Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction
Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction
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DOI：
10.1016/s1097-2765(00)00010-1
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发表时间：
2000-07-01
期刊：
影响因子：
16
通讯作者：
Kahn, CR
中科院分区：
文献类型：
--
作者：
Michael, MD;Kulkarni, RN;Kahn, CR
肝脏在葡萄糖稳态的控制中起着核心作用，并受到底物、胰岛素和其他激素的复杂调节。为了研究肝脏中胰岛素直接作用丧失的影响，我们使用Cre-loxP系统在肝细胞中克隆胰岛素受体基因。肝脏特异性胰岛素受体敲除（LIRKO）小鼠表现出显著的胰岛素抵抗、严重的葡萄糖耐受不良以及胰岛素抑制肝脏葡萄糖产生和调节肝脏基因表达的失败。这些改变被显著的高胰岛素血症所掩盖，高胰岛素血症是由于胰岛素分泌增加和胰岛素清除率降低的组合。随着年龄的增长，LIRKO肝脏表现出形态和功能的变化，代谢表型变得不那么严重，因此，肝脏中的胰岛素信号传导在调节葡萄糖稳态和维持正常肝功能中至关重要。
The liver plays a central role in the control of glucose homeostasis and is subject to complex regulation by substrates, insulin, and other hormones. To investigate the effect of the loss of direct insulin action in liver, we have used the Cre-loxP system to inactivate the insulin receptor gene in hepatocytes. Liver-specific insulin receptor knockout (LIRKO) mice exhibit dramatic insulin resistance, severe glucose intolerance, and a failure of insulin to suppress hepatic glucose production and to regulate hepatic gene expression. These alterations are paralleled by marked hyperinsulinemia due to a combination of increased insulin secretion and decreased insulin clearance. With aging, the LIRKO liver exhibits morphological and functional changes, and the metabolic phenotype becomes less severe, Thus, insulin signaling in liver is critical in regulating glucose homeostasis and maintaining normal hepatic function.