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

基本信息

批准号：
7447315
负责人：
MORRIS SCHAMBELAN
金额：
$ 18.02万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7447315
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

项目摘要

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）：由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感染患者（包括葡萄糖代谢的患者）中许多代谢异常的基础。在此提案中，我们将检验以下假设：补充尿苷，尿苷是一种消除体外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，使用这种有希望的CAM治疗受到生物利用度问题的限制。最近，含有高含量核苷含量的饮食补充剂（NucleoMaxx（R））已被证明将血浆尿苷浓度提高到被认为足以逆转线粒体功能障碍的水平。在旧金山总医院的GCRC进行的研究中，我们将：在正常志愿者中表征单剂量和多剂量的尿苷药代动力学（PK）（AIM 1）；在目前使用含有stavudine或Zidovudine的抗逆转录病毒方案的HIV阳性受试者中，对HIV阳性受试者进行随机的双盲安慰剂对照研究，并有线粒体功能和胰岛素抵抗的迹象（AIM 2）。对于AIM 2，在GCRC中将有20名受试者住院6天，以进行全面的代谢测试和PK研究。然后，它们将以1：1的方式随机分配，以接收NucleoMaxx（R）或安慰剂两个月，然后他们将重复基于6天GCRC的评估。具体而言，我们将测试与安慰剂相比，补充尿苷的假设：提高肝和周围胰岛素敏感性（高胰岛素血症的葡聚糖夹夹，具有稳定的同位素输注）和葡萄糖降低（经常采样静脉内葡萄糖耐度测试）；增加脂质处置；提高线粒体功能（31 p-磁共振光谱，血浆乳酸水平，氧化应激和肌肉mtDNA含量的测量）和肝脂质水平降低（CT SCAN）。我们还将评估补充尿苷对全身和区域脂肪和瘦肉组织分布（双能X射线吸收仪和腹部CT）的影响。 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.