP) is
implicated in the development of insulin resistance in peripheral
tissues and diabetic complications such as nephropathy. We tested
whether increased glucose flux through the HBP perturbs insulin action and induces apoptosis in retinal neuronal cells. Exposure of R28 cells,
a model of retinal neurons, to 20 mM glucose for
24 h attenuated the ability of 10 nM insulin to rescue
them from serum deprivation-induced apoptosis and to phosphorylate Akt
compared with 5 mM glucose. Glucosamine not only impaired
the neuroprotective effect of insulin but also induced apoptosis in R28
cells in a dose-dependent fashion. UDP-N-acetylhexosamines (UDP-HexNAc), end products of the
HBP, were increased ~2- and 15-fold after a 24-h incubation in 20 mM glucose and 1.5 mM glucosamine,
respectively. Azaserine, a glutamine:fructose-6-phosphate amidotransferase inhibitor, reversed the effect of 20 mM
glucose, but not that of 1.5 mM glucosamine, on attenuation
of the ability of insulin to promote cell survival and phosphorylate
Akt as well as accumulation of UDP-HexNAc. Glucosamine also impaired
insulin receptor processing in a dose-dependent manner but
did not decrease ATP content. By contrast, in L6 muscle cells,
glucosamine impaired insulin receptor processing but did not induce
apoptosis. These results suggest that the excessive glucose flux
through the HBP may direct retinal neurons to undergo apoptosis in a
bimodal fashion; i.e. via perturbation of the
neuroprotective effect of insulin mediated by Akt and via induction of
apoptosis possibly by altered glycosylation of proteins. The HBP may be
involved in retinal neurodegeneration in diabetes.
Excessive Hexosamines Block the Neuroprotective Effect of
Insulin and Induce Apoptosis in Retinal Neurons*
,,§,§
Ophthalmology and § Cellular and Molecular
Physiology, Pennsylvania State University College of Medicine,
Hershey, Pennsylvania 17033 and ¶ Division of Endocrinology,
Diabetes and Medical Genetics, Department of Medicine, Medical
University of South Carolina, Charleston, South Carolina 29425
*
This work was supported by the Pennsylvania Lions Sight
Conservation and Eye Research Foundation (to M. N.), National
Institutes of Health Grants EY12021 (to T. W. G.) and DK02001 (to
M. G. B.), Juvenile Diabetes Research Foundation (to T. W. G.,
D. A. A., and K. F. L), American Diabetes Association (to
T. W. G.), Research to Prevent Blindness, and Jack and Nancy
Turner, 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.
To whom correspondence should be addressed: Ulerich
Ophthalmology Research Center, Dept. of Ophthalmology, H166,
Pennsylvania State University College of Medicine, 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.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  H. W. van Dijk, P. H. B. Kok, M. Garvin, M. Sonka, J. H. DeVries, R. P. J. Michels, M. E. J. van Velthoven, R. O. Schlingemann, F. D. Verbraak, and M. D. Abramoff Selective Loss of Inner Retinal Layer Thickness in Type 1 Diabetic Patients with Minimal Diabetic Retinopathy Invest. Ophthalmol. Vis. Sci., July 1, 2009; 50(7): 3404 - 3409. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Luo, Y. Soesanto, and D. A. McClain Protein Modification by O-Linked GlcNAc Reduces Angiogenesis by Inhibiting Akt Activity in Endothelial Cells Arterioscler. Thromb. Vasc. Biol., April 1, 2008; 28(4): 651 - 657. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. E. Fox, X. Han, S. Kelly, A. H. Merrill Jr., R. E. Martin, R. E. Anderson, T. W. Gardner, and M. Kester Diabetes Alters Sphingolipid Metabolism in the Retina: A Potential Mechanism of Cell Death in Diabetic Retinopathy Diabetes, December 1, 2006; 55(12): 3573 - 3580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Antonetti, A. J. Barber, S. K. Bronson, W. M. Freeman, T. W. Gardner, L. S. Jefferson, M. Kester, S. R. Kimball, J. K. Krady, K. F. LaNoue, et al. Diabetic Retinopathy: Seeing Beyond Glucose-Induced Microvascular Disease Diabetes, September 1, 2006; 55(9): 2401 - 2411. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Ola, D. A. Berkich, Y. Xu, M. T. King, T. W. Gardner, I. Simpson, and K. F. LaNoue Analysis of glucose metabolism in diabetic rat retinas Am J Physiol Endocrinol Metab, June 1, 2006; 290(6): E1057 - E1067. