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 (Ϫ0.8 Ϯ 0.5 vs. ϩ0.7 Ϯ 0.3 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 , P ϭ 0.04, stavudine vs. placebo). In addition, muscle biopsy specimens in the stavudine-treated group showed significant reduction in mtDNA/ nuclear DNA (Ϫ52%, P ϭ 0.005), with no change in placebo-treated subjects (ϩ8%, P ϭ 0.9).31 P magnetic resonance spectroscopy (MRS) studies of mitochondrial function correlated with insulin sensitivity measures (r 2 ϭ 0.5, P ϭ 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 RECENT DATA SUGGEST that mitochondrial dysfunction precedes the development of diabetes in insulin-resistant offspring of patients with type 2 diabetes mellitus (DM) (15). Resistance to insulin action at the skeletal muscle is the earliest abnormality in such patients. Evaluation of gene expression in muscle samples from individuals with type 2 DM and impaired glucose tolerance has identified alterations in several genes involved in mitochondrial oxidative phosphorylation (12,14). For example, both peroxisomal proliferator activator receptor-␥ coactivator (PGC1) and nuclear respiratory factor (NRF) are reduced in prediabetic and diabetic human muscle tissue. These data suggest that both individuals with diabetes and those in the prediabetic state without the clinical effect of hyperglycemia show diminished gene expression of elements essential for the mitochondrial respiratory chain oxidative phosphorylation.Animal and human models of DM suggest that mitochondrial dysfunction is significantly related to the development of insulin resistance. Analysis of the muscle tissue from the insulin-resistant obese ob/ob mice compared with thin ob/ϩ littermates revealed a reduction in the expression of a subunit of mitochondrial ATP synthase (20). In addition,...

Insulin resistance predicts endothelial dysfunction and cardiovascular risk in HIV-infected persons on long-term highly active antiretroviral therapy

“…Additionally, the cumulative exposure to HAART, as well as the cumulative exposure to individual drug classes (nucleosides, NNRTIs, protease inhibitors) revealed no significant association with either brachial FMD or CIMT. Studies have also found an association between thymidine analogue use and insulin resistance [20][21][22], but in the present study there was no significant correlation between cumulative exposure/use ever of zidovudine or stavudine and HOMA-IR/Belfiore index, brachial FMD, or CIMT. There have also been conflicting data with regard to effects of body fat changes (lipoatrophy) on FMD [13,23], but in our study we found no significant association between appendicular fat, trunk fat, or trunk/limb fat ratio and FMD.…”

“…Although we did not find a significant association between current protease inhibitor or thymidine analogue use and insulin resistance, brachial FMD, or CIMT, the use of specific antiretrovirals has been strongly associated with insulin resistance in other studies [3,4,[20][21][22]27,28]. The development of insulin resistance in some patients on HAART may have important long-term implications in determining cardiovascular disease risk.…”

Mitochondrial DNA Variation and Changes in Adiponectin and Endothelial Function in HIV-Infected Adults After Antiretroviral Therapy Initiation

“…Some protease inhibitors cause dyslipidemia that contributes to increased rates of cardiovascular disease, and have been associated with endothelial dysfunction in HIV-infected 1 and uninfected [2][3][4] persons. Nucleoside reverse transcriptase inhibitors (NRTIs) are associated with mitochondrial and metabolic toxicities, 5,6 including endothelial dysfunction in some studies, 7,8 but not in others. 9 Mitochondrial DNA (mtDNA) encodes electron transport chain subunits that are critical for energy production, and mitochondrial function influences vascular health.…”

Mitochondrial Metabolism and Insulin Action

“…Similarly, genetic, or high-fat diet-induced obesity and insulin resistance in rodents has been reported by several groups to reduce mitochondrial gene expression, protein expression and mitochondrial respiration in skeletal muscle [107][108][109][110][111]. Providing additional evidence of a link between mitochondrial dysfunction and insulin resistance is the fact that antiretroviral therapy used to suppress human immunodeficiency virus infection causes insulin resistance in association with mtDNA copy number [112]. Collectively, the above studies illustrate that there are many instances where defects in mitochondrial metabolism and impairments in insulin action occur in conjunction with each other in skeletal muscle.…”