Insulin resistance is a cellular antioxidant defense mechanism
Insulin resistance is a cellular antioxidant defense mechanism
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DOI：
10.1073/pnas.0902380106
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发表时间：
2009-10-20
影响因子：
11.1
通讯作者：
James, David E.
中科院分区：
文献类型：
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作者：
Hoehn, Kyle L.;Salmon, Adam B.;James, David E.
我们对细胞通过 AMPK 对饥饿的反应了解很多，但对营养过剩的反应知之甚少。胰岛素抵抗可能是对营养过剩的适当反应，但连接这些参数的细胞传感器仍然不明确。在本研究中，我们提供的证据表明，线粒体超氧化物的产生是脂肪细胞、肌管和小鼠中许多不同胰岛素抵抗模型的共同特征。特别是，当接触线粒体解偶联剂、ETC 抑制剂或线粒体超氧化物歧化酶 (MnSOD) 模拟物时，胰岛素抵抗会迅速逆转。线粒体 MnSOD 的过度表达也观察到类似的效果。此外，使用复合物 III 拮抗剂抗霉素 A 急性诱导线粒体超氧化物产生，导致胰岛素作用快速减弱，与经典 PI3K/Akt 途径的变化无关。这些结果在体内得到了验证，因为 MnSOD 转基因小鼠部分受到 HFD 诱导的胰岛素抵抗的保护，而 MnSOD+/- 小鼠在标准食物饮食中出现葡萄糖不耐受。这些数据将线粒体超氧化物置于细胞内代谢和胰岛素作用控制之间的联系处，可能将其定义为能量过剩的代谢传感器。
We know a great deal about the cellular response to starvation via AMPK, but less is known about the reaction to nutrient excess. Insulin resistance may be an appropriate response to nutrient excess, but the cellular sensors that link these parameters remain poorly defined. In the present study we provide evidence that mitochondrial superoxide production is a common feature of many different models of insulin resistance in adipocytes, myotubes, and mice. In particular, insulin resistance was rapidly reversible upon exposure to agents that act as mitochondrial uncouplers, ETC inhibitors, or mitochondrial superoxide dismutase (MnSOD) mimetics. Similar effects were observed with overexpression of mitochondrial MnSOD. Furthermore, acute induction of mitochondrial superoxide production using the complex III antagonist antimycin A caused rapid attenuation of insulin action independently of changes in the canonical PI3K/Akt pathway. These results were validated in vivo in that MnSOD transgenic mice were partially protected against HFD induced insulin resistance and MnSOD+/- mice were glucose intolerant on a standard chow diet. These data place mitochondrial superoxide at the nexus between intracellular metabolism and the control of insulin action potentially defining this as a metabolic sensor of energy excess.