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Ivy S Samuels, Matthew Tarchick, Timothy D. Trobenter, Michael R. Kozlowski; Systemic reduction of GLUT1 prevents hallmarks of diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5361.
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© ARVO (1962-2015); The Authors (2016-present)
Clinical trials indicate that the severity of diabetic retinopathy (DR) varies with systemic blood glucose: inadequate glycemic control exacerbates retinopathy, while normalization of glucose levels delays its progression. Importantly, elevated blood glucose has a strong negative correlation with measures of EOG and ERG component amplitudes. These data implicate elevations in glucose as an important factor in early retina/RPE dysfunction as well as DR development, progression and severity. Our goal was to determine if reducing glucose within the retina decreased the incidence and severity of hallmarks of DR.
The facilitative glucose transporter, Glut1, is the principal means by which the retina obtains glucose. Glucose transport from the choroid into the RPE via Glut1 is induced by elevations in extracellular glucose levels. Loss of one functional allele of GLUT1 decreases the rate of glucose transport from the blood to the cerebrospinal fluid. In order to reduce glucose in the retina, we utilized wild-type (WT, Glut1+/+) and Glut1+/- mice. Both strains of mice were injected with streptozotocin and analyzed at 2 and 4 wks of diabetes. Glut1 expression in the RPE and retina and retinal structure were compared by immunohistochemistry, western blot and semi-thin plastic sectioning. Retinal and RPE function was assessed by dark-adapted and light-adapted strobe flash and dc-ERG. Oxidative stress and inflammation were measured by dihydroethidium staining and qPCR of inflammatory molecules.
Glut1 levels were elevated in the RPE and retina of diabetic WT mice, specifically at the plasma membrane, while diabetic Glut1+/- mice exhibited a less robust increase in Glut1 levels. The amplitude of a-, b- and c-waves of diabetic WT mice were significantly lower than in diabetic GLUT1+/- mice at both 2 and 4 wks. Similarly, levels of oxidative stress and inflammatory markers were greater in WT diabetic animals as compared to GLUT1+/- mice. However, up to 4 wks of diabetes, no changes in retinal structure were observed in WT or Glut1+/- mice.
The reduction of Glut1 in diabetic mice significantly dampened the severity of defects in retinal function and presence of oxidative stress and inflammation. This data supports the hypothesis that hyperglycemia induces the earliest defects in retinal and RPE cell function associated with DR, and that these defects can be ameliorated by modulating glucose transport.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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