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Research Articles, Neurobiology of Disease

Reduction of Glut1 in the Neural Retina But Not the RPE Alleviates Polyol Accumulation and Normalizes Early Characteristics of Diabetic Retinopathy

Nicholas C. Holoman, Jacob J. Aiello, Timothy D. Trobenter, Matthew J. Tarchick, Michael R. Kozlowski, Emily R. Makowski, Darryl C. De Vivo, Charandeep Singh, Jonathan E. Sears and Ivy S. Samuels
Journal of Neuroscience 7 April 2021, 41 (14) 3275-3299; DOI: https://doi.org/10.1523/JNEUROSCI.2010-20.2021
Nicholas C. Holoman
1Research Service, Veterans Administration Northeast Ohio Healthcare System, Cleveland, Ohio 44106
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Jacob J. Aiello
1Research Service, Veterans Administration Northeast Ohio Healthcare System, Cleveland, Ohio 44106
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Timothy D. Trobenter
1Research Service, Veterans Administration Northeast Ohio Healthcare System, Cleveland, Ohio 44106
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Matthew J. Tarchick
1Research Service, Veterans Administration Northeast Ohio Healthcare System, Cleveland, Ohio 44106
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Michael R. Kozlowski
1Research Service, Veterans Administration Northeast Ohio Healthcare System, Cleveland, Ohio 44106
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Emily R. Makowski
1Research Service, Veterans Administration Northeast Ohio Healthcare System, Cleveland, Ohio 44106
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Darryl C. De Vivo
3Department of Neurology, Columbia University Irving Medical Center, New York, New York 10032
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Charandeep Singh
2Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio 44195
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Jonathan E. Sears
2Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio 44195
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Ivy S. Samuels
1Research Service, Veterans Administration Northeast Ohio Healthcare System, Cleveland, Ohio 44106
2Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio 44195
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Abstract

Hyperglycemia is a key determinant for development of diabetic retinopathy (DR). Inadequate glycemic control exacerbates retinopathy, while normalization of glucose levels delays its progression. In hyperglycemia, hexokinase is saturated and excess glucose is metabolized to sorbitol by aldose reductase via the polyol pathway. Therapies to reduce retinal polyol accumulation for the prevention of DR have been elusive because of low sorbitol dehydrogenase levels in the retina and inadequate inhibition of aldose reductase. Using systemic and conditional genetic inactivation, we targeted the primary facilitative glucose transporter in the retina, Glut1, as a preventative therapeutic in diabetic male and female mice. Unlike WT diabetics, diabetic Glut1+/− mice did not display elevated Glut1 levels in the retina. Furthermore, diabetic Glut1+/− mice exhibited ameliorated ERG defects, inflammation, and oxidative stress, which was correlated with a significant reduction in retinal sorbitol accumulation. Retinal pigment epithelium-specific reduction of Glut1 did not prevent an increase in retinal sorbitol content or early hallmarks of DR. However, like diabetic Glut1+/− mice, reduction of Glut1 specifically in the retina mitigated polyol accumulation and diminished retinal dysfunction and the elevation of markers for oxidative stress and inflammation associated with diabetes. These results suggest that modulation of retinal polyol accumulation via Glut1 in photoreceptors can circumvent the difficulties in regulating systemic glucose metabolism and be exploited to prevent DR.

SIGNIFICANCE STATEMENT Diabetic retinopathy affects one-third of diabetic patients and is the primary cause of vision loss in adults 20-74 years of age. While anti-VEGF and photocoagulation treatments for the late-stage vision threatening complications can prevent vision loss, a significant proportion of patients do not respond to anti-VEGF therapies, and mechanisms to stop progression of early-stage symptoms remain elusive. Glut1 is the primary facilitative glucose transporter for the retina. We determined that a moderate reduction in Glut1 levels, specifically in the retina, but not the retinal pigment epithelium, was sufficient to prevent retinal polyol accumulation and the earliest functional defects to be identified in the diabetic retina. Our study defines modulation of Glut1 in retinal neurons as a targetable molecule for prevention of diabetic retinopathy.

  • diabetic retinopathy
  • electroretinogram
  • glucose
  • photoreceptor
  • retinal pigment epithelium
  • sorbitol

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The Journal of Neuroscience: 41 (14)
Journal of Neuroscience
Vol. 41, Issue 14
7 Apr 2021
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Reduction of Glut1 in the Neural Retina But Not the RPE Alleviates Polyol Accumulation and Normalizes Early Characteristics of Diabetic Retinopathy
Nicholas C. Holoman, Jacob J. Aiello, Timothy D. Trobenter, Matthew J. Tarchick, Michael R. Kozlowski, Emily R. Makowski, Darryl C. De Vivo, Charandeep Singh, Jonathan E. Sears, Ivy S. Samuels
Journal of Neuroscience 7 April 2021, 41 (14) 3275-3299; DOI: 10.1523/JNEUROSCI.2010-20.2021

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Reduction of Glut1 in the Neural Retina But Not the RPE Alleviates Polyol Accumulation and Normalizes Early Characteristics of Diabetic Retinopathy
Nicholas C. Holoman, Jacob J. Aiello, Timothy D. Trobenter, Matthew J. Tarchick, Michael R. Kozlowski, Emily R. Makowski, Darryl C. De Vivo, Charandeep Singh, Jonathan E. Sears, Ivy S. Samuels
Journal of Neuroscience 7 April 2021, 41 (14) 3275-3299; DOI: 10.1523/JNEUROSCI.2010-20.2021
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Keywords

  • diabetic retinopathy
  • electroretinogram
  • glucose
  • photoreceptor
  • retinal pigment epithelium
  • sorbitol

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