PDF(Pubmed)
Abstract：
Background: Class IA phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is an integral mediator of insulin signaling. The p110 catalytic and p85 regulatory subunits of PI3K are the products of separate genes, and while they come together to make the active heterodimer, they have opposing roles in insulin signaling and action. Deletion of hepatic p110α results in an impaired insulin signal and severe insulin resistance, whereas deletion of hepatic p85α results in improved insulin sensitivity due to sustained levels of phosphatidylinositol (3,4,5)-trisphosphate. Here, we created mice with combined hepatic deletion of p110α and p85α (L-DKO) to study the impact on insulin signaling and whole body glucose homeostasis. Methods: Six-week old male flox control and L-DKO mice were studied over a period of 18 weeks, during which weight and glucose levels were monitored, and glucose tolerance tests, insulin tolerance test and pyruvate tolerance test were performed. Fasting insulin, insulin signaling mediators, PI3K activity and insulin receptor substrate (IRS)1-associated phosphatidylinositol kinase activity were examined at 10 weeks. Liver, muscle and white adipose tissue weight was recorded at 10 weeks and 25 weeks. Results: The L-DKO mice showed a blunted insulin signal downstream of PI3K, developed markedly impaired glucose tolerance, hyperinsulinemia and had decreased liver and adipose tissue weights. Surprisingly, however, these mice displayed normal hepatic glucose production, normal insulin tolerance, and intact IRS1-associated phosphatidylinositol kinase activity without compensatory upregulated signaling of other classes of PI3K. Conclusions: The data demonstrate an unexpectedly overall mild metabolic phenotype of the L-DKO mice, suggesting that lipid kinases other than PI3Ks might partially compensate for the loss of p110α/p85α by signaling through other nodes than Akt/Protein Kinase B.
摘要：
背景：IA类磷脂酰肌醇-4,5-二磷酸3-激酶（PI3K）是胰岛素信号传导的完整介质。PI3K的p110催化和p85调节亚基是不同基因的产物，当它们聚集在一起形成活性异二聚体时，它们在胰岛素信号传导和作用中具有相反的作用。肝p110α缺失导致胰岛素信号受损和严重的胰岛素抵抗，而由于磷脂酰肌醇（3,4,5）-三磷酸的持续水平，肝p85α的缺失导致胰岛素敏感性提高。这里,我们创建了p110α和p85α联合肝缺失（L-DKO）的小鼠，以研究对胰岛素信号和全身葡萄糖稳态的影响。方法：研究了6周龄雄性flox对照和L-DKO小鼠，为期18周，在此期间监测体重和葡萄糖水平，和葡萄糖耐量试验,进行胰岛素耐量试验和丙酮酸耐量试验.空腹胰岛素，胰岛素信号介质，在10周时检查PI3K活性和胰岛素受体底物（IRS）1相关的磷脂酰肌醇激酶活性。肝脏,在第10周和第25周记录肌肉和白色脂肪组织的重量.结果：L-DKO小鼠在PI3K下游显示出迟钝的胰岛素信号，出现明显的葡萄糖耐量受损，高胰岛素血症，肝脏和脂肪组织重量降低。令人惊讶的是,然而,这些小鼠显示正常的肝脏葡萄糖产生，正常的胰岛素耐受性，和完整的IRS1相关磷脂酰肌醇激酶活性，没有其他类型PI3K的代偿性上调信号。结论：数据表明，L-DKO小鼠具有出乎意料的总体轻度代谢表型，表明PI3K以外的脂质激酶可能通过Akt/蛋白激酶B以外的其他节点的信号传导来部分补偿p110α/p85α的损失。
