The applicant proposes to focus on quantitative aspects of carbohydrate metabolism in the heart and use 18F-2-deoxy-2-fluoroglucose (FDG) as a tracer analog for glucose transport and phosphorylation. The applicant argues that the original promise of assessment of regional myocardial glucose metabolism by FDG and positron emission tomography (PE) can be realized by a new model for quantitation of glucose uptake. The applicant also argues that glycogen should not be viewed as a storage of excess glucose for anaerobic ATP production but as an active participant in energy metabolism of the normal and insulin-deficient heart.
In Specific Aim 1, the applicant will test the robustness of the new tracer kinetic model for FDG to quantitate rates of glucose transport and phosphorylation under clinically relevant conditions, including high fat, ischemia, reperfusion, and left-ventricular unloading.
In specific Aim 2 the applicant will examine aspects of insulin action in the isolated heart and the insulin-antagonistic effects of TNFalpha. Because insulin improves contractile function in the post-ischemic heart through enhanced rates of glucose metabolism, the applicant considers it important to quantitate rates of glucos uptake.
In Specific Aim 3 the applicant will apply a pulse-chase technique to measure true rates of simultaneous glycogen synthesis and degradation in heart Specifically, the applicant will test the hypotheses that a) glycogen synthesi and degradation do not follow a conventional pattern of """"""""last on-first off"""""""" kinetics, b) glucose derived from glycogen is the preferred substrate for energy production upon adrenergic stimulation, and c) proglycogen is the metabolically active form of glycogen.
In Specific Aim 4 the applicant will employ a triple-tracer technique to determine the causes and functional consequences of altered glycogen metabolism in hearts from insulin-deficient animals. The long term goals of this research are to redefine FDG as a quantitative tracer of glucose uptake, and to transform the concept of glucose and glycogen as essential fuels for energy production in heart muscle from vague operational definitions to concrete physiologic principals.
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| Taegtmeyer, Heinrich; Golfman, Leonard; Sharma, Saumya et al. (2004) Linking gene expression to function: metabolic flexibility in the normal and diseased heart. Ann N Y Acad Sci 1015:202-13 |
| Weisleder, Noah; Soumaka, Elisavet; Abbasi, Shahrzad et al. (2004) Cardiomyocyte-specific desmin rescue of desmin null cardiomyopathy excludes vascular involvement. J Mol Cell Cardiol 36:121-8 |
| Cohen, David M; Guthrie, Patrick H; Gao, Xiaolian et al. (2003) Glutamine cycling in isolated working rat heart. Am J Physiol Endocrinol Metab 285:E1312-6 |
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| Young, Martin E; Wilson, Christopher R; Razeghi, Peter et al. (2002) Alterations of the circadian clock in the heart by streptozotocin-induced diabetes. J Mol Cell Cardiol 34:223-31 |
| Young, Martin E; McNulty, Patrick; Taegtmeyer, Heinrich (2002) Adaptation and maladaptation of the heart in diabetes: Part II: potential mechanisms. Circulation 105:1861-70 |
| Belke, Darrell D; Betuing, Sandrine; Tuttle, Martin J et al. (2002) Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression. J Clin Invest 109:629-39 |
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