The applicant proposes to examine the role of glucose as an energy providing substrate in two broad areas relating, first, to the use of (18F) 2-deoxy-2- fluoroglucose (FDG) to assess glucose uptake, and secondly, the role of glucose as an essential fuel. The applicant would combine the continuous assessment of glucose uptake by FDG with a working heart preparation which performs near physiologic work. The first specific aim will define the role of hexokinase translocation in relation to glucose metabolism and FDG. Specifically, the applicant will define the factors responsible for changes in the relative affinities of hexokinase for glucose as compared to FDG. The second specific aim is based on the observation of two qualitatively different patterns of glucose uptake: immediate and delayed. The applicant hypothesizes that the immediate response to competing substrates reflects regulation of glucose transporter molecules in situ, while the delayed response of glucose uptake to insulin or epinephrine reflects recruitment of transporter molecules (GLUT 4) to the sarcolemma. The two responses will be delineated with the use of tracer studies of glucose in conjunction with immunoblot analysis of the membrane localization of GLUT 4. The third specific aim will delineate the responses of glucose uptake to a variety of stimuli in a system exhibiting coordinated multi-site regulation of glucose metabolism. This work will define the relationship between glucose transport, glycolytic flux, and glycogen metabolism, taking advantage of a unique approach to the simultaneous determinations of glycogen synthesis and degradation. The fourth specific aim concerns glucose as an essential fuel for the heart, by replenishing Krebs cycle intermediates, in addition to serving as an oxidizable substrate. Glucose uptake, contractile function and anaplerosis of the Krebs cycle will be quantitated by combining FDG and 13C-NMR spectroscopy.
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