Role of Pyruvate Dehydrogenase Kinases in Glucose Homeostasis

描述(由申请人提供)： 高血糖是糖尿病的特征之一。了解血糖升高的分子机制对于预防和治疗这种迅速上升的疾病至关重要。这位研究人员目前正在使用小鼠遗传学方法来阐明控制肝脏葡萄糖稳态的调节机制。胰岛素受体底物(IRS)1和2介导了肝脏中胰岛素的大部分作用。在肝细胞(LDKO)中同时缺乏IRS1和IRS2的小鼠会发生严重的糖尿病，并伴有高血糖和胰岛素抵抗。有趣的是，众所周知的糖异生基因，包括磷酸烯醇式丙酮酸羧激酶(PEPCK)和葡萄糖-6磷酸酶(G6Pase)，在LDKO肝脏中的表达没有改变。相反，在这些小鼠的肝脏中，丙酮酸脱氢酶激酶4(PDK4)的表达显著增加。PDK4很重要，因为它调节糖异生的关键底物(丙酮酸)的供应。底物有效性是糖异生最重要的驱动力。为了指导阶段的短期目标，本研究人员将研究腺病毒介导的siRNA抑制肝脏PDK4表达是否可以减弱糖尿病动物模型的糖异生和改善高血糖。同时，还将对PDK4诱导高血糖的机制进行研究。对于独立阶段及以后的长期目标，将从机制上研究PDK4是如何受激素和营养信号调节的。具体地说，营养物质，如丙酮酸，糖异生的主要底物，将被研究其在PDK4基因调控中的潜在作用。SIRT1是一种候选的代谢感受器，它在营养调节的PDK4表达中的功能将被探索。此外，糖尿病中PDK4失调的机制将通过动物模型，特别是Foxo1(A Forkhead转录因子)介导的调节来阐明。了解PDK4如何促进肝脏营养动态平衡，可以为代谢综合征和2型糖尿病的治疗提供新的靶点。拟议项目的总体目标将通过以下三个具体目标实现： 1.PDK4在IRS1和IRS2双重肝脏特异性基因敲除小鼠糖异生中的作用 2.PDK4表达调控中的营养感知。 3.Foxo1在调节PDK4和肝糖稳态中的作用。

DESCRIPTION (provided by applicant): Hyperglycemia is one of the hallmarks of diabetes. Understanding the molecular mechanisms responsible for the elevated blood glucose is crucial for the prevention and cure of this rapidly rising disease. This investigator is currently using mouse genetic approaches to elucidate regulatory mechanisms controlling hepatic glucose homeostasis. Insulin receptor substrate (IRS) 1 and 2 mediate most of the insulin action in the liver. Mice that are deficient of both IRS1 and IRS2 in the hepatocytes (LDKO) develop severe diabetes with hyperglycemia and insulin resistance. Intriguingly, expression of well known gluconeogenic genes including phosphoenolpyruvate carboxykinase (Pepck) and glucose-6 phosphatase (G6Pase) is not altered in the LDKO liver. In contrast, expression of pyruvate dehydrogenase kinase 4 (PDK4) is dramatically increased in the liver of these mice. PDK4 is important because it regulates the critical substrate (pyruvate) supply for gluconeogenesis. Substrate availability is the most important driving force for gluconeogenesis. For the short-term goal in the mentored phase, this investigator will investigate whether suppression of hepatic PDK4 expression by adenovirus-mediated siRNA can attenuate the gluconeogenesis and improve hyperglycemia in diabetic animal models. Meanwhile, mechanisms responsible for the PDK4 induced hyperglycemia will also be investigated. For the long-term goal in the independent phase and beyond, how PDK4 is regulated by hormonal and nutritional signals will be mechanistically studied. Specifically, nutrients such as pyruvate, the primary substrate for gluconeogenesis, will be investigated for its potential role in the regulation of PDK4 gene. SIRT1, a candidate for metabolic sensor, will be explored for its function in the nutrient-regulated PDK4 expression. Furthermore, the mechanisms responsible for the PDK4 dysregulation in diabetes will be elucidated using animal models, particularly Foxo1 (A Forkhead transcription factor) mediated regulation. Understanding how PDK4 contributes to hepatic nutrient homeostasis can reveal novel target for the treatment of metabolic syndrome and type 2 diabetes. The overall goal of the proposed project will be accomplished in the following three specific aims: 1. Role of PDK4 in gluconeogenesis in the IRS1 and IRS2 dual liver-specific knockout mice. 2. Nutrient sensing in the regulation of PDK4 expression. 3. Role of Foxo1 in the regulation of PDK4 and hepatic glucose homeostasis.