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: 7119779
• 负责人: MORRIS SCHAMBELAN
• 金额: $ 18.94万
• 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/7119779
• 关键词: clinical research; glucose metabolism; insulin sensitivity /resistance; pharmacokinetics; placebos; uridine

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)治疗导致的线粒体功能障碍可能是HIV感染患者出现的许多代谢异常的基础，包括葡萄糖代谢异常。在这项建议中，我们将检验补充尿苷的假说，尿苷是一种体外消除NRTI毒性的嘧啶核苷，可以改善此类患者的葡萄糖代谢。到目前为止，这种前景看好的CAM疗法的使用一直受到生物利用度问题的限制。最近，一种高含量核苷的膳食补充剂(NucleomaxX(R))被证明可以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GCRC进行的研究中，我们将：确定正常志愿者中单剂量和多剂量尿苷的药代动力学(目标1)；对目前正在接受含司他夫定或齐多夫定的抗逆转录病毒疗法，且有证据表明线粒体功能受损和胰岛素抵抗的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的方式随机接受为期两个月的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。具体地说，我们将检验这样的假设，即与安慰剂相比，尿苷补充将：改善肝脏和外周胰岛素敏感性(采用稳定同位素输注的高胰岛素正血糖钳夹)和糖耐量(频繁采样的静脉葡萄糖耐量试验)；增加脂质代谢；改善线粒体功能(31P-磁共振波谱、血浆乳酸水平、氧化应激指标和肌肉mtDNA含量)和降低肝脂水平(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线吸收测量法和腹部CT)。如果在这一小部分患有NRTI相关线粒体功能障碍的患者中，尿苷补充改善了葡萄糖代谢而没有有害影响，我们的发现将为在HIV感染患者以及血清阴性的2型糖尿病或糖尿病前期患者以及多囊卵巢综合征和脂肪肝患者进行更大规模的试验提供基础。