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Pan-arterial insulin resistance - a target for clinical intervention

全动脉胰岛素抵抗——临床干预的目标

基本信息

批准号：
8837610
负责人：
EUGENE Joseph BARRETT
金额：
$ 37.58万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-15 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8837610
关键词：
Address Adult Age Angiotensin II Type 1 Receptor Blockers Antihypertensive Agents Arteries Atherosclerosis Biological Markers Blinded Blood Pressure Blood Vessels Blood capillaries Cardiovascular Diseases Clinical Clinical Trials Congestive Heart Failure Cross-Over Studies Data Diet Disease Outcome Elasticity Euglycemic Clamping Evaluation Event Exercise Fatty acid glycerol esters Figs - dietary Functional disorder Glucose Glucose Clamp Health Hour Hyperglycemia Hyperinsulinism Hypertension Individual Insulin Insulin Resistance Intervention Left Ventricular Hypertrophy Measures Mechanics Mediating Metabolic Metabolic syndrome Metformin Methods Mineralocorticoid Receptor Morbidity - disease rate Muscle Myocardial Infarction Non-Insulin-Dependent Diabetes Mellitus Outcome Patients Physiologic pulse Placebos Population Property Randomized Receptor, Angiotensin, Type 1 Relaxation Resistance Risk Risk Factors Selection for Treatments Single-Blind Study Stimulus Stroke Systolic Pressure Testing Tissues Training Trees Ultrasonography Vascular Diseases arterial stiffness arteriole base capillary cardiovascular disorder risk clinical effect contrast enhanced design diet and exercise high risk improved indexing insulin sensitivity mortality novel response saturated fat trial comparing

项目摘要

DESCRIPTION (provided by applicant): Dysfunction throughout the arterial vasculature is responsible for significant morbidity/mortality in patients with type 2 diabetes (DM 2) and metabolic syndrome (MS). The arterial vasculature in healthy subjects responds to insulin and this response is impaired with insulin resistance (IR). Available noninvasive methods allow comprehensive evaluation of insulin action at each of 3 levels of arterial vasculature, including conduit, resistance, and microvascular vessels. Here we propose to use measures of pan-arterial vascular function and insulin sensitivity to address several fundamental questions related to the impact of insulin resistance on vascular function. Our general hypothesis is that IR, either induced experimentally or as occurs with MS and DM 2, impairs vascular function at all levels of the arterial vasculature. We further hypothesize that treatments previously shown to improve vascular outcomes will effectively improve this pan-arterial dysfunction. If these hypotheses prove correct, they may provide: A) a functional mechanism to explain the linkage between IR and cardiovascular diseases (CVD); B) a rationale for the previously observed salutory clinical effects of metformin, type 1 angiotensin II receptor (AT1R) blockers, mineralocorticoid receptor (MR) blockers and diet/exercise on CVD and; C) a basis to suggest that early assessment of pan-arterial function affords a platform to improve candidate treatment selection for later clinical trials. In Aim 1, we will measure pan-arterial vascular function and insulin responsiveness in healthy subjects and assess the effect of a single high-fat meal on insulin's vascular and metabolic actions. In Aim 2, in subjects with MS, we will again measure pan-arterial vascular function and insulin sensitivity before and following 12 weeks treatment with a placebo or metformin with or without a diet low in saturated fat combined with exercise training in a randomized 2 X 2 design. In Aim 3, in metformin-treated DM 2 subjects, we will characterize pan-arterial vascular function and vascular insulin sensitivity before and following 12 weeks treatment with an AT1R blocker, a MR blocker or a placebo in a blinded, crossover study.

描述（由申请方提供）：整个动脉血管系统的功能障碍是2型糖尿病（DM 2）和代谢综合征（MS）患者的显著发病率/死亡率的原因。健康受试者的动脉血管系统对胰岛素有反应，这种反应因胰岛素抵抗（IR）而受损。可用的无创方法允许在动脉血管系统的3个水平中的每一个上全面评价胰岛素作用，包括导管、阻力和微血管。在这里，我们建议使用泛动脉血管功能和胰岛素敏感性的措施，以解决几个基本的问题，胰岛素抵抗对血管功能的影响。我们的一般假设是，IR，无论是实验诱导或发生与MS和DM 2，损害血管功能在所有水平的动脉血管。我们进一步假设，先前显示改善血管结局的治疗将有效改善这种泛动脉功能障碍。如果这些假设被证明是正确的，它们可能提供：A）解释IR和心血管疾病（CVD）之间联系的功能机制; B）先前观察到的二甲双胍、1型血管紧张素II受体（AT 1 R）阻断剂、盐皮质激素受体（MR）阻断剂和饮食/运动对CVD的saltine临床作用的原理; C）一个基础，表明早期评估泛动脉功能提供了一个平台，以改善候选治疗的选择，为以后的临床试验。在目标1中，我们将测量健康受试者的全动脉血管功能和胰岛素反应性，并评估单次高脂肪餐对胰岛素血管和代谢作用的影响。在目标2中，在MS受试者中，我们将再次测量安慰剂或二甲双胍治疗12周前后的全动脉血管功能和胰岛素敏感性，采用随机2 × 2设计，伴或不伴低饱和脂肪饮食和运动训练。在目标3中，在二甲双胍治疗的DM 2受试者中，我们将在一项设盲、交叉研究中描述AT 1 R阻滞剂、MR阻滞剂或安慰剂治疗12周前后的全动脉血管功能和血管胰岛素敏感性。