The role of PI 3-kinase on insulin action and its alteration in diabetic condition

p85/p110型pi激酶的激活已被证明是胰岛素诱导的葡萄糖代谢所必需的。因此，我们研究了(1)胰岛素抵抗条件下p85/p110型pi激酶激活的改变，以及(2)p85/p110型pi激酶对细胞磷酸化磷脂含量的改变及其在细胞活性中的作用。(1)胰岛素抵抗状态下p85/p110型pi激酶激活的改变肥胖和高脂肪饮食被认为是日本人群胰岛素抵抗的最常见原因。我们报道了由暴饮暴食引起的肥胖导致肝脏、肌肉或脂肪组织中p85/p110型pi激酶激活的显著损伤。相比之下，高脂饲料喂养导致肌肉和脂肪组织中p85/p110型pi激酶激活的中度损害，但有趣的是，肝脏中的激活明显增强。这些结果表明，高脂肪饮食引起的胰岛素抵抗机制与暴饮暴食引起的胰岛素抵抗机制有很大不同。(2) p85/p110型pi激酶对细胞磷酸化磷脂含量的影响。我们观察到p85/p110型pi激酶激活后，细胞中PI3- p、pi3,4 - p2、pi3,4,5 - p3以及PI4- p和pi4,5 - p2的含量均显著增加。这表明p85/p110型PI-激酶具有较高的PI- 4激酶活性。此外，我们观察到p85/p110型PI-激酶的PI- 4激酶活性参与肌动蛋白重排和葡萄糖转运体向细胞表面的易位。这些发现令人惊讶，可能是了解NIDDM患者胰岛素作用和/或胰岛素抵抗的分子机制的突破。

Activation of p85/p110 type PI-kinase has been shown to be necessary for the insulin-induced glucose metabolism. Thus, we have investigated (1) The altered p85/p110 type PI-kinase activation in the insulin resistant condition, and (2) The alteration of the cellular content of phosphorylated phospholipid by p85/p110 type PI-kinase end its role on cellular activities.(1) The altered p85/p110 type PI-kinase activation in the insulin resistant condition obesity and high-fat diet are regarded as the most common causes of insulin resistance in Japanese population. We reported that obesity induced by overeating leads to the marked impairment of p85/p110 type PI-kinase activation in either liver, muscle or fat tissues. In contrast, high-fat diet feeding resulted in moderate impairment of p85/p110 type PI-kinase activation in muscle and fat tissues, however, interestingly, in the liver the activation was markedly enhanced. These results indicate that the mechanism of insulin resistance caused by high-fat diet is quite different from that by overeating.(2) The alteration of the cellular content of phosphorylated phospholipid by p85/p110 type PI-kinase. We observed activation of p85/p110 type PI-kinase resulted in the increased cellular content of not only PI3-P, PI3, 4-P2, PI3, 4, 5-P3 but also PI4-P and PI4, 5-P2 markedly. This suggests that p85/p110 type PI-kinase possesses a high PI 4-kinase activity. In addition, we observed the PI 4-kinase activity of p85/p110 type PI-kinase is involved in the actin rearrangement and the translocation of glucose transporter to the cell surface. These findings are surprising and can be a breakthrough to understand the molecular mechanism of insulin action and/or insulin resistance in NIDDM patients.