METABOLIC CONSEQUENCES OF ANTIRETROVIRAL THERAPY

描述：（改编自申请人的摘要）一个新的和差 可以理解的综合征可能包括中心体脂肪再分布， 高脂血症和高血糖症最近已被认识到， 接受高效抗逆转录病毒治疗（HAART）的人 艾滋病毒感染。很可能这些代谢变化， 在库欣综合征中出现的那些， 治疗个体的早发冠状动脉疾病。虽然 显性库欣综合征已被排除在受影响的个体中， 目前还没有基于实际测量的研究报告， 皮质醇产生率或组织对糖皮质激素的敏感性 接受HAART治疗的受试者。同样，尚不清楚HAART是否 治疗方案可以直接刺激腹部脂肪细胞的生长， 对前脂肪细胞的关键转录激活因子--过氧化物酶体增殖物激活受体γ的影响 分化在这项研究中，180名艾滋病毒感染者即将 开始蛋白酶抑制剂治疗，50名未感染的对照受试者将 进行为期一年的区域体敏感测量 组成、脂质和葡萄糖代谢、皮质醇产生，以及 脂肪细胞基因表达本研究的具体目标有两个： 首先，将制定代谢综合征的病例定义 基于对诱发性临床因素的识别， 比较身体组成、脂蛋白水平、ANS 在研究过程中受试者发生的葡萄糖代谢。 与HAART相关的高脂血症的致动脉粥样硬化性将是 通过对脂蛋白亚组分的详细分析完全定义。的 研究的第二个目的是检验以下假设：（a） 生理性高皮质醇血症+皮质醇受体增加 表达，或（B）增加的PPAR γ表达或活化， 腹部前脂肪细胞可预测代谢紊乱的后续发展 接受HAART治疗的受试者的异常。调查决定 这两个假设是基于生物相容性， 潜在的机制和药物的可用性， 用于特异性阻断糖皮质激素作用（RU-486）或增加 外周相对于腹部过氧化物酶体增殖物激活受体γ激活 前脂肪细胞（噻唑烷二酮类）。这些药物的未来试验， 沿着大量的基础研究， 越来越多地持续使用HAART来应对全球范围内的 艾滋病毒感染的流行。

DESCRIPTION: (Adapted from applicant's abstract) A new and poorly understood syndrome that may include central body fat redistribution, hyperlipidemia, and hyperglycemia has recently been recognized in individuals receiving highly active antiretroviral therapy (HAART) for HIV infection. It is likely that these metabolic changes, which resemble those seen in Cushing's syndrome, will significantly increase the risk for premature coronary artery disease in treated individuals. Although overt Cushing's syndrome has been excluded in affected individuals, there have been no reported studies based on actual measurement of cortisol production rates or tissue sensitivity to glucocorticoids in subjects receiving HAART. Similarly, it is not known whether HAART regimens may directly stimulate growth of abdominal adipocytes through an effect on PPAR gamma, a key transcriptional activator of preadipocyte differentiation. In this study, 180 HIV-infected individuals about to begin protease inhibitor therapy and 50 uninfected control subjects will be followed for one year with sensitive measurements of regional body composition, lipid and glucose metabolism, cortisol production, and adipocyte gene expression. The Specific Aims of this study are twofold: First, a case definition of the metabolic syndrome will be formulated based on identification of predisposing clinical factors and a comparison of changes in body composition, lipoprotein levels, ans glucose metabolism occurring in subjects over the course of the study. The atherogenicity of the hyperlipidemia associated with HAART will be fully defined by a detailed analysis of lipoprotein subfractions. The second aim of the study will be to test the hypotheses that (a) physiological hypercortisolemia + increased cortisol receptor expression, or (b) increased expression or activation of PPAR gamma is abdominal preadipocytes predict the subsequent development of metabolic abnormalities in subjects receiving HAART. The decision of investigate these two hypotheses was based on both the biological plausibility of the underlying mechanisms and the availability of drugs that might be used to specifically block glucococorticoid action (RU-486) or increase the activation of PPAR gamma in peripheral relative to abdominal preadipocytes (thiazolidenediones). Future trials of these medications, along with a great deal more basic research, are clearly justified by the increasing and sustained use of HAART to deal with the worldwide epidemic of HIV infection.