The promise of GLUT1 inhibitors in preventing diabetes induced microvasculopathy

Abstract

PurposeDiabetes induced microvasculopathy (DIM) is a leading cause of atherosclerosis, heart failure, stroke, blindness, and renal failure. Current therapeutic interventions still heavily rely on controlling systemic hyperglycemia. Yet, many diabetic patients develop microvasculopathies despite having good glycemic control. Endothelial activation is a common underlying causative factor; however, the molecular basis of such activation remains a big gap in our knowledge. Aberrant glucose transport and metabolism by endothelial cells are attracting great interest as disease‐related mechanisms with little attention in the context of DIM. In this study we aimed to evaluate the pre‐clinical efficacy of the glucose transporter (GLUT)‐1 inhibitor, which is a derivative of Fluoro‐catechol ester of 3‐Hydroxy‐benzoic acid (FCEHBA), to halt microvascular dysfunctions induced by diabetes.MethodsHuman retinal endothelial cells (HRECs) were used and treated with high glucose (HG, 30 mM) or osmotic control with or without low oxygen (1%O2) in presence or absence of FCEHBA (10 mM) or Vehicle (DMSO). Barrier function was assessed by Electric Cell‐substrate Impedance Sensing (ECIS) and immunofluorescence organization of Zonula Occluden‐1 (ZO‐1). The angiogenic potential of HRECs was evaluated by migration; sprouting and tube formation. Group differences were evaluated by ANOVA followed by Tukey Posthoc test.Results(1) Increased glucose influx in HRECs through the increased expression of GLUT1 and its translocation from the cytosol to the plasma membrane have been observed in response to simultaneous insults of diabetes and hypoxia. (2) The increase in glucose influx via recruitment of GLUT1 to the plasma membrane was associated with (a) an accelerated breakdown of HREC barrier integrity, indicated by the significant drop in transendothelial electric resistance (TER); (b) a marked disruption of ZO‐1, a key tight junction protein (TJP) regulating barrier integrity in HRECs; (c) a dramatic enhancement of HRECs migration; and (d) an induction of profound HREC neovascularization and tube formation. (3) Importantly, FCEHBA was able to remarkably restore the drop in barrier function induced by both diabetes and hypoxia and to reverse their disruptive effects on ZO‐1 integrity. (4) FCEHBA was also able to effectively mitigate angiogenic effects of both diabetes and hypoxia on HRECs, including increased cell migration and tube formation, without affecting cell viability.ConclusionTo our knowledge, this study is the first to report that FCEHBA protects against High Glucose/Hypoxia‐induced microvasculopathy. This finding may lead to a new therapeutic approach that could be clinically translated to not only patients with diabetic retinopathy but also those with other related microvascular conditions including atherosclerosis, stroke, and cardiovascular diseases.Support or Funding InformationAmerican Heart Association Grant 18CDA34080403 (ASI) and the National Eye Institute grant R01EY023315 (MA).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.