METABOLIC CONSEQUENCES OF ANTIRETROVIRAL THERAPY

描述：(改编自申请者的摘要)一个新的糟糕的 已了解的综合征，可能包括中心身体脂肪重新分布， 高脂血症和高血糖最近被认为是 接受高效抗逆转录病毒治疗(HAART)的患者 艾滋病毒感染。很可能这些新陈代谢的变化，类似于 那些出现在库欣综合征中的人，将显著增加风险 在接受治疗的个体中用于过早的冠状动脉疾病。虽然 显性库欣综合征已被排除在受影响的个人中， 还没有报道过基于实际测量的研究 皮质醇生成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 治疗方案可能通过以下途径直接刺激腹部脂肪细胞的生长 对前体脂肪细胞关键转录激活因子PPAR-γ的影响 差异化。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名未感染的对照组受试者将 跟踪一年，对区域机构进行敏感的测量 成分、脂肪和葡萄糖代谢、皮质醇的产生以及 脂肪细胞基因表达。这项研究的具体目的有两个： 首先，将制定代谢综合征的病例定义 基于对易感临床因素的识别和对 体成分、脂蛋白水平、ANS变化的比较 受试者在研究过程中发生的葡萄糖代谢。 与HAART相关的高脂血症的动脉粥样硬化将是 通过对脂蛋白亚组分的详细分析而完全定义的。这个 这项研究的第二个目标是检验以下假设：(A) 生理性高皮质醇血症+皮质醇受体增加 表达，或(B)PPARγ表达或激活增加 腹部前脂肪细胞预测代谢的后续发展 接受HAART的受试者中的异常。侦查决定论 这两个假说都是基于生物上的可信性 潜在的机制和药物的可获得性 用于具体阻断糖皮质激素的作用(RU-486)或增加 PPAR-γ在外周相对于腹部的激活 前脂肪细胞(噻唑二酮)。未来这些药物的试验， 以及更多的基础研究，显然是有道理的 不断增加和持续使用HAART来应对世界范围内的 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.