Role of GLUT1 in diabetic cardiomyopathy

ABSTRACT Diabetic cardiomyopathy (DbCM), which occurs in either Type-1 Diabetes (T1D) or Type-2 Diabetes (T2D), defines heart failure (HF) that occurs in the absence of coronary artery disease, hypertension, and valvular disease. Our research has discovered in human myocardial samples and mouse diabetic hearts and cardiomyocytes (CM) that the transcriptional factor Krüppel-like factor 5 (KLF5) is a central component of DbCM. We have also revealed mechanisms of KLF5-dependent cardiotoxicity that involve oxidative stress and lipotoxicity, which combinedly lead to DbCM. Furthermore, we showed that KLF5 upregulation in diabetes is driven by the transcriptional factor FOXO1. New data identify that FOXO1 cannot stimulate KLF5 expression unless myocardial glucose is elevated. Moreover, we show that glucose transporter (GLUT)-1 is essential for cardiac glucose import in both T1D and T2D and leads to DbCM via activation of the FOXO1-KLF5 axis. Based on our data, we hypothesize that in diabetes, cardiac GLUT1 is the main route for glucose uptake and leads το DbCM by stimulating both glucotoxicity and lipotoxicity. To address our hypothesis, we propose the following Aims: Aim 1: Delineate the signaling events via which GLUT1 leads to DbCM. Aim 2: Elucidate the cardiotoxic metabolic pathways in DbCM that are controlled by GLUT1. Aim 3: Explore the therapeutic potential and underlying mechanisms of GLUT1 inhibition for DbCM in T2D. The proposed study will identify GLUT1 as a new therapeutic target for DbCM and will delineate the signaling and metabolic pathways that underlie the cardiotoxic effect of GLUT1 in diabetes. Furthermore, we will map the cardiotoxic pathways that are exclusively dependent on Glucose.