Jeoung Nam Ho, Harris Robert A
Department of Fundamental Medical and Pharmaceutical Sciences, Catholic University of Daegu, Gyeongsan, Korea.
Korean Diabetes J. 2010 Oct;34(5):274-83. doi: 10.4093/kdj.2010.34.5.274. Epub 2010 Oct 31.
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.
在营养充足状态下，丙酮酸脱氢酶复合体（PDC）的活性相对较高，它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，通过保留丙酮酸和其他三碳化合物用于糖异生，有助于维持血糖水平。丙酮酸脱氢酶激酶（PDK）和起相反作用的丙酮酸脱氢酶磷酸酶的相对活性决定了进食和禁食状态下PDC的活性。PDK4的上调在很大程度上导致了禁食状态下PDC的失活。PDK4基因敲除小鼠的空腹血糖水平低于野生型小鼠，这证明PDK4的上调对正常血糖稳态很重要。在2型糖尿病中，PDK4的上调也会使PDC失活，从而促进糖异生，进而导致该疾病的高血糖特征。当喂食高脂肪饮食时，野生型小鼠会出现空腹高血糖，但PDK4基因敲除小鼠仍保持血糖正常，这证明PDK4的上调会导致糖尿病中的高血糖。这些发现表明，PDK4抑制剂可能对2型糖尿病的治疗有用。
