The hypothesis of this proposal posits that human skeletal muscle microvascular recruitment in response to either insulin or exercise occurs earlier than increases in total blood flow and this microvascular recruitment facilitates insulin and glucose delivery to skeletal muscle. To test this hypothesis, we will measure: 1) insulin extraction (arterial-venous concentration) and absolute flux ((A-V) x Flow) by human forearm skeletal muscle and 2) extent of microvascular recruitment by contrast enhanced ultrasound (CEU). Measurements will be made basally and during steady state hyperinsulinemia in four groups: Subjects in whom: (1) insulin uptake and microvascular recruitment are assessed at physiologic levels (2) recruitment is blocked by infusion of the NO synthase inhibitor L-NMMA (3) recruitment is blocked by Intralipid to raise plasma free fatty acids (FFA) and (4) light forearm exercise is performed. Primary endpoints are the rates of insulin and glucose uptake by forearm muscle and differences in microvascular volume. Comparisons will be made by 2-way repeated measures ANOVA with effects of time and treatment. We will integrate uptake curves to determine cumulative glucose and insulin extraction. We will also determine temporal (T1/2) and dimensional (absolute delta) relationships for glucose uptake, insulin extraction, and changes in microvascular volume. ? ? ?
