Reduction of GLUT1 in the BKS.Lepr^db/db mouse model of Type 2 diabetes ameliorates retinal pathology and defects in retinal function.

Abstract

Purpose : We previously demonstrated that reduction of GLUT1 in a mouse model of Type 1 diabetes (T1D) reduced hallmarks of diabetic retinopathy (DR). While nearly all diabetic patients will develop DR at some point following their diagnosis, 90-95% of diabetic patients have Type 2 rather than T1D. The purpose of this study was to determine if reduction of GLUT1 similarly reduced hallmarks of retinopathy in a mouse model of Type 2 diabetes (T2D).

Methods : 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. In order to reduce glucose levels in the diabetic retina, we utilized GLUT1^+/- mice. Obese, hyperglycemic BKS.Lepr^db/db mice were crossed with GLUT1^+/- mice to generate a mouse model of Type 2 diabetes with global reduction of GLUT1. Control (BKS.Lepr^+/+ or Lepr^db/+) and diabetic (BKS.Lepr^db/db) GLUT1^+/+ and GLUT1^+/- mice were analyzed at 8, 16 and 24 weeks of age. GLUT1 expression in the RPE and retina was compared by immunohistochemistry, western blot and qPCR. Retina 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.

Results : GLUT1 and glucose levels were elevated in the retina of BKS.Lepr^db/db;Glut1^+/+ mice, while diabetic Glut1^+/- mice did not exhibit a significant increase in GLUT1 levels or retinal glucose. The amplitude of a-, b- and c-waves of BKS.Lepr^db/db;Glut1^+/+ mice were significantly lower than non-diabetic Glut1^+/+ mice and diabetic GLUT1^+/- mice. Oxidative stress and inflammatory markers were also greater in BKS.Lepr^db/db;Glut1^+/+ animals as compared to non-diabetic controls and diabetic GLUT1^+/- mice.

Conclusions : The reduction of GLUT1 significantly dampened the severity of the defects in retinal function and presence of oxidative stress/inflammation observed in the BKS.Lepr^db/db mouse model of T2D. These data complement our findings in the STZ mouse model of T1D and support the hypothesis that hyperglycemia induces the earliest defects in retinal and RPE cell function associated with DR. They further suggest that modulation of glucose transport to the retina via GLUT1 should be investigated as a preventative therapy for DR.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.