Titchenell Paul M, Chu Qingwei, Monks Bobby R, Birnbaum Morris J
Department of Medicine, Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Nat Commun. 2015 May 12;6:7078. doi: 10.1038/ncomms8078.
Insulin signalling and nutrient levels coordinate the metabolic response to feeding in the liver. Insulin signals in hepatocytes to activate Akt, which inhibits Foxo1 suppressing hepatic glucose production (HGP) and allowing the transition to the postprandial state. Here we provide genetic evidence that insulin regulates HGP by both direct and indirect hepatic mechanisms. Liver-specific ablation of the IR (L-Insulin Receptor KO) induces glucose intolerance, insulin resistance and prevents the appropriate transcriptional response to feeding. Liver-specific deletion of Foxo1 (L-IRFoxo1DKO) rescues glucose tolerance and allows for normal suppression of HGP and gluconeogenic gene expression in response to insulin, despite lack of autonomous liver insulin signalling. These data indicate that in the absence of Foxo1, insulin signals via an intermediary extrahepatic tissue to regulate liver glucose production. Importantly, a hepatic mechanism distinct from the IR-Akt-Foxo1 axis exists to regulate glucose production.
胰岛素信号传导和营养水平协调肝脏对进食的代谢反应。胰岛素在肝细胞中发出信号以激活Akt，Akt抑制Foxo1，从而抑制肝葡萄糖生成（HGP），并使机体过渡到餐后状态。在此，我们提供遗传学证据表明，胰岛素通过直接和间接的肝脏机制调节HGP。肝脏特异性敲除胰岛素受体（L-胰岛素受体敲除）会导致葡萄糖不耐受、胰岛素抵抗，并阻止肝脏对进食做出适当的转录反应。肝脏特异性缺失Foxo1（L-IRFoxo1双敲除）可挽救葡萄糖耐量，并能在胰岛素作用下正常抑制HGP和糖异生基因表达，尽管肝脏缺乏自主胰岛素信号传导。这些数据表明，在缺乏Foxo1的情况下，胰岛素通过中间的肝外组织发出信号来调节肝脏葡萄糖生成。重要的是，存在一种不同于IR-Akt-Foxo1轴的肝脏机制来调节葡萄糖生成。
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