Effect of Nucleoside Reverse
Transcriptase Inhibitors on Mitochondrial Function
Mitochondrial dysfunction may
contribute to the development of insulin resistance and Type II diabetes.
Nucleoside reverse transcriptase inhibitors (NRTI's), 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.