Adiponectin Polymorphisms, Insulin Resistance, and Pharmacokinetics in Obesity

肥胖症中的脂联素多态性、胰岛素抵抗和药代动力学

• 批准号: 8721976
• 负责人: Jerry Ingrande
• 金额: $ 19.83万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721976
• 关键词: Accounting; Adipocytes; Adipose tissue; Affect; Anesthesia procedures; Anesthetics; Anti-Inflammatory Agents; Anti-inflammatory; Atherosclerosis; Biopsy; Blood specimen; Cardiac; Cardiovascular Physiology; Coronary Arteriosclerosis; Cytochrome P450; Cytochrome P450 3A4; Data; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Drug usage; Ensure; Enzymes; Epidemiology; Fellowship; Fentanyl; Functional disorder; Gene Expression; Genes; Genetic Markers; Genetic Polymorphism; Genotype; Glucose; Hepatic Tissue; Heterogeneity; Hybrids; Hypertension; Incidence; Infusion procedures; Insulin; Insulin Resistance; K-Series Research Career Programs; Kinetics; Master of Science; Mentors; Metabolism; Modeling; Morbid Obesity; Nucleotides; Obesity; Opioid; Overweight; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenomics; Pharmacology; Phenotype; Physiological; Population; Process; Property; Propofol; Reaction; Regional Blood Flow; Research; Resistance; Respiratory Failure; Respiratory distress; Respiratory physiology; Risk; Single Nucleotide Polymorphism; Site; Therapeutic; Time; Tissues; Translational Research; United States; Variant; adipocyte differentiation; adiponectin; cohort; drug distribution; drug metabolism; enzyme activity; genetic variant; meetings; mortality; pharmacodynamic model; protein expression; respiratory; response

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.

在过去的三十年里，发达国家病态肥胖症的发病率增加了两倍。 仅在美国，65%的人口超重或肥胖。病理生理学和 与肥胖相关的人体测量学改变改变了药代动力学(PK)和 多种药物的药效学(PD)，包括静脉麻醉剂和阿片类药物。肥胖 受试者扰乱了心血管和呼吸生理学，改变了药效学 (PD)，并使肥胖者面临更高的呼吸窘迫和 服用这些药物后发生呼吸衰竭。最近，有人提出， 肥胖者胰岛素抵抗的存在或不存在在很大程度上解释了 肥胖表型的异质性。与肥胖一起，胰岛素抵抗会增加患糖尿病的风险 动脉粥样硬化、冠状动脉疾病和死亡率，并解释了区域血液的变化 血流、脂肪组织分布和心功能。脂肪组织是一种高度新陈代谢活跃的 组织，负责分泌脂联素，一种具有抗炎和 胰岛素增敏特性。低脂联素血症与舒张期功能障碍相关， 局部血流和全身性高血压，所有这些都可能改变药物分布。此外， 循环脂联素的减少可能是肥胖者胰岛素抵抗的一个标志。 脂联素基因的变异可能改变脂联素的定量表达，以及特定的基因 基因多态性可作为肥胖人群胰岛素抵抗表型的标志物。这个 本研究的主要目的是探讨胰岛素抵抗对高血压病患者PK/PD的影响。 肥胖人群中脂磷脂药物(以异丙酚和芬太尼为模型)的研究。我们将研究 脂联素定量蛋白表达及其单核苷酸变异对脂联素的影响 基因对各种PK和PD表型的影响。我们假设定量的脂联素蛋白 脂联素基因的表达和变异可以预测胰岛素抵抗的表型和 肥胖受试者的药物反应。该职业发展奖将使应聘者获得 在药物基因组学和翻译研究方面的专业知识。候选人已经完成了一项研究 麻醉药理学、PK和PD方面的研究员，并于年获得理学硕士学位 流行病学。已经组建了一支专家导师团队，以确保候选人有足够的 在此职业发展奖励期间提供支持，以满足本项目的目标并成为 药物基因组学专家。