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1 Program in Nutritional Metabolism1, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
2 Program in Nutritional Metabolism1, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States; Department of Infectious Diseases, Skejby Hospital, Aarhus, Denmark
3 Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
4 Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
5 University of Puerto Rico School of Medicine, San Juan, Puerto Rico; Department of Physical Medicine and Rehabilitation, Harvard Medical School , Boston, Massachusetts, United States; Spaulding Rehabilitation Hospital, Boston, Massachusetts, United States
6 Department of Radiology, Massachusetts General Hosptial, Boston, Massachusetts, United States
7 Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, United States
8 Department of Pathology, University of British Columbia, Vancouver, Canada
* To whom correspondence should be addressed. E-mail: sgrinspoon{at}partners.org.
Mitochondrial dysfunction may contribute to the development of insulin resistance and Type II diabetes. Nucleoside reverse transcriptase inhibitors (NRTIs), specifically stavudine, are known to alter mitochondrial function in HIV infected individuals, but the effects of stavudine on glucose disposal and mitochondrial function in muscle have not been prospectively evaluated. In this study, we investigated short-term stavudine administration among healthy control subjects to determine effects on insulin sensitivity. A secondary aim was to determine the effects of stavudine on mitochondrial DNA and function. Sixteen participants without personal or family history of diabetes were enrolled. Subjects were randomized to receive stavudine 30-40 mg twice a day or placebo for 1 month. Insulin sensitivity determined by glucose infusion rate during the hyperinsulinemic euglycemic clamp was significantly reduced after one-month exposure in the stavudine treated subjects compared to placebo (-0.8 ± 0.5 vs. +0.7 ± 0.3 mg/kg/minute, P= 0.04, stavudine vs. placebo). In addition, muscle biopsy specimens in the stavudine treated group showed significant reduction in mitochondrial mtDNA/nuclear DNA (-52%, P=0.005), with no change in placebo treated subjects (+8%, P=0.9). 31P magnetic resonance spectroscopy (MRS) studies of mitochondrial function correlated with insulin sensitivity measures (r2=0.5, P= 0.008). These findings demonstrate that stavudine administration has potent effects on insulin sensitivity among healthy subjects. Further studies are necessary to determine whether changes in mitochondrial DNA resulting from stavudine contribute to effects on insulin sensitivity.
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