FIG. 4.

The decompensated phase of diabetic cardiomyopathy. With continued metabolic stress, cardiac cells enter a decompensated stage during which further mitochondrial dysfunction and ROS generation worsen the imbalance between lipid uptake and oxidation, which overwhelms TAG synthesis pathways and promotes the generation of toxic lipid species such as ceramides and DAG. Excessive ROS production overwhelms the scavenger machinery, leading to oxidative stress. Together, ROS and lipid accumulation trigger inflammation/inflammasome activation and cell death, both of which can contribute to contractile dysfunction and cardiac fibrosis. In addition, mitophagy is impaired, which can lead to further accumulation of ROS-generating mitochondria. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars