Adiponectin Polymorphisms, Insulin Resistance, and Pharmacokinetics in Obesity

描述（由申请人提供）：在过去三十年中，发达国家病态肥胖的发病率增加了两倍。仅在美国，65%的人口超重或肥胖。与肥胖相关的病理生理学和人体测量学变化改变了许多药物的药代动力学（PK）和药效学（PD），包括IV麻醉剂和阿片类药物。肥胖受试者的心血管和呼吸生理功能紊乱，改变了这些药物的药效学（PD），并使肥胖受试者在服用这些药物后呼吸窘迫和呼吸衰竭的风险增加。最近，已经提出肥胖受试者中胰岛素抵抗的存在或不存在占肥胖表型中的显著量的异质性。与肥胖症一起，胰岛素抵抗增加动脉粥样硬化、冠状动脉疾病和死亡率的风险，并导致局部血流、脂肪组织分布和心脏功能的变化。脂肪组织是一种高度代谢活性的组织，负责分泌脂联素，脂联素是一种具有抗炎和胰岛素增敏特性的脂肪因子。低脂联素血症与舒张功能障碍、局部血流改变和全身性高血压有关，所有这些都可能改变药物分布。此外，循环脂联素的减少可作为肥胖受试者胰岛素抵抗的标志。脂联素基因的变异可以改变脂联素的定量表达，特定的基因多态性可以作为肥胖受试者胰岛素抵抗表型的标志物。本研究的主要目的是检查肥胖人群中胰岛素抵抗对高亲脂药物（使用异丙酚和芬太尼作为模型）PK/PD的影响。我们将研究脂联素蛋白定量表达和脂联素基因单核苷酸变异对各种PK和PD表型的影响。我们假设脂联素蛋白定量表达和脂联素基因变异可以预测肥胖患者的胰岛素抵抗表型和药物反应。该职业发展奖将使候选人获得药物基因组学和转化研究方面的专业知识。候选人已完成麻醉药理学，PK和PD的研究奖学金，并已获得流行病学硕士学位。我们组建了一个专家导师团队，以确保候选人在职业发展奖励期间获得充分的支持，以实现该项目的目标，并成为药物基因组学专家。 公共卫生相关性：肥胖受试者发生麻醉药物不良反应的风险增加。胰岛素抵抗可能进一步改变肥胖人群的麻醉药物剂量需求。本项目将使用遗传标记来区分胰岛素抵抗和胰岛素敏感性肥胖受试者，并将确定这些遗传标记与麻醉药物分布、代谢和剂量需求之间的关系。

DESCRIPTION (provided by applicant): The incidence of morbid obesity has tripled over the last three decades in the developed world. In the United States alone, 65% of the population is overweight or obese. The pathophysiologic and anthropometric changes associated with obesity alter the pharmacokinetics (PK) and pharmacodynamics (PD) of numerous drugs, including IV anesthetic agents and opioids. Obese subjects have deranged cardiovascular and respiratory physiology, altering the pharmacodynamics (PD) of these drugs, and placing obese subjects at increased risk for respiratory distress and respiratory failure following administration of these agents. Recently, it has been proposed that the presence or absence of insulin resistance in obese subjects accounts for a significant amount of the heterogeneity in the obese phenotype. Together with obesity, insulin resistance increases the risk of atherosclerosis, coronary artery disease, and mortality, and accounts for changes in regional blood flow, adipose tissue distribution, and cardiac function. Adipose tissue is a highly metabolically active tissue and is responsible for the secretion of adiponectin, an adipokine with anti-inflammatory and insulin sensitizing properties. Hypoadiponectinemia is associated with diastolic dysfunction, changes in regional blood flow, and systemic hypertension, all of which may alter drug distribution. Furthermore, reductions in circulating adiponectin may serve as a marker for the insulin resistance in obese subjects. Variations in the adiponectin gene may alter quantitative adiponectin expression, and specific gene polymorphisms may serve as markers for the insulin resistant phenotype in obese subjects. The primary objective of this study is to examine the effect of insulin resistance on the PK/PD of highly lipophillic drugs (using propofol and fentanyl as models) in the obese population. We will examine the effect of quantitative adiponectin protein expression, and single nucleotide variants in the adiponectin gene on the various PK and PD phenotypes. We hypothesize that quantitative adiponectin protein expression and variants in the adiponectin gene can predict both the insulin resistant phenotype and drug response in obese subjects. This career development award will allow the candidate to gain an expertise in pharmacogenomic and translational research. The candidate has completed a research fellowship in anesthetic pharmacology, PK, and PD, and has obtained a Master of Science degree in epidemiology. A team of expert mentors has been compiled to ensure the candidate has ample support during this career development award period to meet the aims of this project and become an expert in pharmacogenomics. PUBLIC HEALTH RELEVANCE: Obese subjects are at an increased risk for adverse anesthetic drug reactions. Insulin resistance may further alter anesthetic drug dose requirements in the obese population. This project will use genetic markers to differentiate insulin resistant from insulin sensitive obese subjects, and will identify relationships between these genetic markers to anesthetic drug distribution, metabolism, and dose requirement.