HIV Antiretroviral Drugs and Glucose Metabolism

描述（由申请人提供）：使用蛋白酶抑制剂（pi）的高活性抗逆转录病毒疗法的开发与代谢异常有关，包括葡萄糖代谢紊乱、血脂异常和脂肪分布/脂肪营养不良。然而，他们的原因是有争议的。数据显示，并非所有pi的代谢作用都是直接的毒性作用，因为有些是由于恢复健康，重建免疫系统或改变脂肪分布。NRTI的作用正在显现。为了设计具有最小代谢效应的未来HIV药物，有必要确定这些药物的哪些代谢效应是直接毒性药物效应，哪些是继发于疾病状态的变化。鉴于在艾滋病毒阳性患者中解剖出不同贡献者的困难，我们已经开始研究抗逆转录病毒药物对艾滋病毒阴性对照的代谢影响。我们有证据表明，代谢作用是药物特异性的，而不是类别特异性的，pi对葡萄糖和脂质代谢有独立的影响。我们的初步数据表明，PIs影响葡萄糖代谢的几种途径，包括外周胰岛素抵抗、胰岛素分泌和肝脏葡萄糖生成。这三种病变是2型糖尿病发展的关键因素。因此，我们建议测试pi和nrti的作用如下：特定目的1a：确定哪种pi抑制人类胰岛素分泌。特异性目的1b：确定哪些pi会急性阻断人类胰岛素介导的葡萄糖处理。具体目标1c：通过定量糖异生和糖原分解来确定哪些pi增加肝糖生成和确定机制。特定目标2a：证明与瘦健康对照者相比，代谢综合征因素的受试者，口服糖耐量测试中，PIs诱导更多的糖尿病和糖耐量受损。特异性目的2b：确定PIs对代谢综合征的影响是否在胰岛素介导的葡萄糖处置、胰岛素分泌和肝糖生成抵抗水平更严重。特异性目标3a：证明NRTI组合，单独或与PI，在急性或四周研究中影响使用OGTT的HIV阴性受试者的糖代谢。特定目的3b：为了确定NRTI对葡萄糖代谢产生不利影响的机制，我们将评估它们对胰岛素介导的葡萄糖处置、胰岛素分泌和/或肝脏葡萄糖生成的影响。

DESCRIPTION (provided by applicant): The development of highly active anti-retroviral therapy with protease inhibitors (PIs) has been associated with metabolic abnormalities including disturbances in glucose metabolism, dyslipidemia, and fat distribution/lipodystrophy. However their cause is debated. Data show that not all of the metabolic effects of PIs are direct toxic effects, as some are due to restoration to health, reconstitution of immune system or changes in fat distribution. A role for NRTI is emerging. To design future HIV drugs that have the least metabolic effects it is necessary to determine which metabolic effects of these drugs are direct toxic drug effects vs. secondary to changes in disease status. Given the difficulty in dissecting out the different contributors in HIV-positive patients, we have begun studies of the metabolic effects of ARV in HIV-negative controls. We have evidence that the metabolic effects are drug-specific and not class-specific with independent effects of PIs on glucose and lipid metabolism. Our preliminary data suggest that PIs affect several pathways in glucose metabolism including peripheral insulin resistance, insulin secretion and hepatic glucose production. These three lesions are key contributors to the development of type 2 diabetes. Therefore we propose to test the effects of PIs and NRTIs as follows: Specific Aim 1a: To determine which Pls inhibit insulin secretion in humans. Specific Aim 1b: To determine which PIs acutely block insulin mediated glucose disposal in humans. Specific Aim 1c: To determine which PIs increase hepatic glucose production and to determine the mechanisms by quantifying gluconeogenesis and glycogenolysis. Specific Aim 2a: To demonstrate that in subjects with elements of Metabolic Syndrome compared to thin healthy controls, PIs induce more diabetes and impaired glucose tolerance on oral glucose tolerance testing. Specific Aim 2b: To determine if the effects of PIs in Metabolic Syndrome are more severe at the level of resistance to insulin-mediated glucose disposal, insulin secretion and hepatic glucose production. Specific Aim 3a: To demonstrate that NRTI combinations, alone or with a PI, affect glucose metabolism in HIV negative subjects using the OGTT in acute or four-week studies. Specific Aim 3b: To determine the mechanisms by which NRTI adversely affect glucose metabolism, we will assess their effects on insulin mediated glucose disposal, insulin secretion and/or hepatic glucose production.