Neural Mechanism of Thiazide-Induced Insulin Resistance

描述（由申请人提供）：具有里程碑意义的预防心脏病发作的降压和降脂治疗试验（ALLHAT）重新关注噻嗪类利尿剂作为大多数高血压患者的一线治疗。尽管已证实可降低心血管结局和降低成本，但仍存在持续关注，即噻嗪类药物的主要副作用之一-葡萄糖耐受不良-可能加剧目前美国2型糖尿病的流行，其长期心血管影响在典型的5年高血压试验中被低估。经过几十年的临床应用，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中的反射交感神经激活，这是胰岛素介导的葡萄糖处置的主要部位;（B）通过使用盐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，我们将在一个大型多种族高血压受试者队列中测试氯噻酮是否会导致肌肉交感神经活动（SNA）持续增加，促进神经源性血管收缩并减少骨骼肌的葡萄糖提取，以及螺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。该提案的显著特征包括：（1）使用综合生理学中最先进的技术;（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）关注MR拮抗剂对中枢交感神经流出的调节，传统上MR拮抗剂被视为保钾利尿剂。这项转化研究应该填补了我们对噻嗪类利尿剂诱导的胰岛素抵抗的机制理解中的一些重要空白，并提供了一种避免此类神经激素激活和代谢并发症的策略，同时保留螺内酯的降压疗效。

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.