||Insulin resistance is an independent risk factor for heart disease. In cardiac muscle, PI3K-Akt signaling is persistently activated, despite a reduction in glucose uptake. Given that persistent activation of PI3K and Akt in the heart may be a consequence of hyperinsulinemia in insulin resistant states, the study in Chapter 2 was designed to determine if constitutive activation of PI3K and Akt signaling in the heart could independently impair insulin-mediated glucose uptake and GLUT4 translocation. The study was initially predicated on the hypothesis that chronic activation of PI3K and Akt signaling would activate mTORC1-mediated S6K-IRS negative feedback signaling and desensitize insulin-mediated glucose transport. Unexpectedly, the study discovered that PI3K and Akt activation impairs myocardial glucose uptake prior to any evidence of S6K activation despite normal translocation of GLUT4 in cardiomyocytes. These data indicate that activation of PI3K and Akt may impair glucose uptake via mechanisms that impair the intrinsic activity of the GLUT4 transporter. Insulin signaling and many other cellular signaling pathways converge at mTOR, which has been intensively studied in cell culture and different mouse tissues. However, the role of mTOR in cardiac development has never been studied. In Chapter 3, an inducible mTOR deficient mouse model was generated for studying the role of mTOR in cardiac bioenergetics. A decrease of fatty acid utilization, which leads to an impairment in ATP production, was identified in the mTOR deficient heart prior to development of cardiac dysfunction and lethality of the mice. Ongoing studies are focusing on the mechanisms of how mTOR regulates fatty acid metabolism in the heart. Taken together, this dissertation has advanced our understanding of insulin signaling in regulation of glucose uptake and GLUT4 translocation in the heart, as well as the role of mTOR in cardiac development and cardiac bioenergetics.