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

• Published in: American journal of physiology: endocrinology and metabolism Vol. 292; no. 6; pp. E1666 - E1673
• Main Authors: Fleischman, Amy, Johnsen, Stine, Systrom, David M, Hrovat, Mirko, Farrar, Christian T, Frontera, Walter, Fitch, Kathleen, Thomas, Bijoy J, Torriani, Martin, Cote, Helene C. F, Grinspoon, Steven K
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.06.2007
• Subjects: Adult; Antiretroviral drugs; Body Composition - drug effects; Clinical outcomes; DNA, Mitochondrial - metabolism; Drug therapy; Female; Glucose - metabolism; Glucose Clamp Technique; HIV; Human immunodeficiency virus; Human subjects; Humans; Insulin; Insulin Resistance; Magnetic Resonance Spectroscopy; Male; Middle Aged; Mitochondria, Muscle - drug effects; Mitochondria, Muscle - metabolism; Mitochondria, Muscle - physiology; Mitochondrial DNA; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Skeletal - physiology; Phosphocreatine - metabolism; Phosphorus; Protons; Reverse Transcriptase Inhibitors - adverse effects; Reverse Transcriptase Inhibitors - pharmacology; Stavudine - adverse effects; Stavudine - pharmacology
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00550.2006

1 Program in Nutritional Metabolism, 2 Pulmonary and Critical Care Medicine, 3 Athinoula A. Martinos Center for Biomedical Imaging, 5 Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; 4 University 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; 6 Department of Infectious Diseases, Skejby Hospital, Aarhus, Denmark; and 7 Department 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). 31 P magnetic resonance spectroscopy (MRS) studies of mitochondrial function correlated with insulin sensitivity measures ( r 2 = 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 Address for reprint requests and other correspondence: S. K. Grinspoon, Program In Nutritional Metabolism, Mass. General Hospital, 55 Fruit St., LON 207, Boston, MA 02114 (e-mail: sgrinspoon{at}partners.org )