INSULIN MEDIATED FOREARM MUSCLE MICROVASCULAR RECRUITMENT AND INSULIN UPTAKE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 该方案的假设假设胰岛素介导的肌肉微血管募集在健康人中发生得较早，这种微血管募集促进了胰岛素向骨骼肌的输送。为了验证这一假设，我们将直接测量：1)人前臂骨骼肌的胰岛素提取(动-静脉浓度)和绝对流量((A-V)x流量)，以及2)超声造影(CEU)评估的微血管募集程度。将在两组基础上和稳态高胰岛素血症期间进行测量：在正常生理环境下发生胰岛素摄取和胰岛素诱导的微血管募集的受试者，以及通过联合输注Intralipid以提高血浆游离脂肪酸(FFA)来阻断胰岛素诱导的微血管募集的受试者。脂内脂肪已被证明可以阻断胰岛素在啮齿动物体内的毛细血管募集。最后，我们将检验中等强度、低频率的肌肉收缩是否刺激前臂肌肉对胰岛素和葡萄糖的吸收，以及基础胰岛素的状况。主要终点是胰岛素输注和低频运动时前臂肌肉对胰岛素和葡萄糖的摄取率，以及两组之间的微血管体积差异。比较将采用双向重复测量方差分析与时间和处理的影响。对于肌肉胰岛素和葡萄糖摄取的初步比较，我们将对曲线下的面积进行积分，以确定研究过程中总累积葡萄糖和胰岛素摄取的差异。我们还将估计微血管体积与胰岛素和葡萄糖摄取的变化的T1/2和绝对增量，以解决血管募集和肌肉摄取胰岛素之间的时间和空间关系。

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.