May 2006
Volume 47, Issue 13
ARVO Annual Meeting Abstract  |   May 2006
Sphingolipid Metabolism is Altered in the Diabetic Retina: Possible Implications for Diabetic Retinopathy
Author Affiliations & Notes
  • T. Fox
    Penn State University, Hershey, PA
  • X. Han
    Pharmacology, Washington University, St. Louis, MO
  • A. Merrill, Jr.
    Georgia Institute of Technology, Atlanta, GA
  • R. Martin
    University of Oklahoma, Oklahoma City, OK
  • R. Anderson
    University of Oklahoma, Oklahoma City, OK
  • T. Gardner
    Penn State University, Hershey, PA
  • M. Kester
    Penn State University, Hershey, PA
  • Footnotes
    Commercial Relationships  T. Fox, None; X. Han, None; A. Merrill, None; R. Martin, None; R. Anderson, None; T. Gardner, None; M. Kester, None.
  • Footnotes
    Support  The JDRF Diabetic Retinopathy Center at Penn State University and EY015800 HIGHWIRE EXLINK_ID="47:5:4241:1" VALUE="EY015800" TYPEGUESS="GEN" /HIGHWIRE
Investigative Ophthalmology & Visual Science May 2006, Vol.47, 4241. doi:
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      T. Fox, X. Han, A. Merrill, Jr., R. Martin, R. Anderson, T. Gardner, M. Kester; Sphingolipid Metabolism is Altered in the Diabetic Retina: Possible Implications for Diabetic Retinopathy . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4241.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: : Diabetic retinopathy is a debilitating complication of diabetes and a leading cause of vision loss. Diabetic retinopathy is associated with angiogenesis and neuronal apoptosis; however the fundamental mechanisms contributing to vision loss remain undefined. Dysregulated sphingolipid metabolism has been associated with insulin resistance and cellular death in many model systems and diseases. It is thus hypothesized that diabetes alters sphingolipid metabolism contributing to neuronal pathologies in diabetic retinopathy.

Methods: : Ceramide as well as ceramide metabolites were assessed after 2, 4 and 8 weeks of streptozotocin (stz)–induced diabetes by ESI/MS/MS. Fatty acid profiles were assessed by gas chromatography. R28, a retinal neuronal cell line, was used to assess the effects of glycolipids upon insulin signaling.

Results: : After 4 and 8 weeks of stz–diabetes we observed a ∼30% decrease in total ceramide content, concomitant with a significant ∼30% increase in monohexosylceramides (cerebrosides) levels in fed diabetic rats compared to their age–matched controls. Acute insulin therapy as well as a short–term lowering of glucose via fasting did not affect the augmented flux through the glycosphingolipid biosynthetic pathway. This altered sphingolipid metabolism in diabetic retinas occurred without any significant changes of fatty acid composition from total lipid extracts, as assessed by gas chromatography. As a positive control, we observed decreases in 16:1 and 18:1 fatty acids in lipid extracts from diabetic liver. By immunohistochemistry, we demonstrated that the retina expressed glucosylceramide synthase, with strongest immunoreactivity observed within the neuronal plexiform layers and the outer segments of the photoreceptors. Treating R28 retinal neurons with N–butyldeoxyglactonojirimycin, a glucosylceramide synthase inhibitor, increased the phosphorylation of p70 S6 Kinase, an insulin responsive prosurvival kinase whose activity is decreased in diabetic retinas. Exogenous cerebrosides, GD3 and GT1b, but not lactosylceramide and GM3, induced the expression of GRP78, a marker of ER stress. GT1b also induced R28 neuronal cell cytotoxicity.

Conclusions: : It is speculated that an increase in cerebrosides, and possibly higher order glycosphingolipids could contribute to the pathogenesis of diabetic retinopathy by contributing to insulin resistance resulting in neuronal cell death.

Keywords: diabetic retinopathy • lipids • growth factors/growth factor receptors 

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