Metabolic Effects of Antihypertensive Drugs

描述（由申请人提供）：职业发展：这个K-23职业发展奖申请的目标是为候选人成为一名独立的以患者为导向的研究人员做好准备。申请人的主要兴趣领域是通过确定最大化胰岛素敏感性的药理学和药物基因组学组合来减轻代谢综合征患者抗高血压治疗相关的不良代谢影响。佛罗里达大学有资源为申请人提供理想的环境来检查抗高血压治疗中胰岛素抵抗的临床和药物基因组学方面。拟议的职业发展计划包括以流行病学为重点的结构化教学计划，这将导致通过K30计划获得流行病学硕士学位。此外，申请人将参加由代谢综合征的药物基因组学、流行病学和葡萄糖稳态领域的专家主持的研讨会、会议和重点实验室研究教程。临床和实验室调查。以胰岛素抵抗为主要特征的代谢综合征患者患糖尿病的风险增加，通常伴有高血压（HTN）。噻嗪类利尿剂被推荐用于治疗代谢综合征患者的HTN，尽管它与代谢紊乱相关，导致胰岛素抵抗增加。本研究的主要假设是，在代谢综合征和HTN患者中，用血管紧张素转换酶（ACE）抑制剂阻断肾素-血管紧张素系统（RAS）可减轻噻嗪类利尿剂的不良代谢作用。特定的目的是研究这种衰减是否发生在利尿剂中加入ACE抑制剂后和/或作为ACE抑制剂预处理的结果。此外，将在6000名高血压CAD患者的单独队列中进行实验室药物基因组学研究，以确定ACE、ADD1和KCNJ1基因与糖尿病相关的多态性，这些基因是根据ACE抑制剂和利尿反应的关键作用而选择的。本研究旨在克服关于抗高血压药物对代谢综合征患者代谢影响的知识空白，并将为影响未来的处方模式提供数据。

DESCRIPTION (provided by applicant): Career Development: The objective of this K-23 Career Development Award application is to prepare the candidate for a career as an independent patient oriented researcher. The applicant's primary area of interest is in attenuating the adverse metabolic effects associated with antihypertensive therapy in patients with metabolic syndrome by identifying pharmacologic and pharmacogenomic combinations that maximize insulin sensitivity. The University of Florida has the resources to provide the applicant with the ideal setting to examine both the clinical and pharmacogenomic aspects of insulin resistance in the setting of antihypertensive therapy. The proposed career development plan incorporates a structured didactic program focused in epidemiology, which will result in a master's degree in epidemiology via the K30 program. Additionally, the applicant will participate in seminars, conferences and focused laboratory based research tutorials conducted by experts in the field of pharmacogenomics, epidemiology and glucose homeostasis in the setting of metabolic syndrome. Clinical and Laboratory Investigations. Patients with metabolic syndrome, characterized primarily by insulin resistance are at increased risk of developing diabetes and often have hypertension (HTN). Thiazide diuretics are recommended for treating HTN in patients with metabolic syndrome, despite being associated with metabolic disturbances that result in increased insulin resistance. The major hypothesis of this study is that in patients with metabolic syndrome and HTN, blockade of the renin-angiotensin system (RAS) with an angiotensin converting enzyme (ACE) inhibitor attenuates the adverse metabolic effects of a thiazide diuretic. Specific aims are designed to investigate whether this attenuation occurs after the addition of ACE inhibitor to diuretic and/or as a consequence of pretreatment with an ACE inhibitor. Also, laboratory based pharmacogenomic investigations will be conducted in a separate cohort of 6000 hypertensive CAD patients to identify polymorphisms associated with diabetes in the ACE, ADD1 and KCNJ1 genes, selected on the basis of their critical role in ACE inhibitor and diuretic response. This research seeks to overcome gaps in knowledge regarding the metabolic impact of antihypertensive drugs in patients with metabolic syndrome and will provide data to influence future prescribing patterns.