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E.N. Reiter, X. Wu, L. Sandirasegarane, M. Nakamura, K. A. Gilbert, R. S.J. Singh, P. E. Fort, D. A. Antonetti, and T. W. Gardner Diabetes reduces Basal retinal insulin receptor signaling: reversal with systemic and local insulin. Diabetes, April 1, 2006; 55(4): 1148 - 1156. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Kniep, C. Roehlecke, N. Ozkucur, A. Steinberg, F. Reber, L. Knels, and R. H. W. Funk Inhibition of Apoptosis and Reduction of Intracellular pH Decrease in Retinal Neural Cell Cultures by a Blocker of Carbonic Anhydrase. Invest. Ophthalmol. Vis. Sci., March 1, 2006; 47(3): 1185 - 1192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Cooksey, S. Pusuluri, M. Hazel, and D. A. McClain Hexosamines regulate sensitivity of glucose-stimulated insulin secretion in {beta}-cells Am J Physiol Endocrinol Metab, February 1, 2006; 290(2): E334 - E340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Zhou, B. K. Deo, K. Hosoya, T. Terasaki, I. G. Obrosova, F. C. Brosius III, and A. K. Kumagai Increased JNK Phosphorylation and Oxidative Stress in Response to Increased Glucose Flux through Increased GLUT1 Expression in Rat Retinal Endothelial Cells Invest. Ophthalmol. Vis. Sci., September 1, 2005; 46(9): 3403 - 3410. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Cacicedo, S. Benjachareowong, E. Chou, N. B. Ruderman, and Y. Ido Palmitate-Induced Apoptosis in Cultured Bovine Retinal Pericytes: Roles of NAD(P)H Oxidase, Oxidant Stress, and Ceramide Diabetes, June 1, 2005; 54(6): 1838 - 1845. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E Tian, K. G. T. Hagen, L. Shum, H. C. Hang, Y. Imbert, W. W. Young Jr, C. R. Bertozzi, and L. A. Tabak An Inhibitor of O-Glycosylation Induces Apoptosis in NIH3T3 Cells and Developing Mouse Embryonic Mandibular Tissues J. Biol. Chem., November 26, 2004; 279(48): 50382 - 50390. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Seki, T. Tanaka, H. Nawa, T. Usui, T. Fukuchi, K. Ikeda, H. Abe, and N. Takei Involvement of Brain-Derived Neurotrophic Factor in Early Retinal Neuropathy of Streptozotocin-Induced Diabetes in Rats: Therapeutic Potential of Brain-Derived Neurotrophic Factor for Dopaminergic Amacrine Cells Diabetes, September 1, 2004; 53(9): 2412 - 2419. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Yu, R. V. S. Rajala, J. F. McGinnis, F. Li, R. E. Anderson, X. Yan, S. Li, R. V. Elias, R. R. Knapp, X. Zhou, et al. Involvement of Insulin/Phosphoinositide 3-Kinase/Akt Signal Pathway in 17{beta}-Estradiol-mediated Neuroprotection J. Biol. Chem., March 26, 2004; 279(13): 13086 - 13094. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Wu, C. E. N. Reiter, D. A. Antonetti, S. R. Kimball, L. S. Jefferson, and T. W. Gardner Insulin Promotes Rat Retinal Neuronal Cell Survival in a p70S6K-dependent Manner J. Biol. Chem., March 5, 2004; 279(10): 9167 - 9175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E. N. Reiter, L. Sandirasegarane, E. B. Wolpert, M. Klinger, I. A. Simpson, A. J. Barber, D. A. Antonetti, M. Kester, and T. W. Gardner Characterization of insulin signaling in rat retina in vivo and ex vivo Am J Physiol Endocrinol Metab, October 1, 2003; 285(4): E763 - E774. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Assa-Kunik, D. Fishman, S. Kellman-Pressman, S. Tsory, S. Elhyany, O. Baharir, and S. Segal Alterations in the Expression of MHC Class I Glycoproteins by B16BL6 Melanoma Cells Modulate Insulin Receptor-Regulated Signal Transduction and Augments Resistance to Apoptosis J. Immunol., September 15, 2003; 171(6): 2945 - 2952. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Pang, D. L. Hunton, P. Bounelis, and R. B. Marchase Hyperglycemia Inhibits Capacitative Calcium Entry and Hypertrophy in Neonatal Cardiomyocytes Diabetes, December 1, 2002; 51(12): 3461 - 3467. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Vosseller, L. Wells, M. D. Lane, and G. W. Hart Elevated nucleocytoplasmic glycosylation by O-GlcNAc results in insulin resistance associated with defects in Akt activation in 3T3-L1 adipocytes PNAS, April 16, 2002; 99(8): 5313 - 5318. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |