Diabetes is associated with an increased risk of heart failure, independently of other risk factors. There is also increased evidence of diabetic cardiomyopathy as an independent entity. The pi and his collaborators have shown a direct link between cardiac dysfunction and metabolic impairments in myocardial metabolism. Evidence from the investigator's laboratory strongly suggests that the provision of substrates for energy production is impaired at the level of the mitochondrion. Based on these observations, the PI has elaborated the hypothesis that this is indeed the case. Specifically, the investigator proposes that this is manifested in alterations at multiple sites such as lactate uptake and oxidation, fatty acid entry and oxidation, pyruvate oxidation and anaplerosis and citrate cataplerosis. These changes then lead to clinical problems under conditions of increased demand when energy provision cannot match utilization. The tools the PI proposes to use include: 1) The spontaneously diabetic BB/Wor rat and the diabetes-resistant controls. 2) The perfused working heart model with measurement of contractile efficiency, which has now been implemented in the laboratory. 3) Perfusion with buffer containing RBC's to increase oxygen carrying capacity and decrease perfusion rate so that a-v differences can be measured. Simultaneous use of C13 labeled substrates, and in situ and high resolution NMR spectroscopy and GCMS in perfusate and extracted myocardial samples to determine metabolite flux rates using isotopomer analyses. Complementary measurements of enzyme activities, transporters (lactate, fatty acid) and their expression in the myocardial tissue extracts. Finally, linkage of all of the above data using metabolic control analysis to establish the principal control points. It is underlined that the understanding of the relationship between cardiac function and metabolism is essential in instituting appropriate treatment so that therapeutic interventions to improve contractile function do not exacerbate the metabolic problems, ultimately increasing tissue injury.
