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This Article Full Text Full Text (PDF) All Versions of this Article: 292/6/E1666    most recent 00550.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (26) Citing Articles via Google Scholar Google Scholar Articles by Fleischman, A. Articles by Grinspoon, S. K. Search for Related Content PubMed PubMed Citation Articles by Fleischman, A. Articles by Grinspoon, S. K.

Effects of a nucleoside reverse transcriptase inhibitor, stavudine, on glucose disposal and mitochondrial function in muscle of healthy adults

¹Program in Nutritional Metabolism, ²Pulmonary and Critical Care Medicine, ³Athinoula A. Martinos Center for Biomedical Imaging, ⁵Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; ⁴University of Puerto Rico School of Medicine, San Juan, Puerto Rico, and Department of Physical Medicine and Rehabilitation, Harvard Medical School and Spaulding Rehabilitation Hospital, Boston, Massachusetts; ⁶Department of Infectious Diseases, Skejby Hospital, Aarhus, Denmark; and ⁷Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada

Submitted 12 October 2006 ; accepted in final form 31 January 2007

Mitochondrial dysfunction may contribute to the development of insulin resistance and type 2 diabetes. Nucleoside reverse transcriptase inhibitors (NRTIs), specifically stavudine, are known to alter mitochondrial function in human immunodeficiency virus (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 (mtDNA) 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 mo. Insulin sensitivity determined by glucose infusion rate during the hyperinsulinemic euglycemic clamp was significantly reduced after 1-mo exposure in the stavudine-treated subjects compared with placebo (–0.8 ± 0.5 vs. +0.7 ± 0.3 mg·kg^–1·min^–1, P = 0.04, stavudine vs. placebo). In addition, muscle biopsy specimens in the stavudine-treated group showed significant reduction in 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 mtDNA resulting from stavudine contribute to effects on insulin sensitivity.

human immunodeficiency virus; insulin resistance; magnetic resonance spectroscopy

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