Role of phosphatidylinositol 3-kinase activation on insulin action and its alteration in diabetic conditions
Role of phosphatidylinositol 3-kinase activation on insulin action and its alteration in diabetic conditions
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DOI：
10.1248/bpb.30.1610
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发表时间：
2007-09-01
影响因子：
2
通讯作者：
Sakoda, Hideyuki
中科院分区：
文献类型：
--
作者：
Asano, Tomoichiro;Fujishiro, Midorl;Sakoda, Hideyuki
肌醇磷脂在其肌醇环（3-磷酸肌苷）的d3位置磷酸化，在各种细胞事件中起重要作用。磷脂酰肌醇3-激酶的激活对于胰岛素诱导的葡萄糖代谢至关重要，包括GLUT4转运到细胞表面和糖原合成。该酶以异源二聚体的形式存在，含有一个调控亚基和p110催化亚基的两个广泛分布的同工异构体之一：p110 α或p110 β。pi3激酶及其下游AKT的激活已被证明对几乎所有胰岛素诱导的糖脂代谢（如葡萄糖摄取、糖原合成、抑制葡萄糖输出和甘油三酯合成以及胰岛素诱导的有丝分裂）都是必不可少的。积累的PI(3,4,5)P-3可以激活几种含有PH （pleckstrin同源）结构域的丝氨酸/苏氨酸激酶，包括Akt、非典型PKCs、p70S6激酶和GSK。在肥胖诱导的胰岛素抵抗条件下，JNK和p70S6K被激活并磷酸化irs蛋白，从而减少胰岛素诱导的irs蛋白酪氨酸磷酸化，从而损害pi3激酶/AKT的激活。因此，通过抑制JNK或p70S6K、PTEN或SHIP2，恢复胰岛素诱导的受损PI 3-激酶/AKT激活的药物可能成为治疗糖尿病的新药物。
Inositol phospholipids phosphorylated on D3-position of their inositol rings (3-phosphoinositides) are known to play important roles in various cellular events. Activation of PI (phosphatidylinositol) 3-kinase is essential for aspects of insulin-induced glucose metabolism, including translocation of GLUT4 to the cell surface and glycogen synthesis. The enzyme exists as a heterodimer containing a regulatory subunit and one of two widely-distributed isoforms of the p110 catalytic subunit: p110 alpha or p110 beta. Activation of PI3-kinase and its downstream AKT has been demonstrated to be essential for almost all of the insulin-induced glucose and lipid metabolism such as glucose uptake, glycogen synthesis, suppression of glucose output and triglyceride synthesis as well as insulin-induced mitogenesis. Accumulated PI(3,4,5)P-3 activates several serine/threonine kinases containing a PH (pleckstrin homology) domain, including Akt, atypical PKCs, p70S6 kinase and GSK.In the obesity-induced insulin resistant condition, JNK and p70S6K are activated and phosphorylate IRS-proteins, which diminishes the insulin-induced tyrosine phosphorylation of IRS-proteins and thereby impairs the PI3-kinase/AKT activations. Thus, the drugs which restore the impaired insulin-induced PI 3-kinase/AKT activation, for example, by suppressing JNK or p70S6K, PTEN or SHIP2, could be novel agents to treat diabetes mellitus.