Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine, Tucson, AZ 85724, USA.
Mol Cell Endocrinol. 2013 Sep 25;378(1-2):15-22. doi: 10.1016/j.mce.2012.04.011. Epub 2012 May 4.
The canonical renin-angiotensin system (RAS) involves the initial action of renin to cleave angiotensinogen to angiotensin I (ANG I), which is then converted to ANG II by the angiotensin converting enzyme (ACE). ANG II plays a critical role in numerous physiological functions, and RAS overactivity underlies many conditions of cardiovascular dysregulation. In addition, ANG II, by acting on both endothelial and myocellular AT1 receptors, can induce insulin resistance by increasing cellular oxidative stress, leading to impaired insulin signaling and insulin-stimulated glucose transport activity. This insulin resistance associated with RAS overactivity, when coupled with progressive ß-cell dysfunction, eventually leads to the development of type 2 diabetes. Interventions that target RAS overactivity, including ACE inhibitors, ANG II receptor blockers, and, most recently, renin inhibitors, are effective both in reducing hypertension and in improving whole-body and skeletal muscle insulin action, due at least in part to enhanced Akt-dependent insulin signaling and insulin-dependent glucose transport activity. ANG-(1-7), which is produced from ANG II by the action of ACE2 and acts via Mas receptors, can counterbalance the deleterious actions of the ACE/ANG II/AT1 receptor axis on the insulin-dependent glucose transport system in skeletal muscle. This beneficial effect of the ACE2/ANG-(1-7)/Mas receptor axis appears to depend on the activation of Akt. Collectively, these findings underscore the importance of RAS overactivity in the multifactorial etiology of insulin resistance in skeletal muscle, and provide support for interventions that target the RAS to ameliorate both cardiovascular dysfunctions and insulin resistance in skeletal muscle tissue.
经典的肾素-血管紧张素系统（RAS）涉及肾素对血管紧张素原的初始作用，将其切割为血管紧张素 I（ANG I），然后由血管紧张素转换酶（ACE）将其转化为血管紧张素 II（ANG II）。ANG II 在许多生理功能中起着关键作用，而 RAS 过度活跃是许多心血管失调的基础。此外，ANG II 通过作用于内皮细胞和心肌细胞 AT1 受体，通过增加细胞氧化应激来诱导胰岛素抵抗，导致胰岛素信号转导受损和胰岛素刺激的葡萄糖转运活性降低。这种与 RAS 过度活跃相关的胰岛素抵抗，加上β细胞功能逐渐受损，最终导致 2 型糖尿病的发生。针对 RAS 过度活跃的干预措施，包括 ACE 抑制剂、ANG II 受体阻滞剂，以及最近的肾素抑制剂，不仅在降低高血压方面有效，而且在改善全身和骨骼肌胰岛素作用方面也有效，这至少部分归因于 Akt 依赖性胰岛素信号转导和胰岛素依赖性葡萄糖转运活性的增强。ANG-(1-7)由 ACE2 作用于 ANG II 产生，并通过 Mas 受体发挥作用，可抵消 ACE/ANG II/AT1 受体轴对骨骼肌中胰岛素依赖的葡萄糖转运系统的有害作用。ACE2/ANG-(1-7)/Mas 受体轴的这种有益作用似乎依赖于 Akt 的激活。综上所述，这些发现强调了 RAS 过度活跃在骨骼肌胰岛素抵抗的多因素发病机制中的重要性，并为针对 RAS 的干预措施提供了支持，以改善心血管功能障碍和骨骼肌组织中的胰岛素抵抗。
