Uridine Supplementation, Mitochondrial Function, and Glucose Metabolism in HIV

HIV 中的尿苷补充、线粒体功能和葡萄糖代谢

• 批准号: 7268112
• 负责人: MORRIS SCHAMBELAN
• 金额: $ 22.07万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7268112
• 关键词: Abdomen; Accounting; Acute; Adverse effects; Anti-Retroviral Agents; Antioxidants; Biological Availability; Bone Marrow Cells; Bone Marrow Suppression; Case Study; Cells; Chronic; Class; Daily; Dose; Double-Blind Method; Drug Kinetics; Drug or chemical Tissue Distribution; Dual-Energy X-Ray Absorptiometry; Dyslipidemias; Euglycemic Clamping; Fatty Liver; Fatty acid glycerol esters; General Hospitals; Glucose; Glucose Clamp; Glycerol; Growth; HIV; HIV Infections; HIV Seropositivity; HIV-Associated Lipodystrophy Syndrome; Hepatic; Highly Active Antiretroviral Therapy; Hour; In Vitro; Indirect Calorimetry; Infusion procedures; Ingestion; Inpatients; Insulin; Insulin Resistance; Lipids; Lipoatrophy; Lipolysis; Liver; Liver diseases; Magnetic Resonance Spectroscopy; Measures; Metabolic; Mitochondria; Mitochondrial DNA; Morbidity - disease rate; Muscle; Myopathy; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nucleosides; Numbers; Nutritional Support; Oxidative Stress; Patients; Peripheral; Personal Satisfaction; Physiological Processes; Placebos; Plasma; Play; Polycystic Ovary Syndrome; Polyneuropathy; Population; Pyrimidine Nucleosides; RNA chemical synthesis; Randomized; Range; Recruitment Activity; Reporting; Research Personnel; Reverse Transcriptase Inhibitors; Risk; Role; Sampling; San Francisco; Secondary to; Serum; Spleen; Stavudine; Steatohepatitis; Supplementation; Testing; Thinking; Toxic effect; Treatment Protocols; Uridine; Vitamins; X-Ray Computed Tomography; Zidovudine; antiretroviral therapy; base; carbohydrate metabolism; day; density; design; diabetic; dietary supplements; glucose metabolism; glucose production; glucose tolerance; improved; indexing; insulin sensitivity; intravenous glucose tolerance test; metabolic abnormality assessment; mitochondrial dysfunction; mortality; novel; nucleoside analog; oxidation; placebo controlled study; prevent; programs; response; stable isotope; volunteer

DESCRIPTION (provided by applicant): Mitochondrial dysfunction resulting from nucleoside analogue reverse transcriptase inhibitor (NRTI) treatment may underlie many of the metabolic abnormalities seen in HIV-infected patients, including those of glucose metabolism. In this proposal we will test the hypothesis that supplementation with uridine, a pyrimidine nucleoside that abrogates NRTI-toxicity in vitro, can improve glucose metabolism in such patients. To date, use of this promising CAM therapy has been limited by issues of bioavailability. Recently, a dietary supplement with a high content of nucleosides (NucleomaxX(r)) has been shown to increase plasma uridine concentrations to levels thought to be sufficient to reverse mitochondrial dysfunction. In studies performed in the GCRC at San Francisco General Hospital we will: characterize single and multiple dose uridine pharmacokinetics (PK) in normal volunteers (Aim 1); perform a randomized double-blind placebo-controlled study in HIV-positive subjects who are currently on antiretroviral regimens containing stavudine or zidovudine and who have evidence of impaired mitochondrial function and insulin resistance (Aim 2). For Aim 2, 20 subjects will be hospitalized in the GCRC for 6 days to undergo comprehensive metabolic testing and a PK study. They will then be randomized, in a 1:1 fashion, to receive either NucleomaxX(r) or placebo for two months, after which they will repeat the 6-day GCRC-based assessments. Specifically, we will test the hypotheses that, in comparison to placebo, uridine supplementation will: improve hepatic and peripheral insulin sensitivity (hyperinsulinemic euglycemic clamp with stable isotope infusion) and glucose tolerance (frequently sampled intravenous glucose tolerance test); increase lipid disposal; improve mitochondrial function (31 P-magnetic resonance spectroscopy, plasma lactate levels, measures of oxidative stress and muscle mtDNA content) and decrease hepatic lipid levels (CT scan). We will also evaluate the effects of uridine supplementation on whole-body and regional fat and lean tissue distribution (dual-energy X-ray absorptiometry and abdominal CT). If uridine supplementation improves glucose metabolism with no deleterious effects in this small group of patients with NRTI-associated mitochondrial dysfunction, our findings would provide a basis for larger trials in patients with HIV infection as well as in seronegative type 2 diabetics or prediabetics and in patients with the polycystic ovary syndrome and fatty liver disease.

描述（由申请人提供）：核苷类似物逆转录酶抑制剂（NRTI）治疗引起的线粒体功能障碍可能是HIV感染者中观察到的许多代谢异常的基础，包括葡萄糖代谢异常。在本提案中，我们将测试这样的假设：补充尿苷（一种在体外消除 NRTI 毒性的嘧啶核苷）可以改善此类患者的葡萄糖代谢。迄今为止，这种有前途的 CAM 疗法的使用受到生物利用度问题的限制。最近，一种高含量核苷 (NucleomaxX(r)) 的膳食补充剂已被证明可以将血浆尿苷浓度提高到足以逆转线粒体功能障碍的水平。在旧金山综合医院 GCRC 进行的研究中，我们将： 表征正常志愿者中单剂量和多剂量尿苷药代动力学 (PK)（目标 1）；对目前正在接受含有司他夫定或齐多夫定的抗逆转录病毒疗法且有线粒体功能受损和胰岛素抵抗证据的 HIV 阳性受试者进行一项随机双盲安慰剂对照研究（目标 2）。对于目标 2，20 名受试者将在 GCRC 住院 6 天，以接受全面的代谢测试和 PK 研究。然后，他们将以 1:1 的方式随机接受两个月的 NucleomaxX(r) 或安慰剂治疗，之后他们将重复为期 6 天的基于 GCRC 的评估。具体来说，我们将测试以下假设：与安慰剂相比，补充尿苷将： 改善肝脏和外周胰岛素敏感性（稳定同位素输注的高胰岛素正常血糖钳夹）和葡萄糖耐量（频繁采样的静脉内葡萄糖耐量试验）；增加脂质处理；改善线粒体功能（31 P-磁共振波谱、血浆乳酸水平、氧化应激测量和肌肉 mtDNA 含量）并降低肝脂质水平（CT 扫描）。我们还将评估补充尿苷对全身和局部脂肪和瘦肉组织分布的影响（双能 X 射线吸收测定法和腹部 CT）。如果补充尿苷能够改善葡萄糖代谢，并且不会对这一小群患有 NRTI 相关线粒体功能障碍的患者产生有害影响，那么我们的研究结果将为 HIV 感染患者、血清阴性 2 型糖尿病患者或糖尿病前期患者以及多囊卵巢综合征和脂肪肝患者的更大规模试验提供基础。