FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization.
FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization.
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DOI：
10.1038/ncomms8079
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发表时间：
2015-05-12
影响因子：
16.6
通讯作者：
Unterman TG
中科院分区：
文献类型：
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作者：
O-Sullivan I;Zhang W;Wasserman DH;Liew CW;Liu J;Paik J;DePinho RA;Stolz DB;Kahn CR;Schwartz MW;Unterman TG
FoxO蛋白是胰岛素作用的主要靶点。为了更好地确定FoxO1在肝脏中介导胰岛素作用的作用，我们构建了肝脏特异性胰岛素受体敲除（LIRKO）和IR/FoxO1双敲除（LIRFKO）小鼠。根据葡萄糖、胰岛素和c肽水平以及葡萄糖和胰岛素耐量测试，我们发现LIRKO小鼠存在严重的胰岛素抵抗，而肝脏FoxO1的基因缺失逆转了这些影响。13c -葡萄糖和胰岛素钳的研究表明，在LIRFKO小鼠中，肝脏葡萄糖生成（HGP）和葡萄糖利用的调节都受到了损害，这些缺陷在LIRFKO小鼠中也得到了恢复，这与基因表达的变化相对应。我们得出结论：(1)FoxO1的抑制对于胰岛素对HGP和利用的直接（肝脏）和间接影响至关重要；(2)当肝脏FoxO1活性被破坏时，胰岛素的肝外作用足以维持正常的全身和肝脏葡萄糖代谢。
FoxO proteins are major targets of insulin action. To better define the role of FoxO1 in mediating insulin effects in the liver, we generated liver-specific insulin receptor knockout (LIRKO) and IR/FoxO1 double knockout (LIRFKO) mice. Here we show that LIRKO mice are severely insulin resistant based on glucose, insulin and C-peptide levels, and glucose and insulin tolerance tests, and genetic deletion of hepatic FoxO1 reverses these effects. 13C-glucose and insulin clamp studies indicate that regulation of both hepatic glucose production (HGP) and glucose utilization is impaired in LIRKO mice, and these defects are also restored in LIRFKO mice corresponding to changes in gene expression. We conclude that (1) inhibition of FoxO1 is critical for both direct (hepatic) and indirect effects of insulin on HGP and utilization, and (2) extrahepatic effects of insulin are sufficient to maintain normal whole-body and hepatic glucose metabolism when liver FoxO1 activity is disrupted.