Vascular Consequences of Insulin Resistance and Obesity

伴有胰岛素抵抗、代谢综合征和2型糖尿病等肥胖相关现象的患者发生动脉粥样硬化血栓的风险明显增加。调查人员现在认识到这些疾病是对公众健康的主要威胁，我们目前对这些疾病的理解和管理策略是不充分的。研究表明，过量的热量摄入和缺乏身体活动会导致神经-体液失衡，从而促进肥胖和胰岛素抵抗，并伴有全身炎症和血脂异常。在血管壁，全身因素和局部胰岛素抵抗共同改变细胞能量和线粒体功能，激活先天免疫，并损害内皮源性一氧化氮的生物利用度。我们建议在波士顿大学医学院建立一个专门的临床导向研究中心（SCCOR），该中心将采用多学科方法来确定这种情况下血管损伤的机制。我们将检验肥胖和胰岛素抵抗诱导血管炎症和异位脂质沉积从而损害血管功能和促进动脉粥样硬化血栓形成的总体假设。项目1 （Dr. Vita）将测试amp依赖性蛋白激酶活性降低、线粒体衍生活性氧产生增加和先天免疫激活的相互作用对早期胰岛素抵抗患者血管功能障碍的假设。项目2 （Ramachandran博士）将测试循环脂肪因子、神经内分泌和肠道源性激素损害血管功能的假设，并将在Framingham心脏研究中前瞻性地预测肥胖、高血压、血脂异常和代谢综合征的发生风险。项目3 （Dr. Gokce）将测试脂肪组织作为损害肥胖患者血管功能的炎症细胞因子的主要来源的假设，并将检查特定减肥策略对血管功能和脂肪组织炎症的影响。项目4 （Freedman博士）将通过检查来自人类受试者和肥胖小鼠模型的白细胞和血小板中toll样受体（TLR）介导的信号传导机制，来验证先天免疫有助于动脉粥样硬化血栓形成和血管损伤急性反应的假设。项目5 （Hamilton博士）将使用新型磁共振成像和光谱学技术来验证异位脂质沉积是肥胖和代谢综合征中血管功能障碍和加速动脉粥样硬化的标志这一假设。

Patients with obesity-related phenomena such as insulin resistance, the metabolic syndrome, and Type 2 diabetes mellitus, have a markedly increased risk for atherothrombosis. Investigators now recognize these conditions as representing a major threat to public health and that our current understanding and management strategies of these disorders are inadequate. Studies suggest that excess caloric intake and physical inactivity lead to a neuro-humoral imbalance that promotes obesity and insulin resistance in association with systemic inflammation and dyslipidemia. In the vascular wall, systemic factors and local insulin resistance combine to alter cellular energetics and mitochondrial function, activate innate immunity, and impair the bioavailability of endothelium-derived nitric oxide. We propose to establish a Specialized Center of Clinically-Oriented Research (SCCOR) at Boston University School of Medicine that will take a multi-disciplinary approach to define mechanisms of vascular injury in this setting. We will test the overall hypothesis that obesity and insulin resistance induce inflammation and ectopic lipid deposition in vasculature that impairs vascular function and promotes atherothrombosis. Project 1 (Dr. Vita) will test the hypothesis that inter-related effects of reduced activity of AMP-dependent protein kinase, increased production of mitochondrial-derived reactive oxygen species, and activation of innate immunity contribute to vascular dysfunction in human subjects with early insulin resistance. Project 2 (Dr. Ramachandran) will test the hypothesis that circulating adipokines and neuroendocrine and gut-derived hormones impair vascular function and will prospectively predict risk for developing obesity, hypertension, dyslipidemia, and the metabolic syndrome in the Framingham Heart Study. Project 3 (Dr. Gokce) will test the hypothesis that adipose tissue serves as a primary source of inflammatory cytokines that impair vascular function in obese patients and will examine the impact of specific weight loss strategies on vascular function and inflammation in adipose tissue. Project 4 (Dr. Freedman) will test the hypothesis that innate immunity contributes to atherothrombosis and the acute response to vascular injury by examining toll-like receptor (TLR)-mediated signaling mechanisms in leukocytes and platelets from human subjects and mouse models of obesity. Project 5 (Dr. Hamilton) will use novel magnetic resonance imaging and spectroscopy techniques to test the hypothesis that ectopic lipid deposition is a marker of vascular dysfunction and accelerated atherosclerosis in obesity and the metabolic syndrome. This project takes advantage of the unique expertise of the investigators and research resources at the Boston University Medical Campus, including strong statistical support, outstanding programs of research in basic vascular biology, novel imaging resources, clinical programs for the management of obesity, and the Framingham Heart Study. This work will improve our understanding of vascular injury in insulin resistance and obesity and may identify new approaches for patient management.