Role of Pyruvate Dehydrogenase Kinases in Glucose Homeostasis

肝纤维化是糖尿病高血糖发生的重要因素之一。的 肝脏对葡萄糖的持续“pfo'ductionT“需要代谢底物的清除， 乳酸盐和丙氨酸。其中，丙酮酸是肝纤维化最直接的底物。 由于底物的可利用性是葡萄糖异生中最重要的驱动力之一，因此丙酮酸代谢的调节可能是葡萄糖氧化或葡萄糖异生的关键开关。丙酮酸脱氢酶激酶（PDK）通常通过丙酮酸脱氢酶复合物的磷酸化和失活来抑制丙酮酸氧化。PDK激酶之一PDK4在饥饿或糖尿病条件下在肝脏中升高，表明PDK4的调节可能是胚胎发生的重要组成部分，因为其对底物可用性的影响。为了阐明正常和糖尿病条件下葡萄糖稳态和PDK4基因调控的机制，提出了以下具体目标。目的：1、应用动物模型研究PDKs在糖尿病发生发展中的作用。目的2、通过体外和体内实验研究营养信号对PDK 4基因表达的调控。目的3、利用小鼠遗传学方法研究Foxol对PDK4和血糖稳态的调节作用。

Hepatic gluconeogenesis is one of the critical factors in the development of hyperglycemia in diabetes. The sustained"pfo'ductiorTof"glucose by the liverrequireTtuffiaenrmetabollc substrates saerras~pyravate, lactate, and alanine. Among them, pyruvate is the most direct substrate used for hepatic gluconeogenesis. Since substrate availability is one of the most important driving forces in gluconeogenesis, regulation of pyruvate metabolism may be a critical switch for glucose oxidation or gluconeogenesis. Pyruvate dehydrogenase kinases (PDK) normally inhibits pyruvate oxidation through phosphorylation and inactivation of the pyruvate dehydrogenase complex. One of the PDK kinases, PDK4, is elevated in the liver under starvation or diabetic conditions, suggesting that regulation of PDK4 may be an essential component of gluconeogenesis because of its effects on substrate availability. To elucidate the mechanisms of glucose homeostasis and PDK4 gene regulation under normal and diabetic conditions, the following specific aims are proposed. Aim 1, The role of PDKs in gluconeogenesis in the development of diabetes will be examined using animal models. Aim 2, Regulation of PDK4 gene expression by nutrient signals will be investigated by both in vitro and in vivo approaches. Aim 3, Role of Foxol in the regulation of PDK4 and hepatic glucose homeostasis will be investigated using mouse genetic approaches.