Pan-arterial insulin resistance - a target for clinical intervention

描述（由申请人提供）：整个动脉血管功能障碍是2型糖尿病（DM 2）和代谢综合征（MS）患者显著发病率/死亡率的原因。健康受试者的动脉血管对胰岛素有反应，这种反应因胰岛素抵抗（IR）而受损。现有的无创方法可以全面评估胰岛素在3个动脉血管水平的作用，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测量来解决与胰岛素抵抗对血管功能的影响有关的几个基本问题。我们的一般假设是IR，无论是实验诱导的还是与MS和DM 2一起发生的，都会损害所有水平的动脉血管功能。我们进一步假设，先前显示改善血管预后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与心血管疾病（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（AT1R）阻滞剂、矿皮质激素受体（MR）阻滞剂和饮食/运动对心血管疾病的有益临床作用的基本原理；C)提示泛动脉功能的早期评估为后期临床试验提供了一个改进候选治疗选择的平台。在Aim 1中，我们将测量健康受试者的泛动脉血管功能和胰岛素反应性，并评估单顿高脂肪餐对胰岛素血管和代谢作用的影响。在Aim 2中，在MS患者中，我们将再次测量在安慰剂或二甲双胍治疗前后12周的泛动脉血管功能和胰岛素敏感性，同时采用或不采用低饱和脂肪饮食结合运动训练的随机2 × 2设计。在Aim 3中，在二甲双胍治疗的2型糖尿病受试者中，我们将在盲法交叉研究中，在接受AT1R阻滞剂、MR阻滞剂或安慰剂治疗12周前后，对泛动脉血管功能和血管胰岛素敏感性进行表征。

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.