HIV: Metabolic Abnormalities

描述（由申请人提供）：接受高效抗逆转录病毒治疗（HAART）的艾滋病毒感染者的胰岛素抵抗和脂肪再分配的患病率和发病率增加，这两者都与糖尿病和心血管疾病的风险增加有关。艾滋病毒感染者的胰岛素抵抗机制尚不清楚，大多数研究没有根据体脂分布的变化对患者进行检查。中枢性脂肪沉积与外周性脂肪萎缩患者胰岛素抵抗的发病机制可能不同；增加的脂肪分解率可能改变外周肌肉和肝脏的脂肪含量，导致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。这项K23指导患者导向的研究职业发展奖提出了一种转化方法，利用磁共振波谱（MRS）在患有中枢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。本研究的具体目的是：1)利用高血糖胰岛素钳和稳定同位素输注检测伴有中央性脂肪沉积或外周性脂肪萎缩的hiv感染者的外周和肝脏胰岛素敏感性；2)利用MRS测量伴有中央性脂肪沉积或外周性脂肪萎缩的hiv感染者的外周肌肉和肝组织中的脂质含量；3)获得二甲双胍与外周性脂肪萎缩的影响的初步数据。安慰剂对伴有胰岛素抵抗和中心脂肪沉积的hiv感染者外周和肝脏胰岛素敏感性和脂质含量的影响，并评估吡格列酮与安慰剂对伴有胰岛素抵抗和外周脂肪萎缩的hiv感染者外周和肝脏胰岛素敏感性和脂质含量的影响。该职业发展奖将提供葡萄糖/胰岛素钳研究、稳定同位素方法和mrs的动手实验室培训。教学课程将包括高级生物统计学、临床试验设计和临床研究伦理。还将获得开展公开临床试验和建立数据安全监测委员会的实际经验。课程作业、实验室培训、临床试验的完成和多学科指导团队将为独立临床研究者的最终发展提供全面而严格的计划。

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.