Phosphoinositide 3-Kinase-mediated Reduction of Insulin Receptor Substrate-1/2 Protein Expression via Different Mechanisms Contributes to the Insulin-induced Desensitization of Its Signaling Pathways in L6 Muscle Cells*
Phosphoinositide 3-Kinase-mediated Reduction of Insulin Receptor Substrate-1/2 Protein Expression via Different Mechanisms Contributes to the Insulin-induced Desensitization of Its Signaling Pathways in L6 Muscle Cells*
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磷酸肌醇 3-激酶通过不同机制介导的胰岛素受体底物 1/2 蛋白表达减少有助于胰岛素诱导的 L6 肌细胞信号通路脱敏*
DOI：
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发表时间：
2003
影响因子：
4.8
通讯作者：
E. van Obberghen
中科院分区：
文献类型：
--
作者：
L. Pirola;S. Bonnafous;A. M. Johnston;C. Chaussade;F. Portis;E. van Obberghen
糖耐量受损先于2型糖尿病，其特征是高胰岛素血症，其发展以平衡外周胰岛素抵抗。为了深入了解高胰岛素血症对骨骼肌的有害影响，我们研究了长时间胰岛素治疗L6成肌细胞对胰岛素依赖信号通路的影响。24小时的胰岛素治疗使磷酸肌肽3激酶(PI3K)/蛋白激酶B （PKB）和p42/p44 MAPK通路脱敏，导致胰岛素或胰岛素样生长因子-1的第二次刺激，并导致胰岛素诱导的葡萄糖摄取减少。脱敏与胰岛素受体底物(IRS)-1和IRS-2蛋白水平的降低相关，而PI3K抑制剂LY294002可以逆转这一过程。胰岛素和LY294002共同处理细胞，在降低IRS-1总磷酸化的同时，增加了其磷酸酪氨酸含量，增强了IRS-1/PI3K的关联。PDK1、mTOR和MAPK抑制剂不能阻断胰岛素诱导的IRS-1的减少，这表明PI3K丝氨酸激酶活性导致IRS-1丝氨酸磷酸化及其对蛋白酶体降解的承诺。相反，胰岛素诱导的IRS-2下调通过PI3K/mTOR途径发生。LY294002抑制IRS-1/2下调，恢复了PKB和MAPK对急性胰岛素刺激的反应性。相反，腺病毒驱动的组成活性PI3K的表达诱导胰岛素不依赖型IRS-1/2蛋白水平的降低。IRS-2似乎是胰岛素激活MAPK和PKB的主要分子，因为通过RNA干扰敲低IRS-2（而不是IRS-1）会严重损害这两种激酶的激活。综上所述，(i) PI3K通过磷酸化IRS-1介导胰岛素诱导的IRS-1的降低，而PI3K/mTOR通路控制胰岛素诱导的IRS-2的降低，（ii）在L6细胞中，IRS-2是连接胰岛素受体与PKB和MAPK激活的主要适配分子，（iii）与3T3-L1脂肪细胞相比，L6细胞中IRS-1/2下调的机制不同。综上所述，通过不同pi3k介导的机制，IRS蛋白的减少有助于L6成肌细胞胰岛素抵抗状态的发展。
Impaired glucose tolerance precedes type 2 diabetes and is characterized by hyperinsulinemia, which develops to balance peripheral insulin resistance. To gain insight into the deleterious effects of hyperinsulinemia on skeletal muscle, we studied the consequences of prolonged insulin treatment of L6 myoblasts on insulin-dependent signaling pathways. A 24-h long insulin treatment desensitized the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) and p42/p44 MAPK pathways toward a second stimulation with insulin or insulin-like growth factor-1 and led to decreased insulin-induced glucose uptake. Desensitization was correlated to a reduction in insulin receptor substrate (IRS)-1 and IRS-2 protein levels, which was reversed by the PI3K inhibitor LY294002. Co-treatment of cells with insulin and LY294002, while reducing total IRS-1 phosphorylation, increased its phosphotyrosine content, enhancing IRS-1/PI3K association. PDK1, mTOR, and MAPK inhibitors did not block insulin-induced reduction of IRS-1, suggesting that the PI3K serine-kinase activity causes IRS-1 serine phosphorylation and its commitment to proteasomal degradation. Contrarily, insulin-induced IRS-2 down-regulation occurred via a PI3K/mTOR pathway. Suppression of IRS-1/2 down-regulation by LY294002 rescued the responsiveness of PKB and MAPK toward acute insulin stimulation. Conversely, adenoviral-driven expression of constitutively active PI3K induced an insulin-independent reduction in IRS-1/2 protein levels. IRS-2 appears to be the chief molecule responsible for MAPK and PKB activation by insulin, as knockdown of IRS-2 (but not IRS-1) by RNA interference severely impaired activation of both kinases. In summary, (i) PI3K mediates insulin-induced reduction of IRS-1 by phosphorylating it while a PI3K/mTOR pathway controls insulin-induced reduction of IRS-2, (ii) in L6 cells, IRS-2 is the major adapter molecule linking the insulin receptor to activation of PKB and MAPK, (iii) the mechanism of IRS-1/2 down-regulation is different in L6 cells compared with 3T3-L1 adipocytes. In conclusion, the reduction in IRS proteins via different PI3K-mediated mechanisms contributes to the development of an insulin-resistant state in L6 myoblasts.
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影响因子：
15.9
作者：
SAAD, MJA;ARAKI, E;KAHN, CR
通讯作者：
KAHN, CR
影响因子：
7.7
作者：
Sun, XJ;Goldberg, JL;Mitchell, JJ
通讯作者：
Mitchell, JJ
骨细胞中胰岛素样生长因子 II 受体的表征。
影响因子：
5.6
作者：
Mohan,S;Linkhart,T;Rosenfeld,R;Baylink,D
通讯作者：
Baylink,D
胰岛素刺激 3T3-L1 脂肪细胞中 IRS-1 的降解。
影响因子：
3.1
作者：
Rice,KM;Turnbow,MA;Garner,CW
通讯作者：
Garner,CW
影响因子：
15.9
作者：
CARO, JF;SINHA, MK;DOHM, GL
通讯作者：
DOHM, GL