Systemic Reduction of Glut1 Normalizes Retinal Dysfunction, Inflammation, and Oxidative Stress in the Retina of Spontaneous Type 2 Diabetic Mice

• Published in: The American journal of pathology Vol. 193; no. 7; pp. 927 - 938
• Main Authors: Aiello, Jacob J., Bogart, Maislin C., Chan, Wai-Ting, Holoman, Nicholas C., Trobenter, Timothy D., Relf, Chloe E., Kleinman, Dana M., De Vivo, Darryl C., Samuels, Ivy S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2023; American Society for Investigative Pathology
• Subjects: Animals; Cytokines - metabolism; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - metabolism; Diabetic Retinopathy - metabolism; Electroretinography; Glucose Transporter Type 1 - genetics; Glucose Transporter Type 1 - metabolism; Inflammation - metabolism; Mice; Oxidative Stress; Regular; Retina - metabolism
• ISSN: 0002-9440; 1525-2191; 1525-2191
• DOI: 10.1016/j.ajpath.2023.04.003

Defects in the light-evoked responses of the retina occur early in the sequalae of diabetic retinopathy (DR). These defects, identified through the electroretinogram (ERG), 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, systemic reduction of the facilitated glucose transporter type 1, Glut1, in type 1 diabetic mice was shown to reduce retinal sorbitol accumulation, mitigate ERG defects, and prevent retinal oxidative stress and inflammation. Herein, the study investigated whether systemic reduction of Glut1 also diminished hallmarks of DR in type 2 diabetic mice. Transgenic nondiabetic Leprdb/+ and spontaneously diabetic Leprdb/db mice that expressed wild-type (Glut1+/+) or systemically reduced levels of Glut1 (Glut1+/−) were aged and subjected to standard strobe flash electroretinography and c-wave analysis before evaluation of inflammatory cytokines and oxidative stress molecules. Although Leprdb/dbGlut1+/− 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 was 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 diabetic patients should be considered as a novel therapeutic strategy to prevent development and progression of DR.