Uridine Supplementation, Mitochondrial Function, and Glucose Metabolism in HIV

描述（由申请方提供）：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感染患者中观察到的许多代谢异常（包括葡萄糖代谢异常）的基础。在这个提议中，我们将检验补充尿苷（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的假设。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，具有高含量核苷（NucleomaxX（r））的膳食补充剂已被证明可将血浆尿苷浓度增加至被认为足以逆转线粒体功能障碍的水平。在San弗朗西斯科总医院GCRC中进行的研究中，我们将：描述正常志愿者单次和多次给药尿苷的药代动力学（PK）特征（目标1）;在目前正在接受含司他夫定或齐多夫定的抗逆转录病毒治疗方案且有线粒体功能受损和胰岛素抵抗证据的HIV阳性受试者中进行随机双盲安慰剂对照研究（目标2）。对于目标2，20例受试者将在GCRC住院6天，以接受全面代谢检查和PK研究。然后，他们将以1：1的方式随机接受NucleomaxX（r）或安慰剂两个月，之后他们将重复6天的GCRC评估。具体而言，我们将检验以下假设：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葡萄糖钳夹）和葡萄糖耐量（频繁采样静脉葡萄糖耐量试验）;增加脂质处置;改善线粒体功能（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）和降低肝脏脂质水平（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线吸收测定法和腹部CT）。如果补充尿苷能改善糖代谢，而对这一小群NRTI相关线粒体功能障碍患者无有害影响，我们的研究结果将为在HIV感染患者、血清阴性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中进行更大规模的试验提供基础。

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.