The Novel Angiotensin H Receptor Blocker Azilsartan Medoxomil Ameliorates Insulin Resistance Induced by Chronic Angiotensin II Treatment in Rat Skeletal Muscle
The Novel Angiotensin H Receptor Blocker Azilsartan Medoxomil Ameliorates Insulin Resistance Induced by Chronic Angiotensin II Treatment in Rat Skeletal Muscle
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DOI：
10.1159/000353155
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发表时间：
2013-01-01
影响因子：
3.8
通讯作者：
Henriksen, Erik J.
中科院分区：
文献类型：
--
作者：
Lastra, Guido;Santos, Fernando R.;Henriksen, Erik J.
血管紧张素受体（1型）阻滞剂（ARB）可降低局部和全身激活肾素-血管紧张素-醛固酮系统引起的高血压和胰岛素抵抗。目前尚不清楚阿齐沙坦酯（AZIL-M）（一种新型咪唑类ARB）促进血管紧张素II（Ang II）相关胰岛素抵抗疾病代谢改善的有效性。本研究的目的是确定长期AZIL-M治疗对Ang II治疗大鼠红色骨骼肌中葡萄糖转运活性和关键胰岛素信号传导元件的影响。将雄性Sprague-Dawley大鼠用或不用Ang II（200 ng/kg/min）与媒介物或AZIL-M（1 mg/kg/天）组合处理8周。Ang II诱导血压显著升高（p < 0.05），AZIL-M可完全阻止这一作用。此外，血管紧张素II降低胰岛素介导的葡萄糖转运活动在孵育比目鱼肌，和AZIL-M共同治疗增加了这一参数。此外，AZIL-M治疗血管紧张素II输注动物增加了胰岛素信号分子的绝对磷酸化，包括原位冷冻的红色腓肠肌中的Akt [Ser（473）（81%）和Thr（308）（23%）]和AS 160 Thr（642）（42%）。AZIL-M处理后AMPK α（Thr（172））的绝对磷酸化增加（98%），而胰岛素信号负调节因子p70 S6 K1的相对Thr（389）磷酸化降低（51%）。这些结果表明，ARB AZIL-M改善了Ang II诱导的胰岛素抵抗大鼠红比目鱼肌葡萄糖转运的体外胰岛素作用和红腓肠肌原位Akt/AS 160轴的功能，后者的修饰可能与AMPK α增强和p70 S6 K1活化抑制相关。版权所有（c）2013 S. Karger AG，巴塞尔
Angiotensin receptor (type 1) blockers (ARBs) can reduce both hypertension and insulin resistance induced by local and systemic activation of the renin-angiotensin-aldosterone system. The effectiveness of azilsartan medoxomil (AZIL-M), a novel imidazole-based ARB, to facilitate metabolic improvements in conditions of angiotensin II (Ang II)-associated insulin resistance is currently unknown. The aim of this study was to determine the impact of chronic AZIL-M treatment on glucose transport activity and key insulin signaling elements in red skeletal muscle of Ang II-treated rats. Male Sprague-Dawley rats were treated for 8 weeks with or without Ang II (200 ng/kg/min) combined with either vehicle or AZIL-M (1 mg/kg/day). Ang II induced significant (p < 0.05) increases in blood pressure, which were completely prevented by AZIL-M. Furthermore, Ang II reduced insulin-mediated glucose transport activity in incubated soleus muscle, and AZIL-M co-treatment increased this parameter. Moreover, AZIL-M treatment of Ang II-infused animals increased the absolute phosphorylation of insulin signaling molecules, including Akt [both Ser(473) (81%) and Thr(308) (23%)] and AS160 Thr(642) (42%), in red gastrocnemius muscle frozen in situ. Absolute AMPK alpha (Thr(172)) phosphorylation increased (98%) by AZIL-M treatment, and relative Thr(389) phosphorylation of p70 S6K1, a negative regulator of insulin signaling, decreased (51%) with AZIL-M treatment. These results indicate that ARB AZIL-M improves the in vitro insulin action on glucose transport in red soleus muscle and the functionality of the Akt/AS160 axis in red gastrocnemius muscle in situ in Ang II-induced insulin-resistant rats, with the latter modification possibly associated with enhanced AMPK alpha and suppressed p70 S6K1 activation. Copyright (c) 2013 S. Karger AG, Basel