Pan-arterial insulin resistance - a target for clinical intervention

描述(由申请人提供)：在2型糖尿病(DM 2)和代谢综合征(MS)患者中，动脉血管功能障碍是导致显著发病率/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，这种反应在胰岛素抵抗(IR)时受损。可用的非侵入性方法可以全面评估胰岛素在动脉血管系统的3个水平上的作用，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，无论是实验诱导的IR，还是MS和DM-2所发生的IR，都会损害动脉血管系统的所有水平的血管功能。我们进一步假设，以前证明可以改善血管结果的治疗将有效地改善这种泛动脉功能障碍。如果这些假说被证明是正确的，它们可能提供：a)一个解释IR和心血管疾病(CVD)之间联系的作用机制；b)一个先前观察到的二甲双胍、1型血管紧张素II受体(AT1R)阻滞剂、盐皮质激素受体(MR)阻滞剂和饮食/运动治疗心血管疾病临床疗效良好的基础；c)一个基础表明，对泛动脉功能的早期评估为以后的临床试验改进候选治疗选择提供了一个平台。在目标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，并评估单一高脂餐对胰岛素血管和代谢活动的影响。在目标2中，在MS受试者中，我们将以随机的2×2设计，在安慰剂或二甲双胍加或不加低饱和脂肪饮食和运动训练治疗12周之前和之后再次测量泛动脉血管功能和胰岛素敏感性。在目标3中，在接受二甲双胍治疗的2型糖尿病患者中，我们将在使用AT1R阻滞剂、MR阻滞剂或安慰剂治疗12周之前和12周后进行交叉盲法研究，以确定泛动脉血管功能和血管胰岛素敏感性。

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.