Abstract

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 (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.