Exercise training results in a doubling of the rate of myocardial glucose uptake in the rat in vivo. The major objective of this proposal is to understand the effects of chronic exercise training on the regulation of glucose metabolism in well perfused and ischemic myocardium. The relationships between regional myocardial glucose uptake, blood flow, and plasma membrane glucose transporters will be investigated in miniature swine.
The specific aims are: 1) to assess the effects of chronic exercise on regional myocardial blood flow, contractile function, glucose uptake and plasma membrane glucose transporters in normal and ischemic myocardium; 2) to assess the effects of diabetes on myocardial glucose uptake and glucose transporters in well perfused and ischemic myocardium; and 3) to determine the effects of chronic exercise training on myocardial glucose metabolism in well perfused and ischemic diabetic myocardium. This project has direct clinical applications to the treatment of ischemic heart disease in diabetic and nondiabetic individuals. Diabetes will be induced with i.v. streptozotocin. Myocardial ischemia will be induced in the left anterior descending coronary artery (LAD) perfusion bed in anesthetized animals using an extracorporal perfusion circuit. The effects of exercise training (treadmill running 5d/wk 60 min/d) on glucose metabolism will be assessed during normal perfusion and with a 60% reduction in LAD blood flow. Regional glucose uptake will be measured using [6-3H]-2-deoxyglucose, and blood flow with microspheres. The GLUT-4 glucose transporter will be measured in whole tissue and isolated plasma membranes using the antibody binding technique. Eight groups of animal will be studied (n=10) in each group: trained and untrained healthy and diabetic animals will be studied at their ambient glucose and insulin levels. We will use the normoglycemic hyperinsulinemic (100 muU/ml) clamp technique to assess the insulin responsiveness of the heart, and to measure ischemia-induced glucose uptake in trained and untrained diabetic and nondiabetic animals at the same glucose and insulin levels. The results will show if changes in plasma membrane glucose transporters are important in the regulation of myocardial glucose uptake during ischemia, and whether impaired glucose uptake in diabetic animals is due to a lower concentration of glucose transporters in the plasma membrane.
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