Insulin action on Capillary Recruitment in Asian /Whites

描述（由申请人提供）：流行病学研究表明，亚洲印度人有胰岛素抵抗，患糖尿病和心血管疾病的风险增加。我们小组和其他人的研究表明，与身体质量指数（BMI）和年龄匹配的高加索人相比，亚洲印度人更具胰岛素抵抗性，身体成分改变，并且心血管风险的几种标志物水平增加。此外，我们最近发现，健康的非糖尿病亚洲印度人有胰岛素介导的血管舒张功能明显受损，其程度与胰岛素抵抗的严重程度显著相关。血管功能障碍在胰岛素抵抗综合征中起着不可或缺的作用，并可能导致动脉粥样硬化和CAD。基于来自基础血管生物学的原理，可以使用肱动脉超声和造影剂增强超声等技术来更好地了解胰岛素对血管系统的血流动力学作用，从而使我们能够了解血管反应性和骨骼肌葡萄糖摄取之间的关系。这项拨款建议的重点是胰岛素的行动，散装和微血管灌注，以及它们与葡萄糖代谢的胰岛素抵抗非糖尿病亚洲印度人。本项目的主要目标是评估生理水平的胰岛素是否通过毛细血管募集增强人体骨骼肌中的微血管灌注，使用超声造影技术。我们希望看到胰岛素对毛细血管募集和总血流量的作用之间的分离。具体而言，我们假设胰岛素对毛细血管募集的作用早于血流变化，并且毛细血管募集与胰岛素刺激骨骼肌葡萄糖摄取的能力之间存在直接关系。我们的第二个目标是确定健康的亚洲印度人是否有与胰岛素敏感性降低相关的毛细血管募集减弱。BMI和年龄匹配的健康亚洲印度人和高加索人将接受高胰岛素正葡萄糖钳夹试验，并在基线时以及高胰岛素血症30分钟和120分钟后测量毛细血管募集和肱动脉血流量，以评估血管反应性和葡萄糖摄取之间的时间关系。我们预计，生理剂量的胰岛素将增加毛细血管募集和葡萄糖摄取之前，其增加总血流量的影响发生。我们假设，胰岛素抵抗的亚洲印度人将有钝化的毛细血管募集，并将有一个显着的相关性之间的程度钝化和减少葡萄糖摄取的骨骼肌相比，高加索人。我们的研究结果将有助于我们进行研究，探索胰岛素在血管系统中的作用部位和机制，并确定胰岛素增敏剂是否通过增加毛细血管募集导致骨骼肌葡萄糖摄取增强来改善胰岛素抵抗。

DESCRIPTION (provided by applicant): Epidemiological studies suggest that Asian Indians are insulin resistant and at increased risk for diabetes and cardiovascular disease. Studies by our group and others have demonstrated that, compared to Caucasians matched for body mass index (BMI) and age, Asian Indians were more insulin resistant, had altered body composition, and had increased levels of several markers for cardiovascular risk. Furthermore, we have shown more recently that healthy non-diabetic Asian Indians have significant impairment in insulin-mediated vasodilation, the magnitude of which was significantly correlated with the severity of insulin resistance.Vascular dysfunction plays an integral part in the insulin resistance syndrome and can contribute to atherosclerosis and CAD. Based on the principles derived from basic vascular biology, techniques like brachial artery ultrasound and contrast enhanced ultrasound can be used to better understand the hemodynamic actions of insulin on the vasculature, thereby enabling us to understand the relationship between vascular reactivity and glucose uptake in skeletal muscle. This grant proposal focuses on insulin's action on both bulk and microvascular perfusion, and their relation to glucose metabolism in insulin resistant non-diabetic Asian Indians. The primary goal of this project is to assess if physiological levels of insulin enhance microvascular perfusion in human skeletal muscle by capillary recruitment, using the technique of contrast-enhanced ultrasound. We expect to see dissociation between insulin's action on capillary recruitment and total blood flow. Specifically, we hypothesize that insulin's action on capillary recruitment occurs earlier than changes in blood flow, and that there is a direct relationship between capillary recruitment and insulin's ability to stimulate glucose uptake in the skeletal muscle. Our second goal is to determine if healthy Asian Indians have blunted capillary recruitment that is related to their decreased insulin sensitivity. Healthy Asian Indian and Caucasians matched for BMI and age will undergo a hyperinsulinemic euglycemic clamp, and will have capillary recruitment and brachial artery blood flow measured at baseline, and after 30 and 120 minutes of hyperinsulinemia to assess the temporal relationship between vascular reactivity and glucose uptake. We anticipate that physiological doses of insulin will increase capillary recruitment and glucose uptake before its effect on increasing total blood flow occurs. We hypothesize that insulin resistant Asian Indians will have blunting of capillary recruitment, and that there will be a significant correlation between the magnitude of the blunting and the reduction in glucose uptake by the skeletal muscle compared to Caucasians. The results of our investigation will help us to move towards conducting studies exploring the sites and mechanisms of action of insulin in the vasculature, and to determine whether insulin sensitizers improve insulin resistance by increasing capillary recruitment leading to enhanced skeletal muscle glucose uptake.