The Gly→Arg972 amino acid polymorphism in insulin receptor substrate-1 affects glucose metabolism in skeletal muscle cells
The Gly→Arg972 amino acid polymorphism in insulin receptor substrate-1 affects glucose metabolism in skeletal muscle cells
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DOI：
10.1210/jc.85.5.2004
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发表时间：
2000-05-01
影响因子：
5.8
通讯作者：
Sesti, G
中科院分区：
文献类型：
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作者：
Hribal, ML;Federici, M;Sesti, G
胰岛素受体底物-1（IRS-1）的分子扫描显示了几个氨基酸取代。最常见的IRS-1变异，Gly到Arg（972）的变化，在2型糖尿病患者中更为普遍。在这项研究中，我们在L 6骨骼肌细胞中过表达野生型和Arg（972）IRS-1变体，并检查这种多态性对胰岛素代谢信号传导的功能后果。与表达野生型IRS-1（L 6-WT）的L 6细胞相比，表达Arg（972）-IRS-1（L 6-Arg（972））的L 6细胞显示胰岛素刺激的IRS-1相关的磷脂酰肌醇3-二联酶（PI 3-激酶）活性降低，这是PI 3-激酶的p85亚基与IRS-1的结合降低的结果。由于转移到质膜的GLUT 1和GLUT 4的量减少，L 6-Ar-972表现出基础和胰岛素刺激的葡萄糖转运减少。与L 6-WT相比，L 6-Arg（972）中基础和胰岛素刺激的Akt磷酸化均降低。与L 6-WT相比，L 6-Arg（972）中的基础糖原合成酶激酶-3（GSK-3）活性增加，L 6-Arg（972）中胰岛素诱导的GSK-3失活也减少。与L 6-WT相比，L 6-Arg（972）中胰岛素刺激的葡萄糖掺入糖原和糖原合酶活性显著降低，与此相关。这些结果表明Arg（972）-IRS-1多态性通过影响PI 3-激酶/Akt/GSK-3信号通路而损害胰岛素刺激葡萄糖转运、葡萄糖转运蛋白易位和糖原合成的能力。目前的数据表明，IRS-1的密码子972处的多态性可能有助于在该变体携带者中观察到的体内胰岛素抵抗。
Molecular scanning of insulin receptor substrate-1 (IRS-1) revealed several amino acid substitutions. The most common IRS-1 variant, a Gly to Arg(972) change, is more prevalent among type 2 diabetic patients. In this study we overexpressed wild-type and Arg(972)IRS-1 variant in L6 skeletal muscle cells and examined the functional consequences of this polymorphism on insulin metabolic signaling. L6 cells expressing Arg(972)-IRS-1 (L6-Arg(972)) showed a decrease in insulin-stimulated IRS-l-associated phosphatidylinositol 3-binase (PI 3-kinase) activity compared with L6 cells expressing wild-type IRS-1(L6-WT) as a consequence of decreased binding of p85 subunit of PI S-kinase to IRS-1. L6-Ar-972 exhibited a decrease in both basal and insulin-stimulated glucose transport due to a reduction in the amount of both GLUT1 and GLUT4 translocated to the plasma membrane. Both basal and insulin-stimulated Akt phosphorylations were decreased in L6-Arg(972) compared with L6-WT. Basal glycogen synthase kinase-3 (GSK-3) activity was increased in L6-Arg(972) compared with L6-WT, and insulin-induced inactivation of GSK-3 was also reduced in L6-Arg(972). This change was associated with a significant decrease in insulin-stimulated glucose incorporation into glycogen and glycogen synthase activity in L6-Arg(972) compared with L6-WT. These results indicate that the Arg(972)-IRS-1 polymorphism impairs the ability of insulin to stimulate glucose transport, glucose transporter translocation, and glycogen synthesis by affecting the PI 3-kinase/Akt/GSK-3 signaling pathway. The present data indicate that the polymorphism at codon 972 of IRS-1 may contribute to the in vivo insulin resistance observed in carriers of this variant.