588-P: Diabetes Leads to Sodium-Glucose Cotransporter 2 (SGLT2) Increase in the Retina

Abstract

Introduction: Diabetes is the leading cause of microvascular disorders such as diabetic retinopathy (DR). There are no treatments for DR and finding new drug targets is of considerable interest. SGLT2 inhibitors, a newer class of antidiabetics are promising in the management of diabetes, however, the potential role of SGLT2 in diabetic retinal microvasculature remains unknown. We hypothesized that diabetes will lead to an increase in SGLT2 in the retina and that its inhibition will be beneficial in protecting retinal vasculature from the insult of diabetes milieu. Methods: The retinal sections of diabetic (db/db; an animal model of type 2 diabetes) and control (db/m) mice were analyzed for SGLT2 expression using confocal microscopy. In parallel, the mRNA levels of SGLT2 were determined using qRT-PCR. Human retinal endothelial cells (HRECs) were treated with the SGLT2 inhibitor dapagliflozin (0.1, 1, 10 nM) to perform a glucose uptake assay and to determine its effects on mRNA levels of SGLT2. Results: The mRNA levels of SGLT2 were significantly higher (p<0.05) in the retina of db/db mice, 1.1 ± 0.46, n=5, when compared to db/m retinas, 0.06 ± 0.02, n=4. The confocal microscopy revealed SGLT2 expression throughout the retina and around the retinal blood vessels, brighter fluorescence was observed in the db/db retina. Treatment of HRECs with 10 nM dapagliflozin led to a significant decrease in SGLT2 mRNA (p<0.05); dapagliflozin: 7.95 ± 4.7, n=4; vehicle: 26 ± 3.6, n=8. The dapagliflozin inhibition demonstrated a profound decrease in glucose uptake in HRECs at all concentrations. Untreated: 2012 ± 388, n=3; 0.1 nM: 545.7 ± 296, 1 nM: 358.2 ± 241.5, 10 nM: 70.67 ± 138.9; p<0.01 as compared to untreated; n=6. Conclusion: Our studies suggest that SGLT2 is significantly upregulated in the retina during diabetes and that SGLT2 potentially plays a critical role in retinal glucose transport. In future, SGLT2 inhibition could be a useful treatment option to slow down or prevent the onset of diabetic retinopathy. Disclosure S.P. Leley: None. Q. Luo: None. A.L. Alex: None. A.D. Bhatwadekar: None. Funding National Eye Institute; Indiana University Center for Diabetes and Metabolic Diseases