Historically, two parallel lines of evidence have developed linking the regulation of muscle blood flow and muscle metabolism. One originates with clinical investigations examining the action of insulin- on bulk muscle (limb) blood flow and its impairment with insulin resistance. These studies have generated controversy regarding the physiological and clinical relevance of insulin's actions on total blood flow. The second line of evidence originates with more basic studies of the microvasculature and its neurohumoral regulation in muscle. The laboratory of the PI and the Co-investigators began a collaboration 5 years ago directed at developing new methods to study micro-vascular flow distribution within skeletal muscle """"""""in-vivo"""""""". Sufficient preliminary data are now available to support using several approaches to measuring blood flow distribution in skeletal muscle in-vivo. These methods include measurement of the metabolism of exogenously added 1-methylxanthine to 1-methylurate by capillary xanthine oxidase, laser Doppler flowmetry (LDF), and contrast-enhanced ultrasonography (CEU). With these techniques, we propose to address three Aims: First to determine in vivo the time course and dose-response of capillary recruitment by insulin in normal sedentary, in exercise-trained and insulin-resistant rats. Second, we will define in human skeletal muscle the response of the microvasculature to insulin and feeding and whether these responses are altered by DM2, obesity and hypertension. The relationship of the microvascular and metabolic actions of insulin will be correlated to ascertain potential relationships. These studies will test the general hypothesis that insulin at physiologically relevant concentrations and exposure times, regulates skeletal muscle capillary recruitment, preferentially directing flow through a """"""""nutritive"""""""" capillary network and that this can occur even in the absence of changes in total blood flow to a limb. Finally, we will examine the mechanism and anatomic pathways of insulin's microvascular action by testing a series of hypotheses relating to whether insulin vascular action requires glucose metabolism in muscle, whether insulin redirects flow away from connective tissue vessels to vessels in close apposition to myocytes and finally whether insulin's microvascular action differ from those of other vasodilators. In the latter studies we will test directly whether augmenting or diminishing muscle capillary recruitment affects the simultaneously measured action of insulin to promote glucose uptake by skeletal muscle.
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