Increased malonyl-CoA and diacylglycerol content and reduced AMPK activity accompany insulin resistance induced by glucose infusion in muscle and liver of rats
Increased malonyl-CoA and diacylglycerol content and reduced AMPK activity accompany insulin resistance induced by glucose infusion in muscle and liver of rats
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DOI：
10.1152/ajpendo.00316.2005
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发表时间：
2006-03-01
影响因子：
5.1
通讯作者：
Ruderman, NB
中科院分区：
文献类型：
--
作者：
Kraegen, EW;Saha, AK;Ruderman, NB
大鼠输注葡萄糖1-4天导致胰岛素抵抗和红色骨骼肌中甘油三酯、全组织长链脂肪酰辅酶A（LCA-CoA）和丙二酰辅酶A含量增加。尽管如此，这些改变与胰岛素抵抗发作之间的关系尚未确定。我们的目的是：1）确定这些脂质和甘油二酯（DAG）的变化是否先于或伴随葡萄糖输注大鼠胰岛素抵抗的发生，2）确定胰岛素抵抗是否与AMP活化蛋白激酶（AMPK）的改变有关，3）评估肝脏和肌肉中是否发生类似的变化。高胰岛素血症（17-18 mM）通过静脉输注葡萄糖维持大鼠3或5小时，然后恢复正常，并进行2小时高胰岛素钳夹。显著（P < 0.01）的肌肉和肝脏胰岛素抵抗首先出现在葡萄糖输注组的红色四头肌和肝脏中，并且与DAG和丙二酰辅酶A含量的两倍增加以及AMPK和乙酰辅酶A羧化酶（ACC）磷酸化和AMPK活性的50%降低相关。白色股四头肌表现出定性相似的变化，但AMPK或ACC磷酸化没有降低。甘油三酯质量增加，在5小时，只有在肝脏，和整个组织LCA-CoA含量没有增加，在肝脏或肌肉类型。我们得出结论，葡萄糖供过于求诱导的胰岛素抵抗的发病时间与丙二酰辅酶A和DAG含量在所有三个组织中的增加，并减少AMPK磷酸化和活性在红色肌肉和肝脏。相比之下，它与任何组织中的全组织LCA-CoA含量或肌肉中的甘油三酯增加无关，尽管两者都在以后观察到。
Glucose infusion in rats for 1-4 days results in insulin resistance and increased triglyceride, whole tissue long-chain fatty acyl-CoA (LCA-CoA), and malonyl-CoA content in red skeletal muscle. Despite this, the relation between these alterations and the onset of insulin resistance has not been defined. We aimed to 1) identify whether the changes in these lipids and of diacylglycerol (DAG) precede or accompany the onset of insulin resistance in glucose-infused rats, 2) determine whether the insulin resistance is associated with alterations in AMP-activated protein kinase ( AMPK), and 3) assess whether similar changes occur in liver and in muscle. Hyperglycemia (17-18 mM) was maintained by intravenous glucose infusion in rats for 3 or 5 h; then euglycemia was restored and a 2-h hyperinsulinemic clamp was performed. Significant (P < 0.01) muscle and liver insulin resistance first appeared in red quadriceps and liver of the glucose-infused group at 5 h and was associated with a twofold increase in DAG and malonyl-CoA content and a 50% decrease in AMPK and acetyl-CoA carboxylase (ACC) phosphorylation and AMPK activity. White quadriceps showed qualitatively similar changes but without decreases in AMPK or ACC phosphorylation. Triglyceride mass was increased at 5 h only in liver, and whole tissue LCA-CoA content was not increased in liver or either muscle type. We conclude that the onset of insulin resistance induced by glucose oversupply correlates temporally with increases in malonyl-CoA and DAG content in all three tissues and with reduced AMPK phosphorylation and activity in red muscle and liver. In contrast, it was not associated with increased whole tissue LCA-CoA content in any tissue or triglyceride in muscle, although both are observed at later times.