Uridine Supplementation, Mitochondrial Function, and Glucose Metabolism in HIV

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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.