Fumarate as an antioxidant defence mechanism for the type 2 diabetic heart

The leading cause of mortality in people with type 2 diabetes is cardiovascular disease.  Type 2 diabetes is a metabolic disease, causing the heart to change the substrates it uses and the concentrations of metabolites within the cell.  Metabolites can have far reaching effects on cell function, as not only are they fuels but also signalling molecules.  Thus, to understand why diabetes affects the heart we must first understand what metabolites are actually doing within the cell, and the detrimental consequences when their concentrations change.  

 Through this BHF CRE pump priming application we will focus on a specific metabolite – fumarate – which is decreased in the diabetic heart.  Fumarate can signal to a transcription factor Nrf2, and promote the antioxidant defence mechanisms in the cell to protect against oxidative damage.  Therefore, a decrease in fumarate concentrations may contribute to the increased oxidative damage found in the diabetic heart.  We will investigate the mechanisms linking fumarate, Nrf2, its downstream antioxidant defence genes and oxidative damage in T2D, using human cardiomyocytes.  In addition, we will explore therapeutic avenues to increase fumarate concentrations, as an approach to protect the heart in diabetes.