INSULIN MEDIATED FOREARM MUSCLE MICROVASCULAR RECRUITMENT AND INSULIN UPTAKE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 该方案的假设假定健康人体中胰岛素介导的肌肉微血管募集发生较早，并且这种微血管募集促进胰岛素递送至骨骼肌。为了检验这一假设，我们将直接测量：1）人前臂骨骼肌的胰岛素提取（动脉-静脉浓度）和绝对流量（（A-V）x流量），以及2）通过对比增强超声（CEU）评估的微血管募集程度。将在两组中进行基础和稳态高胰岛素血症期间的测量：在正常生理环境中发生胰岛素摄取和胰岛素诱导的微血管募集的受试者，以及胰岛素诱导的微血管募集被Intraperoid联合输注阻断以升高血浆游离脂肪酸（FFA）的受试者。在啮齿类动物中，已证明胰岛素样肽可阻断胰岛素介导的毛细血管募集。最后，我们将研究是否适度强度，低频肌肉收缩刺激胰岛素和葡萄糖摄取前臂肌肉和基础胰岛素的条件。主要终点是胰岛素输注期间和低频运动期间前臂肌肉摄取胰岛素和葡萄糖的速率以及组间微血管容积的差异。将通过双因素重复测量ANOVA进行比较，并考虑时间和给药的影响。对于肌肉胰岛素和葡萄糖摄取的主要比较，我们将对曲线下面积进行积分，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T1/2和微血管体积变化与胰岛素和葡萄糖摄取的绝对Δ，以解决血管募集和肌肉胰岛素摄取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.