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: 7292141
• 负责人: MORRIS SCHAMBELAN
• 金额: $ 3.7万
• 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/7292141
• 关键词: Uridine; Supplementation; Mitochondrial; Function; Glucose

DESCRIPTION: Mitochondrial dysfunction resulting from nucleoside analogue reverse transcriptase (NRTI) treatment may underlie many of the metabolic abnormalities seen in HIV-infected patients, including those in 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. We will perform a randomized double-blind placebo-controlled study in 20 HIV-positive subjects who are currently undergoing treatment with antiretroviral regimens containing stavudine or zidovudine and who have evidence of impaired mitochondrial function and insulin resistance. Subjects will be hospitalized in the General Clinical Research Center (GCRC) at San Francisco General Hospital for 5 days to undergo comprehensive metabolic testing. 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 5-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 fatty acid disposal (13C palmitate turnover and oxidation); improve mitochondrial function (31P-magnetic resonance spectroscopy, plasma lactate levels, 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, by performing dual-energy X-ray absorptiometry and abdominal CT scanning. In terms of broader implications for public health, 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 individuals with type 2 diabetes or prediabetes and in related conditions such as the polycystic ovary syndrome and fatty liver disease.

描述：核苷类似物逆转录酶 (NRTI) 治疗导致的线粒体功能障碍可能是 HIV 感染患者出现许多代谢异常的原因，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。我们将对 20 名 HIV 阳性受试者进行一项随机双盲安慰剂对照研究，这些受试者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治疗，并且有证据表明线粒体功能受损和胰岛素抵抗。受试者将在旧金山总医院的普通临床研究中心（GCRC）住院5天，以接受全面的代谢测试。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 5 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）；增加脂肪酸处理（13C棕榈酸酯周转和氧化）；改善线粒体功能（31P-磁共振波谱、血浆乳酸水平和肌肉 mtDNA 含量）并降低肝脂质水平（CT 扫描）。我们还将通过双能X射线吸收测定法和腹部CT扫描来评估补充尿苷对全身和局部脂肪和瘦肉组织分布的影响。就对公共健康更广泛的影响而言，如果补充尿苷改善了葡萄糖代谢，并且对这一小群患有 NRTI 相关线粒体功能障碍的患者没有有害影响，那么我们的研究结果将为 HIV 感染患者以及患有 2 型糖尿病或糖尿病前期以及相关疾病（如多囊卵巢综合征和肥胖症）的血清阴性个体进行更大规模的试验提供基础。 肝脏疾病。