Insulin regulation of glucose metabolism independent of hepatic Akt

描述（由申请人提供）：糖尿病和肥胖症在美国的流行仍然是突出的公共卫生问题。糖尿病的两个定义特征是餐后高血糖和空腹高血糖，后者是由肝脏葡萄糖生成增加（HGP）引起的。重要的是，肝脏中的异常胰岛素作用对全身生理学具有重大影响，严重影响脂质和葡萄糖代谢。在过去的十年中，在了解胰岛素对HGP的调节以及胰岛素抵抗状态下这一过程如何被破坏方面取得了重大进展。一个共识是，最重要的途径涉及胰岛素激活Akt，Akt抑制Foxo，抑制Foxo 1的转录程序。令人惊讶的是，最近的实验表明，缺乏Akt和Foxo 1的肝脏仍然可以抑制HGP对进食和胰岛素的反应，这表明这些蛋白质不是胰岛素信号传导中的强制性中间体。因此，必须存在替代的、未知的机制介导肝脏中的胰岛素作用，并且这些机制可能代表用于治疗高血糖症的新的治疗靶点。此外，这些数据与越来越多的证据一致，即胰岛素可能在细胞内非自主地发挥作用，通过非肝脏组织发出信号来调节小鼠肝脏葡萄糖和脂质代谢。主要使用遗传功能丧失的方法，该建议旨在阐明胰岛素调节肝葡萄糖输出和致肝细胞癌基因表达的非经典途径。这样做，我将1）确定胰岛素是否作用于肝脏以外的器官，以在缺乏肝脏胰岛素作用的情况下调节HGP，2）确定作用于肝细胞的Akt非依赖性途径。如果在肝脏胰岛素信号传导缺失的情况下胰岛素仍然能够调节肝脏葡萄糖代谢，则将鉴定出传递信号以抑制HGP的胰岛素响应组织-可能的候选者包括脑和脂肪组织。初步数据表明，Stat 3在Akt和Foxo 1无效的肝脏中被激活。肝脏中Stat 3的靶向缺失将检验以下假设：不依赖于Akt和Foxo 1，抑制肝脏HGP需要完整的Stat 3信号传导。最终，这些研究确定的新机制将促进我们对正常代谢的了解，并使我们能够确定治疗代谢紊乱（如糖尿病）的新治疗策略。

DESCRIPTION (provided by applicant): The diabetes and obesity epidemics in the United States remain prominent public health issues. The two defining characteristics of diabete are postprandial and fasting hyperglycemia, the latter resulting from increased hepatic glucose production (HGP). Importantly, abnormal insulin action in the liver has major consequences for whole body physiology, seriously impacting lipid and glucose metabolism. In the last decade, significant progress has been made towards understanding the regulation of HGP by insulin and how this process is disrupted during insulin-resistant states. A consensus has emerged that the most important pathway involves insulin activation of Akt, which inhibits Foxo, suppressing Foxo1's transcriptional program. Surprisingly, recent experiments have shown that livers devoid of Akt and Foxo1 can still suppress HGP in response to both feeding and insulin, establishing that these proteins are not obligate intermediates in insulin signaling. Consequently, there must exist alternative, unknown mechanisms that mediate insulin action in the liver, and these may represent new therapeutic targets for the treatment of hyperglycemia. Moreover, these data are consistent with the increasing body of evidence that insulin may act cell-nonautonomously, signaling through non-hepatic tissues to regulate liver glucose and lipid metabolism in mice. Using primarily genetic loss- of-function approaches, this proposal aims to elucidate the non-canonical pathway by which insulin regulates hepatic glucose output and gluconeogenic gene expression. In doing so, I will 1) determine whether insulin is acting on an organ other than liver to regulat HGP in the absence of hepatic insulin action and 2) determine the Akt-independent pathway acting in hepatocytes. If insulin is still capable of regulating hepatic glucose metabolsm in the absence of hepatic insulin signaling, the insulin responsive tissue that is relaying the signal to suppress HGP will be identified~ likely candidates include brain and adipose tissue. Preliminary data suggest that Stat3 is activated in livers null for Akt and Foxo1. Targeed deletion of Stat3 in the liver will test the hypothesis that intact Stat3 signaling i required to suppress liver HGP independent of Akt and Foxo1. Ultimately, the new mechanisms identified by these studies will advance our knowledge of normal metabolism and will allow us to identify new therapeutic strategies for treatment of metabolic disorders such as diabetes.