CONTRAST ULTRASOUND ASSESSMENT OF MICROVASCULAR FUNCTION IN INSULIN RESISTANT

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 表示子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 骨骼肌毛细血管水平的异常微血管反应可能在胰岛素抵抗和2型糖尿病（DM）的发生发展中发挥病理生理作用。在正常情况下，生理性高胰岛素血症增加毛细血管血容量，这被认为增加了葡萄糖和胰岛素向骨骼肌的递送。这种反应的受损可能导致碳水化合物代谢受损和胰岛素抵抗。在该资助的最初资助期间，我们引入了对比增强超声（CEU）作为一种技术来表征动物模型和人类骨骼肌毛细血管对代谢刺激的反应。CEU的独特之处在于它能够分别快速量化毛细血管血容量和流速的变化。我们的研究提供了重要的信息，对生理性高胰岛素血症，饮食和运动的毛细血管募集的幅度，时间和机制。我们还证实，在肥胖患者中，生理性高胰岛素血症引起的毛细血管募集功能受损， 胰岛素抵抗的人和肥胖和晚期DM的大鼠模型。为了建立毛细血管募集功能受损的病理生理学作用，我们在本研究计划中建议在非人灵长类动物高脂饮食引起的胰岛素抵抗模型中，研究胰岛素抵抗的发生与骨骼肌毛细血管对胰岛素和运动的反应之间的时间关系 和活动限制的研究。具体而言，我们将确定骨骼肌毛细血管对胰岛素的异常反应是否先于或与胰岛素抵抗和葡萄糖代谢异常的发展一致。我们还将测试身体活动和日常锻炼对胰岛素敏感性的有益影响是否与对代谢刺激的毛细血管反应的类似有益影响相关。为了确定胰岛素抵抗发作时血管反应是否存在普遍性缺陷，我们还将研究对胰岛素的异常毛细血管反应是否与对其他生理反应（如运动、反应性充血和NO依赖性血管舒张）的异常毛细血管反应在时间上和比例上相关。我们相信这些研究对于确定异常血管反应在胰岛素抵抗和糖尿病中起着致病作用，而不仅仅是疾病的结果是至关重要的。它们还可以为研究旨在改善的新治疗策略提供基础。 通过在毛细血管水平发挥作用的血管活性剂的葡萄糖利用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Abnormal microvascular response at the skeletal muscle capillary level may play a pathophysiologic role in the development of insulin resistance and type-2 diabetes mellitus (DM). Under normal circumstances, physiologic hyperinsulinemia increases capillary blood volume which is thought to augment glucose and insulin delivery to skeletal muscle. Impairment in this response may lead to impaired carbohydrate metabolism and insulin resistance. In the initial funding period of this grant, we introduced contrast-enhanced ultrasound (CEU) as a technique to characterize skeletal muscle capillary responses to metabolic stimuli in animal models and in humans. CEU is unique in its ability to rapidly quantify changes in capillary blood volume and velocity separately. Our studies provided important information on the magnitude, timing and mechanisms of capillary recruitment that occurs in response to physiologic hyperinsulinemia, meals, and exercise. We also demonstrated that capillary recruitment in response to physiologic hyperinsulinemia is impaired in obese humans with insulin resistance and rat models of obesity and advanced DM. In order to establish a pathophysiologic role of impaired capillary recruitment, we propose in this grant renewal to study the temporal relation between the development of insulin-resistance and skeletal muscle capillary responses to insulin and exercise in a non-human primate model of insulin resistance produced by high fat diet and activity restriction in adult Rhesus macaques. Specifically, we will determine whether the onset of abnormal skeletal muscle capillary responses to insulin precedes or coincides with the development of insulin resistance and abnormalities in glucose metabolism. We will also test whether the beneficial effect of physical activity and daily exercise on insulin sensitivity correlates with similar salutary effects on capillary responses to metabolic stimuli. In order to determine whether there is a generalized deficit in vascular responses at the onset of insulin resistance, we will also study whether abnormal capillary responses to insulin correlate temporally and in proportion to abnormal capillary responses to other physiologic responses such as exercise, reactive hyperemia, and NO-dependent vasodilation. We believe that these studies are critical for establishing that abnormal vascular responses play a causative role in insulin resistance and DM and are not simply a consequence of disease. They may also provide the basis investigating new therapeutic strategy aimed at improving glucose utlization through vasoactive agents that exert an effect at the capillary level.