Inhibition of Cardiac Glucose Transport Corrects Diabetic Cardiomyopathy Even Without Alleviation of Hyperglycemia

Abstract

Healthy hearts rely more on fatty acid (FA) rather than glucose utilization. It remains unclear whether diabetic cardiomyopathy (DbCM) is accounted for by glucotoxicity or lipotoxicity. Previously, we discovered that either insulin deficiency or insulin resistance causes FOXO1‐KLF5 activation in human and murine hearts, which drives cardiac lipotoxicity and oxidative stress. Now, we investigate how glucose activates cardiac KLF5 and causes DbCM. We hypothesized that higher cardiac glucose content in diabetes potentiates FOXO1‐KLF5 activation and causes glucolipotoxicity.We mimicked Type‐1 diabetes (T1D) in C57BL/6 mice via 5 daily intraperitoneal injections of streptozotocin (STZ). In contrast to late T1D (12 Wks post‐STZ), cardiac KLF5 expression levels are not increased in the early T1D (4 Wks post‐STZ). However, mice developed cardiac dysfunction in early T1D. Seahorse analysis in adult cardiomyocytes isolated from mice with early T1D showed suppression of FA dependence in the expense of higher glucose dependence compared to non‐diabetic mice. To confirm whether hyperglycemia or higher cardiac glucose content accounts for cardiac dysfunction in early T1D, we applied anti‐hyperglycemia treatment (Dapagliflozin, DAPA, SGLT2 inhibitor) or GLUT1 inhibition (STF‐31). Either of the two treatments restored cardiac FA dependence and prevented both glucose preference and cardiac dysfunction in early T1D. GC‐MS analysis in hearts of mice with late T1D, which have shifted back to increased FA dependence, showed increased cardiac glucose content ‐presumably unused glucose‐ and subsequent increase of cardiac KLF5, as previously shown, which exacerbates cardiac dysfunction. New data revealed that GLUT1 levels were increased in late T1D compared to early T1D, as well as that this is driven by KLF5 activation. The lack of activation of KLF5 expression in early T1D, which reverses in late T1D, is mirrored by FOXO1 transcriptional activity as shown by expression of FOXO1 targets and lower FOXO1 acetylation in late T1D, which is controlled by Sirtuin‐1. Analysis of hearts from mice with late T1D and a human cardiomyocyte cell line (AC16) that was treated with high glucose indicated higher Sirtuin‐1 expression and Sirtuin‐1 binding on FOXO1. Accordingly, prevention of glucose transport to hearts of diabetic mice via treatment with either DAPA or STF‐31 for 12 Wks lowered cardiac expression of KLF5 and its targets and improved cardiac function.Conclusively, DbCM begins in early T1D with lower mitochondrial FA utilization that is compensated by higher glucose utilization and is exacerbated in late T1D with activation of SIRT1‐FOXO1‐KLF5 axis that causes combined lipotoxicity and glucotoxicity. Inhibition of GLUT1 alleviates DbCM via prevention of both early glucose dependence and late KLF5 activation.