Defects in the light-evoked responses of the retina occur early in the sequalae of diabetic retinopathy. These defects, identified through the electroretinogram, represent dysfunction of retinal neurons and the retinal pigment epithelium and are commonly identifiable at the timing of, or almost immediately following, diabetes diagnosis. Recently we demonstrated that systemic reduction of Glut1 in Type 1 diabetic mice reduced retinal sorbitol accumulation, mitigated ERG defects, and prevented retinal oxidative stress and inflammation. Here, we investigated whether systemic reduction of Glut1 also diminished hallmarks of diabetic retinopathy in Type 2 diabetic mice. Transgenic nondiabetic Lepr and spontaneously diabetic Lepr mice that expressed wildtype (Glut1) or systemically reduced levels of Glut1 (Glut1), were aged and underwent standard strobe flash electroretinography and c-wave analysis prior to evaluation of inflammatory cytokines and oxidative stress molecules. Although LeprGlut1 mice still displayed overt obesity and diabetes, no scotopic, photopic or c-wave ERG defects were present through 16 weeks of age and expression of inflammatory cytokines and oxidative stress molecules were also normalized. These findings suggest that systemic reduction of Glut1 is sufficient to prevent functional retinal pathophysiology in Type 2 diabetes. Targeted, moderate reductions of Glut1 or inhibition of Glut1 activity in the retina of diabetics should be considered as a novel therapeutic strategy to prevent development and progression of diabetic retinopathy.Copyright © 2023. Published by Elsevier Inc.
