Insulin Resistance and Vascular Dysfunction

描述(由申请人提供) 流行病学研究表明，亚裔印第安人(AI)是胰岛素 抵抗(IR)并面临糖尿病和冠状动脉疾病(CAD)的风险 与北欧血统的高加索人(C)相比。增加的风险 人工智能中的CAD不能用高血压等传统危险因素来解释 而血脂异常表明其他因素也起到了作用。一个 我们小组的初步研究表明，与身体匹配的C相比 体重指数(BMI)和年龄、AI更具IR，并改变了体脂 分发。最近，人们对……的作用很感兴趣。 胰岛素抵抗在其他生理性疾病的发病机制中， 包括内皮功能障碍。独立数据表明，IR状态 如肥胖、2型糖尿病以及年轻的正常血糖IR者优先 糖尿病患者的程度亲属存在内皮功能障碍。基于这些 数据，这个项目的主要目标是测试健康的人工智能假设 与胰岛素抵抗、体脂分布改变和内皮功能障碍 C在年龄和BMI方面是匹配的。我们还假设铝有更大的内皮细胞 功能障碍与胰岛素抵抗程度相近的C组相比。这个 次要目标是确定胰岛素增敏剂是否可以改善IR和 AI的内皮功能障碍与C相比。我们假设逆转 使用胰岛素增敏剂的胰岛素抵抗将纠正内皮细胞 与使用类似胰岛素的C组相比，AI组的功能障碍程度较轻 抵抗。高加索糖尿病患者的健康AI、C和一级亲属 与BMI和年龄匹配的人将接受正血糖高胰岛素钳夹治疗 评估IR、肱动脉超声评估血管内皮功能 基础状态和胰岛素刺激状态，CT扫描测量腹部脂肪。它是 预计AI将是IR，并减少对内皮的依赖 基础状态和胰岛素刺激状态下的血管扩张。AI会有更大的 内皮功能障碍程度与IR程度相近的C组比较。这个 胰岛素增敏剂改善IR和内皮功能的能力将 接受AI和C两项检查。受试者将接受16次吡格列酮治疗 几周，并将接受初步研究所做的所有测试。它是 预计IR、内皮细胞将有实质性改善 与年龄和年龄匹配的C相比，Al和C的功能和体脂分布 体重指数。与具有相似IR的C相比，我们预计AI将有更少的 血管内皮细胞功能改善的程度，反映了 残存的血管功能障碍导致他们患冠心病的风险过高。 了解IR的潜在机制可能会有很大的好处 以及AI中的内皮功能障碍。这将使我们能够启动特定的 在这一民族中预防糖尿病和冠心病的治疗。专业知识和 我的导师们的教导和布里格姆&大学丰富的研究环境 女子医院将使我成为一名独立的内科科学家。

DESCRIPTION (provided by applicant) Epidemiological studies have shown that Asian Indians (AI) are insulin resistant (IR) and at risk for diabetes and coronary artery disease (CAD) when compared to Caucasians (C) of northern European ancestry. The increased risk of CAD in AI is not explained by the traditional risk factors like hypertension and lipid abnormalities suggesting that other factors play a role. A preliminary study by our group demonstrated that compared to C matched for body mass index (BMI) and age, AI were more IR and had altered body fat distribution. Recently there has been considerable interest in the role of insulin resistance in the pathogenesis of other physiological disorders, including endothelial dysfunction. Independent data suggests that IR states like obesity, type 2 diabetes and as well as young normoglycemic IR first degree relatives of diabetics have endothelial dysfunction. Based on these data, this project has its primary goal to test the hypothesis that healthy AI have IR, altered body fat distribution and endothelial dysfunction compared to C matched for age and BMI. We also hypothesize that Al have greater endothelial dysfunction compared to C with similar degrees of insulin resistance. The secondary goal is to determine whether insulin sensitizers can improve IR and endothelial dysfunction in AI compared to C. We hypothesize that reversing insulin resistance using insulin sensitizers will correct endothelial dysfunction to a lesser degree in AI when compared to C with comparable insulin resistance. Healthy AI, C, and first degree relatives of Caucasian diabetics matched for BMI and age will undergo euglycemic hyperinsulinemic clamp to assess IR, brachial artery ultrasound to asses endothelial function in the basal and insulin stimulated states, CT scan to measure abdominal fat. It is anticipated that AI will be IR and have decreased endothelium dependent vasodilation in the basal and insulin stimulated states. AI will have greater degree of endothelial dysfunction compared to C with similar degrees of IR. The ability of the insulin sensitizers to improve IR and endothelial function will be examined in both AI and C. Subjects will be placed on pioglitazone for 16 weeks and will undergo all the tests done for the initial study. It is anticipated that there will be a substantial improvement of IR, endothelial function, and body fat distribution in Al compared to C matched for age and BMI. When compared to C with similar IR, we expect that AI will have lesser degree of improvement of their endothelial function, reflecting the presence of residual vascular dysfunction that contributes to their excess risk of CAD. There may be a substantial benefit to understand the underlying mechanism of IR and endothelial dysfunction in AI. This will enable us to initiate specific therapy to prevent diabetes and CAD in this ethnic group. Expertise and teaching from my mentors and a rich research environment at the Brigham & Women's Hospital will enable me to become an independent physician scientist.