Deficiency of PDK1 in liver results in glucose intolerance, impairment of insulin-regulated gene expression and liver failure
Deficiency of PDK1 in liver results in glucose intolerance, impairment of insulin-regulated gene expression and liver failure
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DOI：
10.1042/bj20041782
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发表时间：
2005-02-01
影响因子：
4.1
通讯作者：
Alessi, DR
中科院分区：
文献类型：
--
作者：
Mora, A;Lipina, C;Alessi, DR
肝脏在胰岛素调节的葡萄糖稳态中起重要作用。为了研究PDK 1（3-phospho-inositide-dependent protein kinase-1，3-磷酸肌醇依赖性蛋白激酶1）信号通路在胰岛素介导肝脏作用中的作用，我们采用CRE重组酶/lexP技术建立了肝细胞PDK 1表达缺失且胰岛素不能诱导肝脏PKB活化的L（liver）-PDK 1（-1-）小鼠模型。L-PDKI-1-小鼠没有胰岛素不耐受性，在正常喂养条件下具有正常水平的血糖和胰岛素，但是当注射葡萄糖时，明显地葡萄糖不耐受。L-PDK 1（-1-）小鼠的肝糖原水平也比对照组低10倍，并且在注射胰岛素后2 In内无法使血糖水平正常化。L-PDK 1（-1-）小鼠的葡萄糖耐受不良可能是由于葡萄糖不能通过糖原生成途径抑制肝脏葡萄糖输出，因为编码肝脏PEPCK（磷酸烯醇丙酮酸羧激酶）、G6-磷酸酶（葡萄糖-6-磷酸酶）和SREBP 1（固醇调节元件结合蛋白1）的mRNA调节糖原生成，不再受进食控制。此外，其他三个胰岛素控制的基因，即IGFBP 1（胰岛素样生长因子结合蛋白-1），IRS 2（胰岛素受体底物2）和葡萄糖激酶，通过在PDK 1缺陷小鼠的肝脏中进食而受到异常调节。最后，L-PDK 1（-1-）小鼠在4-16周龄之间死于肝功能衰竭。这些结果表明，PDK 1信号通路在调节葡萄糖稳态和控制胰岛素调节基因的表达中起着重要作用。他们认为，肝脏中PDK 1通路的缺乏可能导致糖尿病的发展以及肝功能衰竭。
The liver plays an important role in insulin-regulated glucose homoeostasis. To study the function of the PDK1 (3-phospho-inositide-dependent protein kinase-1) signalling pathway in mediating insulin's actions in the liver, we employed CRE recombinase/lexP technology to generate L(liver)-PDK1(-1-) mice, which lack expression of PDK1 in hepatocytes and in which insulin failed induce activation of PKB in liver. The L-PDKI-1- mice were not insulin-intolerant, possessed normal levels of blood glucose And insulin under normal feeding conditions, but were markedly,glucose-intolerant when injected with glucose. The L-PDK1 (-1-) mice also possessed 10-fold lower levels of hepatic glycogen compared with control littermates, and were unable to normalize their blood glucose levels within 2 In after injection of insulin. The glucose intolerance of the L-PDK1(-1-) mice may be due to an inability of glucose to suppress hepatic glucose output through the gluconcogenic pathway, since the mRNA encoding hepatic PEPCK (phosphoenolpyruvate carboxykinase), G6Pase (glucose-6-phosphatase) and SREBP1 (sterol-regulatory-element-binding protein 1), which regulate gluconeogenesis, are no longer controlled by feeding. Furthermore, three other insulin-controlled genes, namely IGFBP1 (insulin-like-growth-factor-binding protein-1), IRS2 (insulin receptor substrate 2) and glucokinase, were regulated abnormally by feeding in the liver of PDK1-deficient mice. Finally, the L-PDK1(-1-) mice died between 4-16 weeks of age due to liver failure. These results establish that the PDK1 signalling pathway plays an important role in regulating glucose homoeostasis and controlling expression of insulin-regulated genes. They suggest that a deficiency of the PDK1 pathway in the liver could contribute to development of diabetes, as well as to liver failure.