Insulin regulation of glucose metabolism independent of hepatic Akt

胰岛素对葡萄糖代谢的调节不依赖于肝脏 Akt

• 批准号: 8764642
• 负责人: Paul Michael Titchenell
• 金额: $ 5.15万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8764642
• 关键词: Adipose tissue; Behavior Therapy; Boxing; Brain; CREB1 gene; Cells; Cerebrum; Characteristics; Complex; Consensus; Data; Defect; Development; Diabetes Mellitus; Diet Modification; Disease; Distal; Epidemic; Family; Fasting; Gene Deletion; Gene Expression; Genetic; Gluconeogenesis; Glucose; Glycogen; Goals; Hepatic; Hepatocyte; Hormones; Hyperglycemia; Hypothalamic structure; Individual; Infusion procedures; Insulin; Insulin Receptor; Insulin Resistance; Knock-out; Knockout Mice; Knowledge; Lipids; Liver; Mediating; Metabolic; Metabolic Diseases; Metabolism; Modeling; Mus; Neuraxis; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Organ; Pancreas; Pathway interactions; Peripheral; Phenotype; Phosphorylation; Physiology; Process; Protein-Serine-Threonine Kinases; Proteins; Public Health; Regulation; Role; Signal Pathway; Signal Transduction; Site; Starvation; Stat3 protein; Testing; Tissues; Translations; United States; Vagotomy; Ventricular; Wild Type Mouse; Work; brain tissue; cell growth; diabetic; diabetic patient; energy balance; feeding; forkhead protein; glucose metabolism; glucose output; glucose production; in vivo; innovation; insulin signaling; lipid metabolism; loss of function; meetings; new therapeutic target; novel; novel therapeutics; programs; public health relevance; research study; response; restoration; treatment strategy

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.

描述（由申请人提供）：美国的糖尿病和肥胖症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和空腹高血糖，后者是由肝葡萄糖生成（HGP）增加引起的。重要的是，肝脏中的胰岛素作用异常会对全身生理产生重大影响，严重影响脂质和葡萄糖代谢。在过去的十年中，人们在了解胰岛素对 HGP 的调节以及在胰岛素抵抗状态下这一过程如何受到干扰方面取得了重大进展。人们已经达成共识，最重要的途径涉及 Akt 的胰岛素激活，Akt 会抑制 Foxo，从而抑制 Foxo1 的转录程序。令人惊讶的是，最近的实验表明，缺乏 Akt 和 Foxo1 的肝脏仍然可以抑制 HGP 对进食和胰岛素的反应，证实这些蛋白质不是胰岛素信号转导中的必然中间体。因此，必须存在替代的、未知的机制来介导肝脏中的胰岛素作用，并且这些可能代表治疗高血糖的新治疗靶点。此外，这些数据与越来越多的证据相一致，即胰岛素可能非自主地细胞作用，通过非肝组织发出信号来调节小鼠的肝脏葡萄糖和脂质代谢。该提案主要使用遗传功能丧失方法，旨在阐明胰岛素调节肝葡萄糖输出和糖异生基因表达的非典型途径。在此过程中，我将 1) 确定胰岛素是否作用于肝脏以外的器官，在没有肝胰岛素作用的情况下调节 HGP；2) 确定作用于肝细胞的 Akt 独立途径。如果在没有肝脏胰岛素信号传导的情况下，胰岛素仍然能够调节肝脏葡萄糖代谢，那么将识别出传递信号以抑制 HGP 的胰岛素反应组织——可能的候选组织包括大脑和脂肪组织。初步数据表明 Stat3 在 Akt 和 Foxo1 无效的肝脏中被激活。肝脏中 Stat3 的定向删除将检验以下假设：完整的 Stat3 信号传导需要独立于 Akt 和 Foxo1 来抑制肝脏 HGP。最终，这些研究确定的新机制将增进我们对正常代谢的了解，并使我们能够确定治疗糖尿病等代谢性疾病的新治疗策略。