Presentation description

Diabetes Mellitus II (T2D) and heart failure (HF) are highly comorbid diseases whose incidence continues to increase despite many FDA blood glucose lowering therapies. Insulin resistance, an essential driver of T2D, causes an increase in blood glucose levels and promotes atherosclerosis. Our lab has shown that the accumulation of toxic sphingolipids, specifically ceramide C16:0, prevents activation of Akt leading to insulin resistance. Moreover, circulating ceramides are now used in clinical settings to determine an individual's risk of coronary artery disease and HF. Previous experiments involving whole-body deletion of gene Degs1, which encodes for an enzyme essential in the ceramide synthesis pathway, showed that a total decrease in ceramide levels improves cardiac ejection fraction and insulin tolerance in leptin-deficient mice.

To understand the relationship between ceramides and HF, we designed an experiment using mice that overexpress the human CERS6 gene specifically in the cardiomyocyte. Cardiomyocyte CERS6 overexpressing mice, compared to littermate controls, developed systolic dysfunction, and had increased expression of pro-fibrotic genes. These studies suggest that accumulation of toxic C16:0 ceramides specifically in the cardiomyocyte is sufficient to drive HF and that inhibition of ceramide synthesis may provide a means of treating this insidious disease. Future studies are underway to determine if overexpression of CERS6 in the liver are sufficient to drive both T2D and HF.