In Skeletal Muscle Advanced Glycation End Products (AGEs) Inhibit Insulin Action and Induce the Formation of Multimolecular Complexes Including the Receptor for AGEs
In Skeletal Muscle Advanced Glycation End Products (AGEs) Inhibit Insulin Action and Induce the Formation of Multimolecular Complexes Including the Receptor for AGEs
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DOI：
10.1074/jbc.m801698200
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发表时间：
2008-12-26
影响因子：
4.8
通讯作者：
Miele, Claudia
中科院分区：
文献类型：
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作者：
Cassese, Angela;Esposito, Iolanda;Miele, Claudia
慢性高血糖症至少部分通过增加晚期糖基化终产物（AGEs）的形成来促进胰岛素抵抗。我们以前已经表明，在L 6肌管人糖化白蛋白（HGA）诱导胰岛素抵抗通过激活蛋白激酶C α（PKC α）。在这里，我们表明，HGA诱导的PKC α激活是由Src介导的。共沉淀实验表明，Src与HGA处理的L 6细胞中的AGE受体（AGE）和PKC α相互作用。还检测到PKC α与Src和胰岛素受体底物-1（IRS-1）的直接相互作用。此外，IRS-1表达的沉默消除了HGA诱导的RAGE-PKC α共沉淀。AGEs也能够在体内诱导胰岛素抵抗，因为胰岛素耐量试验显示喂食高AGEs饮食（HAD）的C57/BL 6小鼠的胰岛素敏感性显著受损。在HAD喂养小鼠的胫骨肌中，胰岛素诱导的葡萄糖摄取和蛋白激酶B磷酸化减少。这被PKC α活性增加2.5倍所抵消。与体外观察结果相似，HAD喂养小鼠胫骨肌中Src磷酸化增加，共沉淀实验表明Src与β-淀粉样蛋白和PKC α相互作用。这些结果表明AGEs对肌肉中胰岛素作用的损害可能是通过形成一种包括PKC α和IRS-1/Src的多分子复合物来介导的
Chronic hyperglycemia promotes insulin resistance at least in part by increasing the formation of advanced glycation end products (AGEs). We have previously shown that in L6 myotubes human glycated albumin (HGA) induces insulin resistance by activating protein kinase C alpha(PKC alpha). Here we show that HGA-induced PKC alpha activation is mediated by Src. Coprecipitation experiments showed that Src interacts with both the receptor for AGE (RAGE) and PKC alpha in HGA-treated L6 cells. A direct interaction of PKC alpha with Src and insulin receptor substrate-1 (IRS-1) has also been detected. In addition, silencing of IRS-1 expression abolished HGA-induced RAGE-PKC alpha co-precipitation. AGEs were able to induce insulin resistance also in vivo, as insulin tolerance tests revealed a significant impairment of insulin sensitivity in C57/BL6 mice fed a high AGEs diet (HAD). In tibialis muscle of HAD-fed mice, insulin-induced glucose uptake and protein kinase B phosphorylation were reduced. This was paralleled by a 2.5-fold increase in PKC alpha activity. Similarly to in vitro observations, Src phosphorylation was increased in tibialis muscle of HAD-fed mice, and co-precipitation experiments showed that Src interacts with both RAGE and PKC alpha. These results indicate that AGEs impairment of insulin action in the muscle might be mediated by the formation of a multimolecular complex including RAGE/IRS-1/Src and PKC alpha