Lisa Heather - Cardiac Sciences / Metabolism & Endocrinology - 'Metabolites as dysregulated signalling molecules in the type 2 diabetic heart'

Diabetes affects around 1/10 people in the UK, with the majority having type 2 diabetes. Despite causing complications in many organs in the body, the leading cause of mortality in people with type 2 diabetes is cardiovascular disease. Diabetes is a metabolic disease, changing substrates supplied to and those utilised by the heart. However, it is currently unclear why abnormal cardiac metabolism deleteriously affects the heart, causing diabetic cardiomyopathy (DCM) and heart failure with preserved ejection fraction (HFpEF). These are important questions to answer as we currently have no treatments for DCM or HFpEF. In our lab we are trying to understand what processes metabolism regulates within the cell. Specifically, we are studying the role of metabolites as regulators of cell function, due to their ability to regulate transcription factors, post-translational modifications, and as allosteric regulators of enzyme function. Thus, metabolites are not simply sources of energy, but also regulated signalling molecules that can determine rates of transcription, trafficking and enzyme activity. We have shown previously that metabolites can regulate signalling processes in many compartments in the cell, including the mitochondria, nucleus, cell membrane and cytosol. We have shown that in diabetes when the concentration of these metabolites changes within the heart, this has consequences for many cellular processes such as the response to ischaemia, increased workload and change in nutrition. We use a range of techniques including cell culture, heart perfusion, in vivo imaging, metabolomics, and molecular biology approaches. We are interested in understanding whether pharmacologically targeting metabolism is beneficial for the diabetic heart.