AMPK和运动骨骼肌摄取葡萄糖和胰岛素敏感性.docx

1、AMPK和运动骨骼肌摄取葡萄糖和胰岛素敏感性AMPK和运动：骨骼肌摄取葡萄糖和胰岛素敏感性AMPK是一个进化保守的细胞能量感受器，在运动过程中被激活。激活的AMPK可以增加骨骼肌葡萄糖摄取、脂肪酸氧化、线粒体生物合成和胰岛素敏感性，这些过程在肥胖患者体内减弱，从而易引发胰岛素抵抗。运动促进葡萄糖摄取的机制涉及AMPK，但不明确AMPK是否参与运动提高胰岛素敏感性的过程。了解这些代谢过程将为治疗肥胖和胰岛素抵抗提供新的契机，故本综述将讨论AMPK如何参与调节骨骼肌代谢（葡萄糖的摄取和胰岛素敏感性）。AMPK和运动运动时，为了给肌肉收缩提供足够的能量，骨骼肌中ATP代谢速度增加（100倍）1。在这

2、种情况下，AMP和ADP浓度迅速增加，而ATP水平只略有下降。AMPK是细胞能量感受器，能被AMP和ADP激活，与此相一致，啮类动物和人类的骨骼肌中AMPK在运动过程中被激活2-5。运动通过AMPK介导的胰岛素非依赖性机制调节葡萄糖摄取6。重要的是，在2型糖尿病患者的骨骼肌中，运动调节GLUT4转运的通路没有受损7，并且，运动可以提高胰岛素的敏感性。由于这些原因，运动通常被建议用于预防和治疗胰岛素抵抗。因此，理解运动调节葡萄糖的摄取潜在机制是一个重要的研究领域。骨骼肌摄取葡萄糖的调节胰岛素促进骨骼肌摄取葡萄糖 胰岛素生物学效应通过信号转导而实现，随着分子生物学的发展，人们对胰岛素信号转导途径中

3、的的系列级联反应逐步明确。简言之，胰岛素通过IRIRSPI3KAkt/PKC/AS160信号通路调节GLUT4转运到细胞膜上，从而促进葡萄糖的摄取。运动促进骨骼肌摄取葡萄糖 同胰岛素，运动也是通过调节GLUT4转运到质膜和横小管，增加骨骼肌葡萄糖摄取。但是，在骨骼肌中，胰岛素和运动/收缩通过不同的机制调节对葡萄糖的摄取。此观点来自于以下发现：1）PI3激酶抑制剂渥曼霉素（Wortmannin）抑制胰岛素刺激的葡萄糖摄取，但不抑制收缩刺激的葡萄糖摄取。收缩不促进IRS-1自身磷酸化或增加PI3激酶的活性8-11。2）基因敲除主要的胰岛素信号蛋白IRS1和AKT2，不影响收缩介导的葡萄糖摄取42-

4、43。3）胰岛素与收缩刺激葡萄糖的摄取有叠加作用14-15。4）胰岛素抵抗患者和啮齿动物，收缩介导的葡萄糖摄取不受影响16-19。相反，也有研究发现离体骨骼肌收缩使Akt磷酸化水平上升，并且Goodyear等人报道，PI3激酶抑制剂Wortmannin和LY294002可抑制收缩引起的Akt活性增加。究竟运动/骨骼肌收缩是否激活PI3K-Akt还有待进一步的研究证实。慢性运动训练虽然有研究表明肥胖者体内的AMPK活性和蛋白表达降低，但慢性运动训练仍能增强AMPK的蛋白表达和活性30。因此，AMPK可能通过TBC1D1 和TBC1D4 的磷酸化，增强胰岛素的敏感性。基于人类和大鼠的研究都表明，慢

5、性运动训练增加了TBC1D4 的蛋白表达和PAS磷酸化，这一结果支持了上述观点。正常情况下，肥胖2型糖尿病患者骨骼肌中TBC1D4的磷酸化被削弱，但10周的耐力训练可以使TBC1D4的磷酸化恢复到非糖尿病患者的水平31。目前尚不知TBC1D1是否有类似的发现。有趣的是，旨在为肥胖者减重的两周的饮食干预改善了胰岛素敏感性，却没有影响TBC1D1的磷酸化。而相反研究报道，饮食干预的确增加了TBC1D1 Ser231和Ser660，却没有像锻炼那样增加Ser700或PAS的磷酸化32。肥胖的2型糖尿病患者的耐力训练和健康男性的耐力训练都导致了AMPK 3表达减少33。而敲除3亚基则会损害锻炼后的糖元

6、合成。一种可能的解释是，3表达的减少是一种对运动的应激反应，提高了机体氧化能力和脂肪氧化，而增加糖原利用率。近期有研究认为，考虑到3的表达减弱，AMPK 活性水平的增加可能是由于与1有关的复合物的形成。结论总之，AMPK在运动调节葡萄糖摄取过程中起重要作用，并可能参与急性和慢性两种运动的胰岛素增敏作用。许多研究已经提出了一些介导运动的胰岛素增敏作用的可能机制，但明确定义AMPK在其中的作用需要进一步的研究。运动为健康提供无限益处，是预防和治疗肥胖诱导的胰岛素抵抗最经济有效的方法之一。因此，未来关于运动的胰岛素增敏作用机制的研究至关重要，它可以为相关疾病的药物和非药物（如运动）治疗的发展提供新的

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