HIV: Metabolic Abnormalities

描述（由申请人提供）：接受高效抗逆转录病毒治疗（HAART）的HIV感染者胰岛素抵抗和脂肪再分布的患病率和发生率增加，这两者均与糖尿病和心血管疾病的风险增加相关。艾滋病毒感染者胰岛素抵抗的机制知之甚少，大多数研究没有根据体脂分布的变化来检查人。中心脂肪沉积与外周脂肪萎缩患者的胰岛素抵抗发病机制可能不同;脂解速率增加可能改变外周肌肉和肝脏中的脂肪含量，导致对外周和肝脏胰岛素敏感性的不同影响。更好地了解艾滋病毒感染者的胰岛素抵抗将有助于有针对性的治疗和预防工作。这个K23指导的以患者为导向的研究职业发展奖提出了一种转化方法，使用磁共振波谱（MRS）在患有中央脂肪沉积或外周脂肪萎缩的HIV感染受试者中检查胰岛素抵抗的主要部位和机制。本提案的具体目的是：1）在具有中心脂肪沉积或外周脂肪萎缩的HIV感染受试者中，使用丁酰甘油高胰岛素钳夹和稳定同位素输注检查外周和肝脏胰岛素敏感性; 2）在具有胰岛素抵抗和中心脂肪沉积或外周脂肪萎缩的HIV感染受试者中，使用MRS测量外周肌肉和肝脏组织中的脂质含量; 3）在伴有胰岛素抵抗和中心脂肪沉积的HIV感染受试者中获得二甲双胍与安慰剂相比对外周和肝脏胰岛素敏感性和脂质含量影响的初步数据，并评估吡格列酮与安慰剂相比对伴有胰岛素抵抗和外周脂肪萎缩的HIV感染受试者中外周和肝脏胰岛素敏感性和脂质含量的影响。该职业发展奖将允许在葡萄糖/胰岛素钳夹研究，稳定同位素方法和MRS方面进行实验室培训。教学课程将包括先进的生物统计学，临床试验设计和临床研究伦理学。还将获得进行开放式临床试验和建立数据安全监测委员会的实际经验。课程，实验室培训，完成临床试验和多学科指导团队将为最终发展提供全面而严格的计划作为独立的临床研究者。 公共卫生相关性：在引入高效抗逆转录病毒治疗后不久，描述了身体脂肪的变化，包括躯干、颈部、胸部和上背部的脂肪沉积（中央脂肪沉积）和手臂、腿部和面部的脂肪萎缩（外周脂肪萎缩），作为HIV脂肪营养不良的一部分，这是一种以胰岛素抵抗、血脂异常和体型变化为特征的综合征。HIV感染者胰岛素抵抗的主要部位和机制尚不清楚，可能与体脂异常有关。本提案的目的是利用K23指导的以患者为导向的研究职业发展奖，使用丁酰肼高胰岛素钳夹、稳定同位素输注和磁共振波谱检查具有孤立性中央脂肪沉积或孤立性外周脂肪萎缩的HIV感染者的胰岛素抵抗的主要部位。

DESCRIPTION (provided by applicant): HIV-infected persons on highly active antiretroviral therapy (HAART) experience an increased prevalence and incidence of insulin resistance and fat redistribution, which are both associated with a heightened risk of diabetes and cardiovascular disease. The mechanism of insulin resistance in HIV-infected persons is poorly understood, and most studies have not examined persons based on changes in body fat distribution. The pathogenesis of insulin resistance in persons with central fat deposition vs. peripheral fat atrophy may differ; increased rates of lipolysis may alter fat content in the peripheral muscle and liver, leading to differential effects on peripheral and hepatic insulin sensitivity. A better understanding of insulin resistance in HIV-infected persons will allow targeted treatment and preventive efforts. This K23 Mentored Patient-Oriented Research Career Development Award proposes a translational approach to examine the primary site and mechanism of insulin resistance, using magnetic resonance spectroscopy (MRS), in HIV-infected subjects with either central fat deposition or peripheral fat atrophy. The specific aims of this proposal are 1) To examine peripheral and hepatic insulin sensitivity using eugylcemic hyperinsulinemic clamp and stable isotope infusion in HIV-infected subjects with either central fat deposition or peripheral fat atrophy 2) To measure lipid content in peripheral muscle and hepatic tissue using MRS in HIV-infected subjects with insulin resistance and either central fat deposition or peripheral fat atrophy 3) To obtain preliminary data on the effect of metformin vs. placebo on peripheral and hepatic insulin sensitivity and lipid content in HIV-infected subjects with insulin resistance and central fat deposition, and to assess the effect of pioglitazone vs. placebo on peripheral and hepatic insulin sensitivity and lipid content in HIV-infected subjects with insulin resistance and peripheral fat atrophy. This Career Development Award will allow hands-on laboratory training in glucose/insulin clamp studies, stable isotope methods, and MRS. Didactic coursework will include advanced biostatistics, clinical trial design, and ethics of clinical investigation. Practical experience in conducting an open clinical trial and establishing a data safety monitoring board will also be gained. The coursework, laboratory training, completion of a clinical trial, and multidisciplinary mentoring team will provide a comprehensive and rigorous program for ultimate development as an independent clinical investigator. PUBLIC HEALTH RELEVANCE: Changes in body fat, including fat deposition in the trunk, neck, chest, and upper back (central fat deposition) and fat atrophy in the arms, legs, and face (peripheral fat atrophy) were described soon after the introduction of highly active antiretroviral therapy, as part of HIV lipodystrophy, a syndrome characterized by insulin resistance, dyslipidemia, and body shape changes. The primary site and mechanism of insulin resistance in HIV-infected persons is not well understood, and likely differs by abnormalities in body fat. The objective of this proposal is to use the K23 Mentored Patient-Oriented Research Career Development Award to examine the primary site of insulin resistance in HIV-infected persons with either isolated central fat deposition or isolated peripheral fat atrophy using eugylcemic hyperinsulinemic clamp, stable isotope infusion, and magnetic resonance spectroscopy.