Restoration of glucokinase expression in the liver normalizes postprandial glucose disposal in mice with hepatic deficiency of PDK1
Restoration of glucokinase expression in the liver normalizes postprandial glucose disposal in mice with hepatic deficiency of PDK1
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DOI：
10.2337/db06-1322
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发表时间：
2007-04-01
期刊：
影响因子：
7.7
通讯作者：
Kasuga, Masato
中科院分区：
文献类型：
--
作者：
Okamoto, Yasuo;Ogawa, Wataru;Kasuga, Masato
磷酸肌醇依赖性激酶 1 (PDK1) 作为磷酸肌醇 3 激酶依赖性信号传导的关键介质，参与胰岛素的代谢作用。在这里，我们发现肝脏特异性PDK1缺乏的小鼠表现出肝脏中胰岛素代谢作用的各种缺陷，以及以明显的高胰岛素血症和餐后高血糖为特征的2型糖尿病样表型。在这些小鼠中，葡萄糖激酶的肝脏丰度显着降低，葡萄糖激酶是肝细胞中葡萄糖通量和葡萄糖诱发信号传导的重要决定因素。使用腺病毒载体恢复肝葡萄糖激酶表达，在肝脏中诱导胰岛素样作用，并使这些动物的空腹高胰岛素血症和餐后高血糖几乎完全正常化。这些结果表明，如果肝脏中葡萄糖激酶的丰度得以维持，即使在肝脏中近端胰岛素信号传导没有急性激活（例如 Akt 激活）的情况下，摄入的葡萄糖也通常会被处理掉。
Phosphoinositide-dependent kinase-1 (PDK1) is implicated in the metabolic effects of insulin as a key mediator of phosphoinositide 3-kinase-dependent signaling. Here we show that mice with liver-specific PDK1 deficiency manifest various defects in the metabolic actions of insulin in the liver as well as a type 2 diabetes-like phenotype characterized by marked hyperinsulinemia and postprandial hyperglycemia. The hepatic abundance of glucokinase, an important determinant of glucose flux and glucose-evoked signaling in hepatocytes, was substantially reduced in these mice. Restoration of hepatic glucokinase expression, with the use of an adenoviral vector, induced insulin-like effects in the liver and almost completely normalized the fasting hyperinsulinemia and postprandial hyperglycemia in these animals. These results indicate that, if the hepatic abundance of glucokinase is maintained, ingested glucose is normally disposed of even in the absence of acute activation of proximal insulin signaling, such as the activation of Akt, in the liver.