August Krogh Section for Human Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen 2100, Denmark.
Department of Biomedical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
Sci Adv. 2024 Nov;10(44):eadq4461. doi: 10.1126/sciadv.adq4461. Epub 2024 Oct 30.
Preclinical models suggest mitochondria-derived oxidative stress as an underlying cause of insulin resistance. However, it remains unknown whether this pathophysiological mechanism is conserved in humans. Here, we used an invasive in vivo mechanistic approach to interrogate muscle insulin action while selectively manipulating the mitochondrial redox state in humans. To this end, we conducted insulin clamp studies combining intravenous infusion of a lipid overload with intake of a mitochondria-targeted antioxidant (mitoquinone). Under lipid overload, selective modulation of mitochondrial redox state by mitoquinone enhanced insulin-stimulated glucose uptake in skeletal muscle. Mechanistically, mitoquinone did not affect canonical insulin signaling but augmented insulin-stimulated glucose transporter type 4 (GLUT4) translocation while reducing the mitochondrial oxidative burden under lipid oversupply. Complementary ex vivo studies in human muscle fibers exposed to high intracellular lipid levels revealed that mitoquinone improves features of mitochondrial bioenergetics, including diminished mitochondrial HO emission. These findings provide translational and mechanistic evidence implicating mitochondrial oxidants in the development of lipid-induced muscle insulin resistance in humans.
临床前模型表明，线粒体来源的氧化应激是胰岛素抵抗的潜在原因。然而，这种病理生理机制在人类中是否保守仍然未知。在这里，我们使用一种侵入性的体内机制方法来研究肌肉胰岛素作用，同时在人类中选择性地操纵线粒体氧化还原状态。为此，我们进行了胰岛素钳夹研究，将静脉内输注脂质过载与摄入线粒体靶向抗氧化剂（mitoquinone）相结合。在脂质过载下，mitoquinone 对线粒体氧化还原状态的选择性调节增强了骨骼肌中胰岛素刺激的葡萄糖摄取。从机制上讲，mitoquinone 不影响经典的胰岛素信号转导，但在脂质过供应下增加了胰岛素刺激的葡萄糖转运蛋白 4（GLUT4）易位，同时减轻了线粒体氧化负担。在暴露于高细胞内脂质水平的人类肌肉纤维的补充性离体研究中，mitoquinone 改善了线粒体生物能量学的特征，包括减少线粒体 HO 发射。这些发现为线粒体氧化剂在人类脂质诱导的肌肉胰岛素抵抗的发展中提供了转化和机制证据。
