Glucose infusion causes insulin resistance in skeletal muscle of rats without changes in Akt and AS160 phosphorylation
Glucose infusion causes insulin resistance in skeletal muscle of rats without changes in Akt and AS160 phosphorylation
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DOI：
10.1152/ajpendo.00133.2007
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发表时间：
2007-11-01
影响因子：
5.1
通讯作者：
Kraegen, Edward W.
中科院分区：
文献类型：
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作者：
Hoy, Andrew J.;Bruce, Clinton R.;Kraegen, Edward W.
高血糖是 1 型和 2 型糖尿病的一个定义特征。高血糖也会导致胰岛素抵抗，我们的小组（Kraegen EW，Saha AK，Preston E，Wilks D，Hoy AJ，Cooney GJ，Ruderman NB.Am J Physiol Endocrinol Metab Endocrinol Metab 290：E471-E479，2006）最近证明，葡萄糖输注产生的高血糖会在5小时后而不是3小时后导致胰岛素抵抗。 h.本研究的目的是调查葡萄糖输注导致骨骼肌胰岛素抵抗的可能机制，特别是检查这是否与胰岛素信号的变化有关。在插管的雄性 Wistar 大鼠中产生高血糖（类似于 10 mM）长达 5 小时。维持高血糖所需的葡萄糖输注速率在 5 小时内逐渐减少（减少 25%，5 小时时 P < 0.0001），而血浆胰岛素水平没有任何与胰岛素抵抗的发展一致的变化。与输注3小时后相比，输注5小时后肌肉体内葡萄糖摄取量（44%；P < 0.05）和糖原合成率（52%；P < 0.001）降低。尽管有这些变化，多种胰岛素信号传导中间体 [胰岛素受体、Akt、AS160（160 kDa 的 Akt 底物）、糖原合酶激酶 3β] 的磷酸化状态在同一时间过程中没有降低。在取自对照或 1 小时或 5 小时葡萄糖输注动物的分离比目鱼肌条中，胰岛素刺激的 2-脱氧葡萄糖转运相似，但 5 小时肌肉样品中的糖原合成显着减少（68% 与 1 小时样品相比；P < 0.001）。这些结果表明，急性高血糖 5 小时后，大鼠肌肉葡萄糖摄取减少更多是由于过量糖原储存的代谢影响，而不是胰岛素信号或葡萄糖转运的缺陷。
Hyperglycemia is a defining feature of Type 1 and 2 diabetes. Hyperglycemia also causes insulin resistance, and our group (Kraegen EW, Saha AK, Preston E, Wilks D, Hoy AJ, Cooney GJ, Ruderman NB. Am J Physiol Endocrinol Metab Endocrinol Metab 290: E471-E479, 2006) has recently demonstrated that hyperglycemia generated by glucose infusion results in insulin resistance after 5 h but not after 3 h. The aim of this study was to investigate possible mechanism(s) by which glucose infusion causes insulin resistance in skeletal muscle and in particular to examine whether this was associated with changes in insulin signaling. Hyperglycemia (similar to 10 mM) was produced in cannulated male Wistar rats for up to 5 h. The glucose infusion rate required to maintain this hyperglycemia progressively lessened over 5 h (by 25%, P < 0.0001 at 5 h) without any alteration in plasma insulin levels consistent with the development of insulin resistance. Muscle glucose uptake in vivo (44%; P < 0.05) and glycogen synthesis rate (52%; P < 0.001) were reduced after 5 h compared with after 3 h of infusion. Despite these changes, there was no decrease in the phosphorylation state of multiple insulin signaling intermediates [insulin receptor, Akt, AS160 (Akt substrate of 160 kDa), glycogen synthase kinase-3 beta] over the same time course. In isolated soleus strips taken from control or 1-or 5-h glucose-infused animals, insulin-stimulated 2-deoxyglucose transport was similar, but glycogen synthesis was significantly reduced in the 5-h muscle sample (68% vs. 1-h sample; P < 0.001). These results suggest that the reduced muscle glucose uptake in rats after 5 h of acute hyperglycemia is due more to the metabolic effects of excess glycogen storage than to a defect in insulin signaling or glucose transport.