Michael M D, Kulkarni R N, Postic C, Previs S F, Shulman G I, Magnuson M A, Kahn C R
Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
Mol Cell. 2000 Jul;6(1):87-97.
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.
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。为了研究肝脏中直接胰岛素作用丧失的影响，我们使用Cre-loxP系统在肝细胞中使胰岛素受体基因失活。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、严重的葡萄糖不耐受，以及胰岛素无法抑制肝葡萄糖生成和调节肝脏基因表达。由于胰岛素分泌增加和胰岛素清除减少的共同作用，这些改变伴随着明显的高胰岛素血症。随着年龄的增长，LIRKO肝脏表现出形态和功能变化，代谢表型变得不那么严重。因此，肝脏中的胰岛素信号对于调节葡萄糖稳态和维持正常肝功能至关重要。
