Role of pyruvate dehydrogenase kinase 4 in regulation of blood glucose levels.
Role of pyruvate dehydrogenase kinase 4 in regulation of blood glucose levels.
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DOI：
10.4093/kdj.2010.34.5.274
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发表时间：
2010-10
期刊：
影响因子：
--
通讯作者：
Harris RA
中科院分区：
文献类型：
--
作者：
Jeoung NH;Harris RA
在营养充足的状态下，丙酮酸脱氢酶复合体(PDC)相对较高的活性通过将丙酮酸的碳导入柠檬酸循环来降低血糖水平。在禁食状态下，PDC的活性相对较低，通过保存丙酮酸和其他三种碳化合物用于糖异生，有助于维持血糖水平。在摄食和禁食状态下，丙酮酸脱氢酶激酶(PDKs)和相对的丙酮酸脱氢酶磷酸酶的相对活性决定了PDC的活性。在禁食状态下，PDK4的上调是PDC失活的主要原因。与野生型小鼠相比，PDK4基因敲除小鼠的空腹血糖水平较低，这证明PDK4上调对正常血糖稳态非常重要。在2型糖尿病中，PDK4的上调也会使PDC失活，后者促进糖异生，从而导致这种疾病的高血糖特征。当饲喂高脂饮食时，野生型小鼠出现空腹高血糖，但PDK4基因敲除小鼠保持正常血糖，证明PDK4上调有助于糖尿病的高血糖。这些发现表明，PDK4抑制剂可能被证明在治疗2型糖尿病方面有用。
In the well-fed state a relatively high activity of the pyruvate dehydrogenase complex (PDC) reduces blood glucose levels by directing the carbon of pyruvate into the citric acid cycle. In the fasted state a relatively low activity of the PDC helps maintain blood glucose levels by conserving pyruvate and other three carbon compounds for gluconeogenesis. The relative activities of the pyruvate dehydrogenase kinases (PDKs) and the opposing pyruvate dehydrogenase phosphatases determine the activity of PDC in the fed and fasted states. Up regulation of PDK4 is largely responsible for inactivation of PDC in the fasted state. PDK4 knockout mice have lower fasting blood glucose levels than wild type mice, proving that up regulation of PDK4 is important for normal glucose homeostasis. In type 2 diabetes, up regulation of PDK4 also inactivates PDC, which promotes gluconeogenesis and thereby contributes to the hyperglycemia characteristic of this disease. When fed a high fat diet, wild type mice develop fasting hyperglycemia but PDK4 knockout mice remain euglycemic, proving that up regulation of PDK4 contributes to hyperglycemia in diabetes. These finding suggest PDK4 inhibitors might prove useful in the treatment of type 2 diabetes.