AMPK activation restores the stimulation of glucose uptake in an in vitro model of insulin-resistant cardiomyocytes via the activation of protein kinase B
AMPK activation restores the stimulation of glucose uptake in an in vitro model of insulin-resistant cardiomyocytes via the activation of protein kinase B
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DOI：
10.1152/ajpheart.01269.2005
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发表时间：
2006-07-01
影响因子：
4.8
通讯作者：
Vanoverschelde, JL
中科院分区：
文献类型：
--
作者：
Bertrand, L;Ginion, A;Vanoverschelde, JL
已知糖尿病心脏更易患缺血性疾病。双胍类药物，如二甲双胍，是已知的抗糖尿病药物，通过减少肝脏葡萄糖的产生和增加肌肉中葡萄糖的处置来降低血糖浓度。这些代谢效应的一部分被认为是由AMP活化蛋白激酶（AMPK）的活化介导的。在这项工作中，我们研究了AMPK激活和葡萄糖摄取刺激的双胍和寡霉素，另一种AMPK激活剂，在胰岛素敏感和胰岛素抵抗的心肌细胞之间的关系。在胰岛素敏感的心肌细胞中，胰岛素、双胍和寡霉素能够以相同的效率刺激葡萄糖摄取。胰岛素或双胍类药物对葡萄糖摄取的刺激分别与蛋白激酶B（PKB）或AMPK活化相关，并且是相加的。在胰岛素抵抗的心肌细胞，胰岛素刺激葡萄糖摄取大大减少，双胍或寡霉素，在胰岛素的情况下，诱导更高的刺激葡萄糖摄取比在胰岛素敏感的细胞。这种刺激与AMPK和PKB的激活相关，并且对磷脂酰肌醇-3-激酶/PKB通路抑制剂敏感。最后，腺病毒介导的AMPK组成型活性形式的表达增加了胰岛素抵抗心肌细胞中PKB磷酸化和葡萄糖摄取。我们的结论是，AMPK激活剂，如双胍类和寡霉素，能够恢复葡萄糖摄取刺激，在胰岛素抵抗的心肌细胞中，在胰岛素的情况下，通过添加剂激活AMPK和PKB。我们的研究结果表明，AMPK激活可以恢复正常的葡萄糖代谢在糖尿病心脏和可能是一个潜在的治疗方法来治疗胰岛素抵抗。
Diabetic hearts are known to be more susceptible to ischemic disease. Biguanides, like metformin, are known antidiabetic drugs that lower blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in muscle. Part of these metabolic effects is thought to be mediated by the activation of AMP-activated protein kinase (AMPK). In this work, we studied the relationship between AMPK activation and glucose uptake stimulation by biguanides and oligomycin, another AMPK activator, in both insulin-sensitive and insulin-resistant cardiomyocytes. In insulin-sensitive cardiomyocytes, insulin, biguanides and oligomycin were able to stimulate glucose uptake with the same efficiency. Stimulation of glucose uptake by insulin or biguanides was correlated to protein kinase B (PKB) or AMPK activation, respectively, and were additive. In insulin-resistant cardiomyocytes, where insulin stimulation of glucose uptake was greatly reduced, biguanides or oligomycin, in the absence of insulin, induced a higher stimulation of glucose uptake than that obtained in insulin-sensitive cells. This stimulation was correlated with the activation of both AMPK and PKB and was sensitive to the phosphatidylinositol-3-kinase/PKB pathway inhibitors. Finally, an adenoviral-mediated expression of a constitutively active form of AMPK increased both PKB phosphorylation and glucose uptake in insulin-resistant cardiomyocytes. We concluded that AMPK activators, like biguanides and oligomycin, are able to restore glucose uptake stimulation, in the absence of insulin, in insulin-resistant cardiomyocytes via the additive activation of AMPK and PKB. Our results suggest that AMPK activation could restore normal glucose metabolism in diabetic hearts and could be a potential therapeutic approach to treat insulin resistance.