Role of Pyruvate Dehydrogenase Kinases in Glucose Homeostasis

肝糖异生是糖尿病高血糖发生的关键因素之一。这个 通过肝脏需要代谢底物SAERRAS~PATRATE来维持葡萄糖的“PFO‘Dductior”T， 乳酸和丙氨酸。其中，丙酮酸是肝糖异生最直接的底物。 由于底物的可获得性是糖异生最重要的驱动力之一，丙酮酸代谢的调节可能是葡萄糖氧化或糖异生的关键开关。丙酮酸脱氢酶激酶(PDK)通常通过磷酸化和丙酮酸脱氢酶复合体失活来抑制丙酮酸氧化。其中一种PDK4在饥饿或糖尿病条件下在肝脏中升高，这表明PDK4的调节可能是糖异生的一个重要组成部分，因为它影响底物的可获得性。为了阐明正常和糖尿病条件下糖稳态和PDK4基因调控的机制，提出了以下具体目标。目的1、通过动物模型研究PDKs在糖异生中的作用。目的2，通过体外和体内方法研究营养信号对PDK4基因表达的调节。目的3，用小鼠遗传学方法研究Foxol在调节PDK4和肝脏葡萄糖动态平衡中的作用。

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.