HIV Antiretroviral Drugs and Glucose Metabolism

HIV 抗逆转录病毒药物与葡萄糖代谢

• 批准号: 6858556
• 负责人: Carl Grunfeld
• 金额: $ 37.13万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6858556
• 关键词: adolescence (12-20); adult human (21+); antiviral agents; clinical research; gluconeogenesis; glucose metabolism; glucose tolerance; glycogenolysis; human immunodeficiency virus; human subject; human therapy evaluation; insulin sensitivity /resistance; microorganism disease chemotherapy; patient oriented research; protease inhibitor

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.

描述(申请人提供)：用蛋白水解酶抑制剂(PI)进行高效抗逆转录病毒治疗的发展与代谢异常有关，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，他们的事业仍有争议。数据显示，PIs的代谢影响并不都是直接的毒性影响，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的角色正在浮现。为了设计对新陈代谢影响最小的未来HIV药物，有必要确定这些药物的哪些新陈代谢影响是直接的毒性药物影响，而不是疾病状态变化的继发性影响。考虑到很难在HIV阳性患者中剖析出不同的致病因素，我们已经开始研究HIV阴性对照中ARV对代谢的影响。我们有证据表明，代谢效应是药物特异性的，而不是类别特异性的，PI对葡萄糖和脂肪代谢的独立影响。我们的初步数据表明，PI影响糖代谢的几个途径，包括外周胰岛素抵抗、胰岛素分泌和肝脏葡萄糖产生。这三种病变是2型糖尿病发生的关键因素。因此，我们建议测试PIs和NRTIs的效果如下：特定目标1a：确定哪种Pls抑制人类胰岛素分泌。具体目标1b：确定哪些PI可显著阻断胰岛素介导的人类葡萄糖处置。具体目标1c：通过定量测定糖异生和糖原分解，确定哪些PI可增加肝脏葡萄糖产量，并确定其机制。具体目的2a：证明在有代谢综合征元素的受试者中，与消瘦的健康对照组相比，在口服葡萄糖耐量试验中，PI会导致更多的糖尿病和糖耐量受损。具体目的2b：确定代谢综合征的PI在胰岛素介导的葡萄糖处置抵抗、胰岛素分泌和肝脏葡萄糖产生方面的影响是否更严重。具体目标3a：在急性或四周的研究中，使用OGTT证明NRTI组合，单独或与PI一起，影响HIV阴性受试者的葡萄糖代谢。具体目标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/或肝脏葡萄糖产生的影响。