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

• DOI: 10.1523/jneurosci.2010-20.2021
• Publication Date: 2021-02-23T18:55:46Z
• Authors: 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
• Keywords: Polyol pathway; Sorbitol dehydrogenase

Hyperglycemia is a key determinant for development of diabetic retinopathy (DR). Inadequate glycemic control exacerbates retinopathy, while normalization glucose levels delays its progression. In hyperglycemia, hexokinase saturated and excess metabolized to sorbitol by aldose reductase via the polyol pathway. Therapies reduce retinal accumulation prevention DR have been elusive because low dehydrogenase in retina inadequate inhibition reductase. Using systemic conditional genetic inactivation, we targeted primary facilitative transporter retina, Glut1, as preventative therapeutic male female mice. Unlike WT diabetics, Glut1 +/− mice did not display elevated retina. Furthermore, exhibited ameliorated ERG defects, inflammation, oxidative stress, which was correlated with significant reduction accumulation. Retinal pigment epithelium-specific prevent an increase content or early hallmarks DR. However, like mice, specifically mitigated diminished dysfunction elevation markers stress inflammation associated diabetes. These results suggest that modulation photoreceptors can circumvent difficulties regulating metabolism be exploited SIGNIFICANCE STATEMENT Diabetic affects one-third patients cause vision loss adults 20-74 years age. While anti-VEGF photocoagulation treatments late-stage threatening complications loss, proportion do respond therapies, mechanisms stop progression early-stage symptoms remain elusive. We determined moderate levels, but epithelium, sufficient earliest functional defects identified Our study defines neurons targetable molecule retinopathy.