Abstract GS111: Inhibition Of Cardiac Glucose Transporter 1 Suppresses Early Glucose Dependency And Klf5 Activation And Treats Cardiomyopathy In Diabetes

Healthy hearts use more fatty acids (FA) than glucose for ATP synthesis but diabetic cardiomyopathy (DbCM) occurs with higher FA dependency. It remains controversial whether glucotoxicity or lipotoxicity or both account for DbCM. We recently discovered that insulin signaling inhibition and eventual FOXO1 activation stimulate cardiac KLF5 expression, which drives lipotoxicity and causes cardiac dysfunction. In the present study, we investigated the relative contribution of glucose in the activation of cardiac KLF5 and DbCM. We induced Type-1 diabetes (T1D) in C57BL/6 mice via intraperitoneal injections of streptozotocin (STZ). In contrast to late-stage diabetes (12 weeks post-STZ), cardiac KLF5 mRNA and protein levels were not increased in the early T1D stage (4 weeks post-STZ) although mice have mild cardiac dysfunction already. Seahorse analysis in adult cardiomyocytes isolated from mice with early T1D showed higher glucose and lower FA dependency compared to non-diabetic mice and mice in late T1D. To confirm whether hyperglycemia causes cardiac dysfunction, we treated diabetic mice with Dapagliflozin (DAPA, SGLT2 inhibitor) or STF-31, a GLUT1 inhibitor. These treatments restored normal dependency on fatty acids and prevented cardiac dysfunction. GC-MS analysis showed that the reversal of fuel dependency from glucose to fatty acids in late T1D is accompanied by increased glucose content opposite to the early T1D. Accordingly cardiac KLF5 is increased in late T1D, accompanied by severe cardiac dysfunction. The expression changes of KLF5 are mirrored by transcriptional activity of FOXO1 -shown by expression of FOXO1 targets- in early and late T1D. The changes in transcriptional activity are accompanied by differential FOXO1 acetylation, which is controlled by Sirtuin-1 and modulates its DNA affinity. Analysis of mouse cardiac tissue in early T1D and a human cardiomyocyte cell line (AC16) that was treated with high glucose showed higher Sirtuin-1 expression and stronger protein-protein interaction with FOXO1. To this end, mice that were subjected to treatment with either DAPA or STF31 for 12 Wks had improved cardiac function, lower cardiac KLF5 expression and decreased expression of cardiac KLF5 gene targets. Interestingly, GLUT1 mRNA levels were increased in late T1D compared to early T1D. Cardiomyocyte-specific KLF5 overexpression or adenovirus-mediated KLF5 overexpression in AC16 cells stimulated GLUT1 expression. Collectively, in early T1D, hearts rely more on glucose utilization in mitochondria. In late T1D, SIRT1-FOXO1-KLF5 axis causes lipotoxicity and subsequent induction of GLUT1 expression that contributes to glucotoxicity. Inhibition of GLUT1-dependent glucose uptake alleviates diabetic cardiomyopathy via inhibition of both early glucose dependency and late KLF5 activation.