Aldosterone Inhibits Insulin-Induced Glucose Uptake by Degradation of Insulin Receptor Substrate (IRS) 1 and IRS2 via a Reactive Oxygen Species-Mediated Pathway in 3T3-L1 Adipocytes
Aldosterone Inhibits Insulin-Induced Glucose Uptake by Degradation of Insulin Receptor Substrate (IRS) 1 and IRS2 via a Reactive Oxygen Species-Mediated Pathway in 3T3-L1 Adipocytes
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DOI：
10.1210/en.2008-1018
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发表时间：
2009-04-01
期刊：
影响因子：
4.8
通讯作者：
Sasaoka, Toshiyasu
中科院分区：
文献类型：
--
作者：
Wada, Tsutomu;Ohshima, Satoshi;Sasaoka, Toshiyasu
临床上已知血清醛固酮水平与体重和胰岛素抵抗相关。由于潜在的分子机制尚不清楚，我们研究了醛固酮对胰岛素诱导的代谢信号导致3T3-L1脂肪细胞葡萄糖摄取的影响。醛固酮以时间和剂量依赖的方式减少胰岛素受体底物(IRS)1和IRS2的数量。结果，胰岛素诱导的Akt-1和Akt-2的磷酸化以及随后对2-脱氧葡萄糖的摄取减少。糖皮质激素受体拮抗剂和抗氧化剂N-乙酰半胱氨酸能有效地阻止IRSS的降解，但不能被盐皮质激素受体拮抗剂阻止。由于醛固酮诱导IRS1在Ser(307)处的磷酸化，所以我们研究了相关的激酶，我们发现雷帕霉素和BMS345541，而SP600125和calphostin C都不能降解IRSs。虽然lactacystin阻止了胰岛素样生长因子的降解，但葡萄糖摄取并未被保存。重要的是，蔗糖梯度沉淀胞内分数分析表明，lactacystin不能有效地恢复低密度微粒组分中IRS1的减少，而IRS1是胰岛素代谢信号转导的重要环节。这些结果表明，醛固酮通过糖皮质激素受体介导的活性氧产生、I-kappaB-Kinase-β和雷帕霉素复合体1靶标的激活，促进IRS1和IRS2的降解，从而恶化胰岛素的代谢作用。因此，醛固酮可能是内脏肥胖中胰岛素抵抗发生的一个新的关键因素。(内分泌学150：1662-1669,2009)
Serum aldosterone level is clinically known to correlate with body weight and insulin resistance. Because the underlying molecular mechanism is largely unknown, we examined the effect of aldosterone on insulin-induced metabolic signaling leading to glucose uptake in 3T3-L1 adipocytes. Aldosterone reduced the amounts of insulin receptor substrate (IRS) 1 and IRS2 in a time-and dose-dependent manner. As a result, insulin-induced phosphorylation of Akt-1 and-2, and subsequent uptake of 2-deoxyglucose were decreased. Degradation of IRSs was effectively prevented by a glucocorticoid receptor antagonist and antioxidant N-acetylcysteine, but not by a mineralocorticoid receptor antagonist. Because aldosterone induced phosphorylation of IRS1 at Ser(307), responsible kinases were investigated, and we revealed that rapamycin and BMS345541, but neither SP600125 nor calphostin C, conferred for degradation of IRSs. Although lactacystin prevented the degradation of IRSs, glucose uptake was not preserved. Importantly, sucrose-gradient-sediment intracellular fraction analysis revealed that lactacystin did not effectively restore the reduction of IRS1 in the low-density microsome fraction, important for the transduction of insulin's metabolic signaling. These results indicate that aldosterone deteriorates metabolic action of insulin by facilitating the degradation of IRS1 and IRS2 via glucocorticoid receptor-mediated production of reactive oxygen species, and activation of I kappa B Kinase beta and target of rapamycin complex 1. Thus, aldosterone appears to be a novel key factor in the development of insulin resistance in visceral obesity. (Endocrinology 150: 1662-1669, 2009)