Neural Mechanism of Thiazide-Induced Insulin Resistance

噻嗪类药物诱导胰岛素抵抗的神经机制

• 批准号: 7340203
• 负责人: WANPEN VONGPATANASIN
• 金额: $ 36.98万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7340203
• 关键词: Adverse effects; Affinity; Ambulatory Blood Pressure Monitoring; Androgens; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arts; Attention; Baroreflex; Blood Pressure; Cardiovascular system; Chlorthalidone; Chronic; Clinical; Data; Diuresis; Diuretics; Dose; Epidemic; Essential Hypertension; Glucose; Glucose Intolerance; Hemodialysis; Hour; Hypertension; Impairment; Insulin; Insulin Resistance; Lead; Lipids; Measures; Mediating; Metabolic Activation; Microelectrodes; Mineralocorticoid Receptor; Muscle; Myocardial Infarction; Nerve; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Patients; Pharmaceutical Preparations; Physiology; Potassium; Progesterone Receptors; Property; Reflex action; Research Personnel; Role; Site; Skeletal Muscle; Spironolactone; Staging; Supplementation; Sympatholytics; Techniques; Testing; Thiazide Diuretics; Translational Research; cohort; cost; eplerenone; falls; glucose disposal; glucose uptake; insulin sensitivity; neuromechanism; prevent; programs; thiazide; vasoconstriction

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.

描述(申请人提供)：具有里程碑意义的降压和降脂治疗以预防心脏病发作试验(ALLHAT)将注意力重新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。尽管已证实可以降低心血管疾病的结果和降低成本，但人们一直担心，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，在高血压试验的典型5年期间，这种疾病对心血管的长期影响被低估了。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糖耐量异常的。我的初步数据让我假设：(A)这些药物在骨骼肌中触发反射性交感神经激活，这是胰岛素介导的葡萄糖处置的主要部位，以及(B)交感神经激活和葡萄糖耐量异常可以通过使用盐皮质激素受体拮抗剂而不是噻嗪利尿剂作为高血压的一线治疗药物来避免。因此，我们将在一大批多民族的高血压受试者中测试氯苯妥酮是否会导致肌肉交感神经活性(SNA)的持续增加，促进神经源性血管收缩和减少骨骼肌的葡萄糖提取，以及螺内酯是否可以避免这种交感神经激活和由此产生的葡萄糖耐量异常。这一建议的显著特点包括：(1)综合生理学中最先进的技术的使用；(2)专注于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)专注于MR拮抗剂对中枢交感神经流出的调节，传统上它被简单地视为一种省钾利尿剂。这项转化研究将填补我们对噻嗪类利尿剂引起的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疗效。

项目成果

Hydrochlorothiazide is not the most useful nor versatile thiazide diuretic.

• DOI: 10.1097/hco.0000000000000178
• 发表时间: 2015-07
• 期刊: Current opinion in cardiology
• 影响因子: 2.3
• 作者: Vongpatanasin W

Differential effects of nebivolol versus metoprolol on functional sympatholysis in hypertensive humans.

• DOI: 10.1161/hypertensionaha.113.01302
• 发表时间: 2013-06
• 期刊: Hypertension (Dallas, Tex. : 1979)
• 作者: Price A;Raheja P;Wang Z;Arbique D;Adams-Huet B;Mitchell JH;Victor RG;Thomas GD;Vongpatanasin W
• 通讯作者: Vongpatanasin W

Spironolactone prevents chlorthalidone-induced sympathetic activation and insulin resistance in hypertensive patients.

• DOI: 10.1161/hypertensionaha.112.194787
• 发表时间: 2012-08
• 期刊: Hypertension (Dallas, Tex. : 1979)
• 作者: Raheja P;Price A;Wang Z;Arbique D;Adams-Huet B;Auchus RJ;Vongpatanasin W
• 通讯作者: Vongpatanasin W