Genetic inactivation of pyruvate dehydrogenase kinases improves hepatic insulin resistance induced diabetes.
Genetic inactivation of pyruvate dehydrogenase kinases improves hepatic insulin resistance induced diabetes.
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DOI：
10.1371/journal.pone.0071997
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Dong XC
中科院分区：
文献类型：
--
作者：
Tao R;Xiong X;Harris RA;White MF;Dong XC
丙酮酸脱氢酶激酶（PDK 1 -4）在抑制线粒体丙酮酸脱氢酶复合物中起关键作用，特别是当血糖水平低并且丙酮酸可以被保存用于线粒体异生时。在糖尿病条件下，Pdk基因，特别是Pdk 4，经常被诱导，并且Pdk 4基因表达的升高与肝脏中的增生增加和外周组织中的葡萄糖利用减少有关。然而，目前还没有直接的证据表明肝脏Pdk基因的失调在多大程度上导致体内高血糖和胰岛素抵抗。为了解决这个问题，我们将Pdk 2或Pdk 4缺失小鼠与肝脏胰岛素受体底物1和2（Irs 1/2）缺陷的糖尿病模型进行杂交。代谢分析显示，Pdk 4基因的缺失比Pdk 2基因的敲除在高血糖和葡萄糖耐量方面具有更好的改善，而Pdk 2基因的缺失在Irs 1/2敲除遗传背景下显示出比Pdk 4基因失活更好的胰岛素耐受性。为了研究Pdks对糖尿病的特异性肝脏作用，我们还使用特异性shRNA敲低了Pdk 2或Pdk 4基因。数据还表明，Pdk 4基因敲低导致比Pdk 2基因敲低更好的葡萄糖耐量。总之，我们的数据表明，肝脏Pdk 4可能是关键参与糖尿病的发病机制。
Pyruvate dehydrogenase kinases (PDK1-4) play a critical role in the inhibition of the mitochondrial pyruvate dehydrogenase complex especially when blood glucose levels are low and pyruvate can be conserved for gluconeogenesis. Under diabetic conditions, the Pdk genes, particularly Pdk4, are often induced, and the elevation of the Pdk4 gene expression has been implicated in the increased gluconeogenesis in the liver and the decreased glucose utilization in the peripheral tissues. However, there is no direct evidence yet to show to what extent that the dysregulation of hepatic Pdk genes attributes to hyperglycemia and insulin resistance in vivo. To address this question, we crossed Pdk2 or Pdk4 null mice with a diabetic model that is deficient in hepatic insulin receptor substrates 1 and 2 (Irs1/2). Metabolic analyses reveal that deletion of the Pdk4 gene had better improvement in hyperglycemia and glucose tolerance than knockout of the Pdk2 gene whereas the Pdk2 gene deletion showed better insulin tolerance as compared to the Pdk4 gene inactivation on the Irs1/2 knockout genetic background. To examine the specific hepatic effects of Pdks on diabetes, we also knocked down the Pdk2 or Pdk4 gene using specific shRNAs. The data also indicate that the Pdk4 gene knockdown led to better glucose tolerance than the Pdk2 gene knockdown. In conclusion, our data suggest that hepatic Pdk4 may be critically involved in the pathogenesis of diabetes.
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影响因子：
29
作者：
Dong XC;Copps KD;Guo S;Li Y;Kollipara R;DePinho RA;White MF
通讯作者：
White MF
二甲双胍通过诱导孤儿核受体小型异二聚体伴侣抑制生长激素介导的肝PDK4基因表达。
影响因子：
7.7
作者：
Kim YD;Kim YH;Tadi S;Yu JH;Yim YH;Jeoung NH;Shong M;Hennighausen L;Harris RA;Lee IK;Lee CH;Choi HS
通讯作者：
Choi HS
影响因子：
4.8
作者：
Rowles, J;Scherer, SW;Prochazka, M
通讯作者：
Prochazka, M
DOI：
10.1016/0167-4889(92)90137-z
发表时间：
1992-06-10
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
STACE, PB;FATANIA, HR;RANDLE, PJ
通讯作者：
RANDLE, PJ
影响因子：
2.9
作者：
Bao, HY;Kasten, SA;Roche, TE
通讯作者：
Roche, TE