Insulin action on Capillary Recruitment in Asian /Whites

胰岛素对亚洲/白人毛细血管募集的作用

• 批准号: 6900593
• 负责人: annaswamy raji
• 金额: $ 8.73万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6900593
• 关键词: Asians; age difference; body composition; capillary; cardiovascular function; caucasian American; clinical research; coronary disorder; disease /disorder proneness /risk; glucose clamp technique; glucose metabolism; hemodynamics; human subject; insulin sensitivity /resistance; microcirculation; noninsulin dependent diabetes mellitus; racial /ethnic difference; striated muscles; ultrasonography

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.

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）和年龄相匹配的白种人相比，亚洲印度人的胰岛素耐受性更强，身体成分发生了变化，心血管风险的几个指标水平也有所提高。此外，我们最近的研究表明，健康的非糖尿病亚洲印第安人在胰岛素介导的血管舒张方面有显著的损害，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冠心病。基于基础血管生物学的原理，肱动脉超声和增强超声等技术可以更好地了解胰岛素对血管的血流动力学作用，从而使我们能够了解血管反应性与骨骼肌葡萄糖摄取之间的关系。本资助提案的重点是胰岛素对非糖尿病亚洲印第安人胰岛素抵抗的大血管和微血管灌注的作用及其与葡萄糖代谢的关系。本项目的主要目的是利用超声造影技术，评估生理水平的胰岛素是否通过毛细血管募集来增强人体骨骼肌的微血管灌注。我们期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。具体来说，我们假设胰岛素对毛细血管募集的作用早于血流的变化，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有关的毛细血管募集变钝。BMI和年龄匹配的健康亚洲印度人和白种人将接受高胰岛素正糖钳夹，并在基线和高胰岛素血症30分钟和120分钟后测量毛细血管募集和肱动脉血流，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会在增加总血流量之前增加毛细血管募集和葡萄糖摄取。我们假设胰岛素抵抗的亚洲印第安人毛细血管募集会变钝，并且与白种人相比，变钝的程度与骨骼肌葡萄糖摄取减少之间存在显著的相关性。我们的研究结果将有助于我们进一步开展研究，探索胰岛素在脉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从而增强骨骼肌葡萄糖摄取来改善胰岛素抵抗。