Fridlyand L E, Philipson L H
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Diabetes Obes Metab. 2006 Mar;8(2):136-45. doi: 10.1111/j.1463-1326.2005.00496.x.
The early stages of type 2 diabetes mellitus are characterized by the development of insulin resistance (IRe) in muscle cells and adipocytes with the concomitant loss of beta-cell compensation. We have extensively reviewed the literature related to metabolic and signalling pathways of reactive oxygen species (ROS) in regard to the coordinated development of oxidative stress and IRe. We considered the hypothesis that oxidative stress leads to IRe in muscle cells and adipocytes, but found that the data are more consistent with the hypothesis that the cellular mechanisms that protect against oxidative stress per se are capable of creating an ROS-dependent insulin-resistant state. Furthermore, ROS-induced mitochondrial dysfunction can lead to disruptions of lipid metabolism, increasing the intracellular lipid content, and, in addition, contribute to lipid-dependent IRe in myocytes. Together, these two ROS-activated pathways to IRe can contribute to a global state of profound resistance to insulin action. Therapeutic strategies should, therefore, be directed towards reducing insulin resistance without an increase in ROS production or concentration. Pharmacological or other approaches to IRe that result in the activation of mitochondrial biogenesis in particular could be highly beneficial in the prevention or treatment of both insulin resistance and type 2 diabetes.
2型糖尿病的早期阶段，其特征是肌肉细胞和脂肪细胞中出现胰岛素抵抗（IRe），同时β细胞代偿功能丧失。我们广泛回顾了与活性氧（ROS）的代谢和信号通路相关的文献，这些文献涉及氧化应激和IRe的协同发展。我们考虑了氧化应激导致肌肉细胞和脂肪细胞出现IRe这一假说，但发现现有数据更符合另一种假说，即本身用于抵御氧化应激的细胞机制能够产生一种依赖ROS的胰岛素抵抗状态。此外，ROS诱导的线粒体功能障碍可导致脂质代谢紊乱，增加细胞内脂质含量，并且还会导致心肌细胞中依赖脂质的IRe。这两条由ROS激活的导致IRe的途径共同作用，可导致对胰岛素作用产生严重抵抗的整体状态。因此，治疗策略应旨在降低胰岛素抵抗，而不增加ROS的产生或浓度。特别是那些能够激活线粒体生物合成的针对IRe的药理学或其他方法，可能对预防或治疗胰岛素抵抗和2型糖尿病都非常有益。
