Neural Mechanism of Thiazide-Induced Insulin Resistance

描述（由申请人提供）：具有里程碑意义的降压和降脂治疗预防心脏病发作试验（ALLHAT）重新将注意力集中在噻嗪类利尿剂作为大多数高血压患者的一线治疗上。尽管已证实噻嗪类药物可减少心血管疾病的预后，且成本较低，但人们仍担心噻嗪类药物的主要副作用之一——葡萄糖耐受不良——可能会加剧目前美国2型糖尿病的流行，在典型的5年高血压试验期间，其对心血管的长期影响被低估了。经过几十年的临床使用，我们仍然不知道噻嗪类利尿剂是如何引起葡萄糖耐受不良的。我的试验数据使我假设：(a)这些药物触发骨骼肌反射性交感神经激活，这是胰岛素介导的葡萄糖处理的主要部位；(b)通过使用矿皮质激素受体拮抗剂而不是噻嗪类利尿剂作为高血压的一线治疗，可以避免交感神经激活和葡萄糖耐受不良。因此，我们将在一个大型的多民族高血压受试者队列中测试氯噻酮是否会引起肌肉交感神经活动（SNA）的持续增加，促进神经源性血管收缩，减少骨骼肌的葡萄糖提取，以及螺旋内酯是否会避免这种交感神经激活和由此产生的葡萄糖耐受不良。该提案的显著特点包括：(1)在综合生理学中使用最先进的技术；(2)关注肌肉交感神经活动对骨骼肌葡萄糖摄取和全身胰岛素敏感性的功能作用；(3) MR拮抗剂对中枢交感神经外流的调节，传统上认为MR拮抗剂只是一种节省钾的利尿剂。这项转化性研究将填补我们对噻嗪类利尿剂诱导胰岛素抵抗机制理解的一些重要空白，并提供一种策略，以避免这种神经激素激活和代谢并发症，同时保持螺内酯的降压效果。

DESCRIPTION (provided by applicant): The landmark Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) has refocused attention on the thiazide-type diuretics as the first-line therapy for most patients with hypertension. Despite proven reduction in cardiovascular outcomes and low costs, there is on-going concern that one of the major side effect of the thiazides--glucose intolerance--may fuel the current U.S. epidemic of type 2 diabetes, the long-term cardiovascular impact of which is underestimated in the typical 5 year duration of a hypertension trial. After decades of clinical use, we still do not know how thiazide diuretics cause glucose intolerance. My pilot data lead me to hypothesize that (a) these drugs trigger reflex sympathetic activation in the skeletal muscle, a major site of insulin-mediated glucose disposal and (b) the sympathetic activation and the glucose intolerance can be avoided by using mineralocorticoid receptor antagonists rather than thiazide diuretics as first-line therapy for hypertension. Accordingly, we will test, in a large multiethnic cohort of hypertensive subjects, whether chlorthalidone causes a sustained increase in muscle sympathetic nerve activity (SNA), promoting neurogenic vasoconstriction and reducing glucose extraction by skeletal muscle and if spironolactone avoids such sympathetic activation and the resultant glucose intolerance. The distinctive features of this proposal include the: (1) use of state-of-the-art techniques in integrative physiology; (2) focus on the functional role of muscle sympathetic nerve activity on skeletal muscle glucose uptake and total body insulin sensitivity; and (3) the focus on modulation of central sympathetic outflow by MR antagonist, which traditionally has been viewed simply as a potassium sparing diuretic agent. This translational research should fill in some important gaps in our mechanistic understanding of the thiazidediuretics induced insulin resistance and offer a strategy to avoid such neurohormonal activation and metabolic complications while preserving antihypertensive efficacy with spironolactone.