Reduced insulin sensitivity is a key factor in the pathogenesis of type 2 diabetes and hypertension. Skeletal muscle insulin resistance is particularly important for its major role in insulin-mediated glucose disposal. Angiotensin II (ANG II) is integral in regulating blood pressure and plays a role in the pathogenesis of hypertension. In addition, we have documented that ANG II-induced skeletal muscle insulin resistance is associated with generation of reactive oxygen species (ROS). However, the linkage between ROS and insulin resistance in skeletal muscle remains unclear. To explore potential mechanisms, we employed the transgenic TG(mRen2)27 (Ren-2) hypertensive rat, which harbors the mouse renin transgene and exhibits elevated tissue ANG II levels, and skeletal muscle cell culture. Compared with Sprague-Dawley normotensive control rats, Ren-2 skeletal muscle exhibited significantly increased oxidative stress, NF-kappaB activation, and TNF-alpha expression, which were attenuated by in vivo treatment with an angiotensin type 1 receptor blocker (valsartan) or SOD/catalase mimetic (tempol). Moreover, ANG II treatment of L6 myotubes induced NF-kappaB activation and TNF-alpha production and decreased insulin-stimulated Akt activation and GLUT-4 glucose transporter translocation to plasma membranes. These effects were markedly diminished by treatment of myotubes with valsartan, the antioxidant N-acetylcysteine, NADPH oxidase-inhibiting peptide (gp91 ds-tat), or NF-kappaB inhibitor (MG-132). Similarly, NF-kappaB p65 small interfering RNA reduced NF-kappaB p65 subunit expression and nuclear translocation and TNF-alpha production but improved insulin-stimulated phosphorylation (Ser(473)) of Akt and translocation of GLUT-4. These findings suggest that NF-kappaB plays an important role in ANG II/ROS-induced skeletal muscle insulin resistance.

译文

胰岛素敏感性降低是2型糖尿病和高血压发病的关键因素。骨骼肌胰岛素抵抗因其在胰岛素介导的葡萄糖处置中的主要作用而特别重要。血管紧张素II (ANG II) 在调节血压中不可或缺,并在高血压的发病机理中起作用。此外,我们已经记录了ANG II诱导的骨骼肌胰岛素抵抗与活性氧 (ROS) 的产生有关。然而,骨骼肌中ROS与胰岛素抵抗之间的联系仍不清楚。为了探索潜在的机制,我们使用了转基因TG(mRen2)27 (Ren-2) 高血压大鼠,该大鼠具有小鼠肾素转基因并表现出升高的组织ANG II水平和骨骼肌细胞培养。与Sprague-Dawley正常血压对照组大鼠相比,Ren-2骨骼肌表现出明显增加的氧化应激,NF-κ b活化和TNF-α 表达,这些作用通过血管紧张素1型受体阻滞剂 (缬沙坦) 或SOD/过氧化氢酶模拟物 (tempol) 的体内处理而减弱。此外,ANG II处理L6肌管可诱导NF-κ b活化和TNF-α 产生,并减少胰岛素刺激的Akt活化和GLUT-4葡萄糖转运蛋白向质膜的转运。通过用缬沙坦,抗氧化剂N-乙酰半胱氨酸,NADPH氧化酶抑制肽 (gp91 ds-tat) 或NF-κ b抑制剂 (MG-132) 处理肌管,这些作用显着减弱。类似地,NF-κ b p65小干扰RNA降低NF-κ b p65亚基表达和核易位和TNF-α 产生,但改善Akt的胰岛素刺激磷酸化 (Ser(473)) 和GLUT-4的易位。这些发现表明,NF-κ b在ANG II/ROS诱导的骨骼肌胰岛素抵抗中起重要作用。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录