Long term glucagon receptor (GCGR) agonism is associated with hyperglycemia and glucose intolerance, while acute GCGR agonism enhances whole-body insulin sensitivity and hepatic AKTSer473 phosphorylation. These divergent effects establish a critical gap in knowledge surrounding GCGR action. mTOR Complex 2 (mTORC2) is composed of seven proteins, including RICTOR, which dictates substrate binding and allows for targeting of AKTSer473. We utilized a liver specific Rictor knockout mouse (RictorΔLiver) to investigate whether mTORC2 is necessary for insulin-receptor (INSR) and GCGR crosstalk. RictorΔLiver mice were characterized by impaired Akt signaling and glucose intolerance. Intriguingly, RictorΔLiver mice were also resistant to GCGR-stimulated hyperglycemia. Consistent with our prior report, GCGR agonism increased glucose infusion rate and suppressed hepatic glucose production during hyperinsulinemic-euglycemic clamp of control animals. However, these benefits to insulin sensitivity were ablated in RictorΔLiver mice. We observed diminished AKTSer473 and GSK3α/βSer21/9 phosphorylation in RictorΔLiver mice, whereas phosphorylation of AKTThr308 was unaltered in livers from clamped mice. These signaling effects were replicated in primary hepatocytes isolated from RictorΔLiver and littermate control mice, confirming cell autonomous crosstalk between GCGR and INSR pathways. In summary, our study reveals the necessity of RICTOR, and thus mTORC2, in GCGR-mediated enhancement of liver and whole-body insulin action.

中文翻译：

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肝脏 TORC2 信号传导促进小鼠胰高血糖素受体急性增强胰岛素刺激的血糖稳态

长期胰高血糖素受体 (GCGR) 激动与高血糖和葡萄糖不耐受有关，而急性 GCGR 激动可增强全身胰岛素敏感性和肝脏 AKTSer473 磷酸化。这些不同的影响在围绕 GCGR 行动的知识方面造成了重大差距。mTOR 复合物 2 (mTORC2) 由七种蛋白质组成，其中包括 RICTOR，它决定底物结合并允许靶向 AKTSer473。我们利用肝脏特异性 Rictor 基因敲除小鼠 (RictorΔLiver) 来研究 mTORC2 是否是胰岛素受体 (INSR) 和 GCGR 串扰所必需的。RictorΔLiver 小鼠的特点是 Akt 信号传导受损和葡萄糖不耐受。有趣的是，RictorΔLiver 小鼠也能抵抗 GCGR 刺激的高血糖。与我们之前的报告一致，在对照动物的高胰岛素-正常血糖钳夹过程中，GCGR 激动剂增加了葡萄糖输注速率并抑制了肝葡萄糖的产生。然而，这些对胰岛素敏感性的益处在 RictorΔLiver 小鼠中被消除了。我们观察到 RictorΔLiver 小鼠中 AKTSer473 和 GSK3α/βSer21/9 磷酸化减少，而 AKTThr308 磷酸化在被夹紧的小鼠肝脏中没有改变。这些信号传导效应在从 RictorΔLiver 和同窝对照小鼠分离的原代肝细胞中得到复制，证实了 GCGR 和 INSR 通路之间的细胞自主串扰。总之，我们的研究揭示了 RICTOR 以及 mTORC2 在 GCGR 介导的肝脏和全身胰岛素作用增强中的必要性。