This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The hypothesis of this protocol posits that insulin-mediated muscle microvascular recruitment in healthy humans occurs early and this microvascular recruitment facilitates insulin delivery to skeletal muscle. To test this hypothesis, we will directly measure: 1) insulin extraction (arterial-venous concentration) and absolute flux ((A-V) x Flow) by human forearm skeletal muscle, and 2)the extent of microvascular recruitment as assessed by contrast enhanced ultrasound (CEU). Measurements will be made basally and during steady-state hyperinsulinemia in two groups: subjects in whom insulin uptake and insulin-induced microvascular recruitment occur in a normal physiologic setting, and those in whom insulin-induced microvascular recruitment is blocked by the co-infusion of Intralipid to raise plasma free fatty acids (FFA). Intralipid has been shown to block insulin-mediated capillary recruitment in rodents. Finally, we will examine whether modest intensity, low-frequency muscle contraction stimulates insulin and glucose uptake by forearm muscle and conditions of basal insulin. Primary endpoints are the rate of insulin and glucose uptake by forearm muscle during insulin infusion and during low-frequency exercise and the difference in microvascular volume between groups. Comparisons will be made by a 2-way repeated measures ANOVA with effects of time and treatment. For the primary comparison of muscle insulin and glucose uptake, we will integrate the area under the curve to determine differences in total cumulative glucose and insulin uptake during the course of the study. We will also estimate the T1/2 and the absolute delta for changes in microvascular volume versus insulin and glucose uptake to address both the temporal and dimensional relationships between vascular recruitment and insulin uptake by muscle.
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