The research in my laboratory is focused on understanding how diabetes affects the heart so better treatment options can be developed. This is especially important given the high rate of diabetes and associated cardiovascular complications. Indeed, diabetes induces changes to cardiac function in the absence of other risk factors through mechanisms that remain unclear.

One of our projects examines the beta-adrenergic signaling pathway and diabetes, and how related changes may exacerbate heart stress. Activation of cAMP-dependent protein kinase (PKA) via beta-adrenergic receptor signaling is a primary means of increasing cardiac contractility. Dysregulation of this pathway is a major driver of diabetic cardiomyopathy, life-threatening arrhythmias, and heart failure. However, the mechanisms that disrupt this pathway are largely unknown. In the healthy heart, PKA increases contractility by amplifying calcium cycling and concertedly activating phosphofructose kinase-2 (PFK-2) to promote glucose oxidation. In this manner, workload and metabolic demand are finely orchestrated. We have identified important changes in both PKA signaling and PFK-2 activation that may drive diabetic cardiomyopathy. Ongoing studies are determining the molecular mechanisms of this signaling dysfunction to identify potential treatment targets.

Our second project examines mitochondrial function and diabetes. The heart’s constant demand for energy is primarily derived from fatty acids and glucose. Diabetes leads to metabolic inflexibility, in which the heart’s capacity to use glucose is greatly diminished. While changes in glucose metabolism occur in the cytoplasm, we have shown that alterations in mitochondrial function further promote metabolic flexibility. This may be an important determinant in diabetic cardiomyopathy. We have shown that these changes are mediated, in part, by the overabundance of acetylated proteins. We are working to understand how hyper-acetylation occurs, how it affects mitochondrial function, and how it can be alleviated. There are currently no therapies that target mitochondrial abnormalities and diabetic cardiomyopathy. The results of this research will determine if preventing or reversing mitochondrial acetylation is a promising target for therapeutic intervention.

My Publications