In a clinical setting, infusion of a high concentration of glucose, insulin and potassium reduces injury following a myocardial infarction. Cardiomyocytes normally oxidize fatty acids and glucose to meet cellular energy demands. Substrate oxidation is limited during ischemic episodes and glycolysis becomes an important source of energy. Glucose transport through GLUT4 is a rate limiting steps in cardiac glucose utilization under insulin action. GLUT1 and GLUT8 are also expressed in the heart. The relative importance of each glucose transporter in substrate utilization under normal and stress (ischemia) conditions has yet to be determined. Mice devoid of GLUT4 (-/- or null) are have a severe reduction in body fat and display a unique hypertrophy independent of hypertension or a switch in myosin isoform expression. GLUT8 is upregulated in GLUT4 null heart which may result in improved glucose metabolism even in the absence of GLUT4. Surprisingly, GLUT4 null hearts are resistant to loss of function due to reperfusion injury and apoptosis following global ischemia. The anti-apoptotic signaling molecule, Akt is activated under basal conditions in GLUT4 null hearts that may contribute to the protection from reperfusion injury. GLUT4 null hearts also display increases in mitochondria, PCr:ATP, GSH, glycogen content and hexokinase II (HKII) activity which may provide cardioprotection. Adipose cells from GLUT4 null mice overexpress/secrete Acrp30 which may influence insulin sensitivity, substrate utilization and the cardiovascular system. The overall hypothesis tested in this proposal is that glucose transporters, in particular GLUT8, participate in the response of cardiomyocytes to ischemia-reperfusion by altering substrate utilization to favor glucose metabolism, glycolytic generation of ATP and enhanced flux of substrates into the pentose phosphate pathway leading to increases in reducing equivalents and the antioxidant GSH. The upregulation of GLUT8 activity may be mediated by Akt which is known to confer resistance to apoptosis following reperfusion. The relative roles of high glucose and insulin in mediating these effects will also be determined. This hypothesis will be tested using genetically engineered mice to determine: 1) correlation between GLUT8, HKII, Akt expression and mitochondrial biogenesis with cardioprotection; 2) the influence of genetic modulation of GLUT8 expression specifically in heart on cardioprotection; 3) influence of genetic modulation ofAkt, HKII or Acrp30/adiponectin on GLUT8 expression, mitochondrial biogenesis and cardioprotection in GLUT4 null hearts. Determining the role of GLUT8 in glucose metabolism and cardioprotection should provide novel insight into treatment of myocardial infarction and ischemic heart disease. ? ?
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