Novel strategies to resolve metabolic defects in the diabetic heart

点击翻译按钮获取中文摘要

ABSTRACT Diabetic cardiomyopathy is an independent risk factor for heart failure characterized by diastolic dysfunction and left ventricular hypertrophy. Diabetic cardiomyopathy features striking changes in cardiomyocyte fuel metabolism, which promote the transition into an advanced pathological state. Alterations in fuel metabolism include an increased reliance on fatty acid oxidation for mechanical energy production, at the expense of other substrates such as glucose. The resultant loss of metabolic flexibility can result in reduced cardiac work efficiency and contractile dysfunction. The cellular mechanisms that drive changes in fuel substrate utilization are not fully understood, and this deficiency represents a major impediment to the development of novel treatments. In this proposal, we aim to investigate the utility of a novel peptide – adropin – to reverse the fuel metabolism defects observed in diabetic cardiomyopathy. In Aim 1, we will investigate the effects of adropin on novel cellular pathways that regulate glucose oxidation in the heart. In Aim 2, we will examine the role played by adropin signaling pathways in regulating mitochondrial fuel metabolism. In Aim 3, we will examine whether adropin is a candidate molecule for diabetic cardiomyopathy treatment in pre-clinical animal models. It is expected that these studies will elucidate new cellular pathways that are central to the metabolic dysfunction observed in diabetic cardiomyopathy, and will highlight potential new treatment pathways for this disorder.