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

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.

Fig. 1

Change in glucose infusion rate (GIR; determined from the euglycemic hyperinsulinemic clamp) from baseline to the end of the study, shown for each participant in the placebo (A) and the stavudine-treated groups (B). C: mean changes in GIRs during euglycemic hyperinsulinemic clamp for each group (P = 0.04, stavudine vs. placebo). Results are means ± SE.

Fig. 2

Comparison of insulin levels in stavudine-treated and placebo groups during clamp at baseline and 1 mo. P values for the difference between groups were P = 0.4 at baseline and P = 0.3 at 1 mo, as determined by MMANOVA. Error bars represent SD.

Fig. 3

Change in mitochondrial DNA/nuclear DNA in muscle tissue. P = 0.005 for change in stavudine group, and P = 0.9 for change in placebo group. Results are means ± SE. P = 0.15 for the change between groups.

Fig. 4

A: correlation of phosphocreatine (PCr) recovery slope by ³¹P magnetic resonance spectroscopy (MRS) and GIR by hyperinsulinemic euglycemic clamp (r² = 0.52, P = 0.008). B: correlation of intramyocellular lipid (IMCL) of tibialis muscle and GIR by hyperinsulinemic euglycemic clamp (r² = 0.35, P = 0.08).

Fig. 5

PCr recovery curves for each participant at baseline and at 1 mo. The PCr recovery slope for each patient is indicated.