Department of Sport Medicine, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning Province, China.
PLoS One. 2012;7(12):e51709. doi: 10.1371/journal.pone.0051709. Epub 2012 Dec 13.
Exercise can increase skeletal muscle sensitivity to insulin, improve insulin resistance and regulate glucose homeostasis in rat models of type 2 diabetes. However, the potential mechanism remains poorly understood. In this study, we established a male Sprague-Dawley rat model of type 2 diabetes, with insulin resistance and β cell dysfunction, which was induced by a high-fat diet and low-dose streptozotocin to replicate the pathogenesis and metabolic characteristics of type 2 diabetes in humans. We also investigated the possible mechanism by which chronic and acute exercise improves metabolism, and the phosphorylation and expression of components of AMP-activated protein kinase (AMPK) and downstream components of phosphatidylinositol 3-kinase (PI3K) signaling pathways in the soleus. As a result, blood glucose, triglyceride, total cholesterol, and free fatty acid were significantly increased, whereas insulin level progressively declined in diabetic rats. Interestingly, chronic and acute exercise reduced blood glucose, increased phosphorylation and expression of AMPKα1/2 and the isoforms AMPKα1 and AMPKα2, and decreased phosphorylation and expression of AMPK substrate, acetyl CoA carboxylase (ACC). Chronic exercise upregulated phosphorylation and expression of AMPK upstream kinase, LKB1. But acute exercise only increased LKB1 expression. In particular, exercise reversed the changes in protein kinase C (PKC)ζ/λ phosphorylation, and PKCζ phosphorylation and expression. Additionally, exercise also increased protein kinase B (PKB)/Akt1, Akt2 and GLUT4 expression, but AS160 protein expression was unchanged. Chronic exercise elevated Akt (Thr(308)) and (Ser(473)) and AS160 phosphorylation. Finally, we found that exercise increased peroxisome proliferator-activated receptor-γ coactivator 1 (PGC1) mRNA expression in the soleus of diabetic rats. These results indicate that both chronic and acute exercise influence the phosphorylation and expression of components of the AMPK and downstream to PIK3 (aPKC, Akt), and improve GLUT4 trafficking in skeletal muscle. These data help explain the mechanism how exercise regulates glucose homeostasis in diabetic rats.
运动可以增加 2 型糖尿病大鼠模型中骨骼肌对胰岛素的敏感性，改善胰岛素抵抗，调节葡萄糖稳态。然而，其潜在机制仍知之甚少。在这项研究中，我们建立了雄性 Sprague-Dawley 大鼠 2 型糖尿病模型，该模型通过高脂肪饮食和低剂量链脲佐菌素诱导，模拟了人类 2 型糖尿病的发病机制和代谢特征，存在胰岛素抵抗和β细胞功能障碍。我们还研究了慢性和急性运动改善代谢的可能机制，以及慢性和急性运动对比目鱼肌中 AMP 激活的蛋白激酶 (AMPK) 成分和磷酸肌醇 3-激酶 (PI3K) 信号通路下游成分的磷酸化和表达的影响。结果显示，糖尿病大鼠的血糖、甘油三酯、总胆固醇和游离脂肪酸显著升高，而胰岛素水平逐渐下降。有趣的是，慢性和急性运动降低了血糖，增加了 AMPKα1/2 和 AMPKα1 和 AMPKα2 的同工型的磷酸化和表达，降低了 AMPK 底物乙酰辅酶 A 羧化酶 (ACC) 的磷酸化和表达。慢性运动上调了 AMPK 上游激酶 LKB1 的磷酸化和表达。但急性运动仅增加了 LKB1 的表达。特别是，运动逆转了蛋白激酶 C (PKC)ζ/λ 磷酸化、PKCζ 磷酸化和表达的变化。此外，运动还增加了蛋白激酶 B (PKB)/Akt1、Akt2 和 GLUT4 的表达，但 AS160 蛋白表达不变。慢性运动增加了 Akt (Thr(308)) 和 (Ser(473)) 和 AS160 的磷酸化。最后，我们发现运动增加了糖尿病大鼠比目鱼肌中过氧化物酶体增殖物激活受体-γ 共激活物 1 (PGC1)mRNA 的表达。这些结果表明，慢性和急性运动均影响 AMPK 成分及其下游至 PIK3(aPKC、Akt)的磷酸化和表达，并改善骨骼肌中 GLUT4 的转运。这些数据有助于解释运动如何调节糖尿病大鼠的葡萄糖稳态的机制。
