HIV Antiretroviral Drugs and Glucose Metabolism

HIV 抗逆转录病毒药物与葡萄糖代谢

• 批准号: 7162646
• 负责人: Carl Grunfeld
• 金额: $ 35.2万
• 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 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7162646
• 关键词: Acute; Affect; Anti-Retroviral Agents; Central obesity; Class; Data; Defect; Development; Diabetes Mellitus; Disease; Dose; Drug Design; Drug usage; Dyslipidemias; Elements; Fasting; Fatty acid glycerol esters; Functional disorder; Future; Gluconeogenesis; Glucose; Grant; HIV; HIV Infections; HIV Protease Inhibitors; HIV Seropositivity; Health; Hepatic; Highly Active Antiretroviral Therapy; Human; Hyperglycemia; Hypertriglyceridemia; Immune; Immune response; Immune system; Individual; Insulin; Insulin Resistance; LDL Cholesterol Lipoproteins; Lead; Lesion; Lipodystrophy; Mediating; Metabolic; Metabolic syndrome; Metabolism; Non-Insulin-Dependent Diabetes Mellitus; Nucleosides; OGTT; Outcome; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Physicians; Protease Inhibitor; Reporting; Resistance; Reverse Transcriptase Inhibitors; Role; Secondary to; Syndrome; Testing; Tissues; Toxic effect; Very low density lipoprotein; Viral; Visceral; Week; base; design; glucose disposal; glucose metabolism; glucose output; glucose production; glucose tolerance; glycogenolysis; impaired glucose tolerance; improved; insulin secretion; lipid metabolism; metabolic abnormality assessment; prevent; reconstitution; restoration; volunteer

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（由申请人提供）：使用蛋白酶抑制剂（PI）的高度活性抗逆转录病毒疗法的发展与代谢异常有关，包括葡萄糖代谢，血脂异常和脂肪分布/脂肪症的疾病。但是他们的原因是辩论的。数据表明，并非所有PI的代谢作用都是直接毒性作用，因为有些是由于恢复了健康，免疫系统的重建或脂肪分布的变化。 NRTI的角色正在出现。为了设计具有最低代谢作用的未来艾滋病毒药物，必须确定这些药物的哪些代谢作用是直接有毒药物作用，而不是疾病状况变化的次数。鉴于难以剖析HIV阳性患者的不同贡献者，我们已经开始研究ARV在HIV阴性控制中的代谢作用。我们有证据表明，代谢作用是药物特异性的，而不是特定于类别的PI对葡萄糖和脂质代谢的独立作用。我们的初步数据表明，PI会影响葡萄糖代谢的多种途径，包括外周胰岛素抵抗，胰岛素分泌和肝葡萄糖产生。这三个病变是2型糖尿病发展的关键因素。因此，我们建议测试PIS和NRTIS的效果如下：特定目的1a：确定哪些PL抑制人类的胰岛素分泌。特定目标1B：确定哪些PI急性阻断人类中胰岛素介导的葡萄糖处置。特定目标1C：确定哪些PI会增加肝葡萄糖的产生，并通过量化糖异生和糖原分解来确定机制。具体目标2a：证明，与薄的健康对照组相比，在患有代谢综合征元素的受试者中，PI会诱导更多的糖尿病和口服葡萄糖耐受性测试的葡萄糖耐受性受损。具体目标2B：确定PI在代谢综合征的影响是否在胰岛素介导的葡萄糖处置，胰岛素分泌和肝葡萄糖产生的耐药水平上是否更为严重。特定目标3a：为了证明使用急性或四周研究中的OGTT，单独或使用PI单独或使用PI会影响HIV阴性受试者的葡萄糖代谢。特定目的3b：为了确定NRTI不利影响葡萄糖代谢的机制，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/或肝葡萄糖产生的影响。