Background:  Data for individuals at risk for type 2 diabetes mellitus (DM) and for those with HIV infection, suggest that mitochondrial dysfunction may contribute to the development of insulin resistance. Nucleoside reverse transcriptase inhibitors (NRTI), specifically stavudine (d4T), are known to alter mitochondrial function in HIV-infected individuals, but effects may be confounded by other factors. The direct effects on muscle have not been investigated. The current study was designed to test the hypothesis that the use of d4T in a double-blind, placebo-controlled trial in healthy humans results in alteration of muscle mitochondrial function and insulin sensitivity. 

Methods:  We enrolled in the study 16 healthy participants without personal or family history of diabetes mellitus. Subjects were randomized to receive d4T 30 to 40 mg twice a day, or placebo for 1 month. Insulin sensitivity was assessed by hyperinsulinemic euglycemic clamp, muscle mitochondrial content was determined, and mitochondrial function investigated by ³¹P spectroscopy of phosphocreatine recovery rates. ANOVA was utilized to detect differences between placebo- and d4T-treated participants. Matched pairs analyses were performed for within group changes.

Results:  The study is closed to enrollment and the data presented are final. In the d4T-treated subjects, insulin sensitivity by hyperinsulinemic euglycemic clamp was significantly reduced after 1-month exposure compared to placebo (–0.8±0.5 vs +0.7±0.3 mg/kg/minute, p = 0.04, d4T vs placebo, respectively). In addition, muscle biopsy specimens in the d4T-treated group showed significant reduction in mitochondrial mtDNA/nuclear DNA (–52%, p = 0.004), with no change in placebo-treated subjects (+8%, p = 0.9). The ³¹P magnetic resonance spectroscopy studies of mitochondrial function, correlated with insulin sensitivity measures (r² = 0.5, p = 0.008).

Conclusions:  This is the first study to demonstrate that d4T causes alterations in muscle mitochondrial content and insulin sensitivity in healthy individuals. The current study supports the hypothesis that alterations in mitochondrial function in muscle contribute to the development of insulin resistance in non HIV-infected patients and also demonstrates an important mechanism of toxicity in HIV-infected patients.