Fleischman Amy, Johnsen Stine, Systrom David M, Hrovat Mirko, Farrar Christian T, Frontera Walter, Fitch Kathleen, Thomas Bijoy J, Torriani Martin, Côté Hélène C F, Grinspoon Steven K
Program In Nutritional Metabolism, Massachusetts General Hospital, 55 Fruit St., LON 207, Boston, MA 02114, USA.
Am J Physiol Endocrinol Metab. 2007 Jun;292(6):E1666-73. doi: 10.1152/ajpendo.00550.2006. Epub 2007 Feb 6.
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.
线粒体功能障碍可能促使胰岛素抵抗和2型糖尿病的发展。已知核苷类逆转录酶抑制剂（NRTIs），尤其是司他夫定，会改变人类免疫缺陷病毒（HIV）感染者的线粒体功能，但司他夫定对肌肉中葡萄糖代谢及线粒体功能的影响尚未得到前瞻性评估。在本研究中，我们对健康对照受试者进行短期司他夫定给药，以确定其对胰岛素敏感性的影响。第二个目的是确定司他夫定对线粒体DNA（mtDNA）和功能的影响。招募了16名无糖尿病个人或家族史的参与者。受试者被随机分为两组，一组每天两次接受30 - 40 mg司他夫定，另一组接受安慰剂，为期1个月。与安慰剂组相比，司他夫定治疗组在接受1个月暴露后，通过高胰岛素正常血糖钳夹期间的葡萄糖输注率测定的胰岛素敏感性显著降低（-0.8±0.5 vs. +0.7±0.3 mg·kg⁻¹·min⁻¹，P = 0.04，司他夫定组 vs. 安慰剂组）。此外，司他夫定治疗组的肌肉活检标本显示mtDNA/核DNA显著减少（-52%，P = 0.005），而安慰剂治疗组无变化（+8%，P = 0.9）。线粒体功能的³¹P磁共振波谱（MRS）研究与胰岛素敏感性测量结果相关（r² = 0.5，P = 0.008）。这些发现表明，在健康受试者中，司他夫定给药对胰岛素敏感性有显著影响。有必要进一步研究司他夫定导致的mtDNA变化是否会影响胰岛素敏感性。
