Pioglitazone ameliorates the lowered exercise capacity and impaired mitochondrial function of the skeletal muscle in type 2 diabetic mice.
Pioglitazone ameliorates the lowered exercise capacity and impaired mitochondrial function of the skeletal muscle in type 2 diabetic mice.
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Pioglitazone 可改善 2 型糖尿病小鼠运动能力下降和骨骼肌线粒体功能受损。
DOI：
10.1016/j.ejphar.2014.06.008
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发表时间：
2014
影响因子：
5
通讯作者：
Tsutsui H
中科院分区：
文献类型：
--
作者：
Takada S;Hirabayashi K;Kinugawa S;Yokota T;Matsushima S;Suga T;Kadoguchi T;Fukushima A;Homma T;Mizushima W;Masaki Y;Furihata T;Katsuyama R;Okita K;Tsutsui H
我们已经报道了高脂饮食（HFD）诱导的糖尿病小鼠的运动能力降低，并且这种降低与骨骼肌（SKM）中线粒体功能受损有关。然而，糖尿病的治疗是否能改善运动能力的降低仍有待澄清。因此，我们研究了胰岛素增敏药物吡格列酮是否可以提高HFD小鼠的运动能力。对C57 BL/6 J小鼠饲喂正常饮食（ND）或HFD，然后用或不用吡格列酮（3 mg/kg/天）处理，得到以下4组：ND+溶媒、ND+吡格列酮、HFD+溶媒和HFD+吡格列酮（每组n=10）。8周后，与ND+溶媒组相比，HFD+溶媒组的体重、血糖和胰岛素显著增加。吡格列酮使HFD喂养小鼠的胰岛素水平正常化，但不影响体重或血糖。在HFD+溶媒组中，通过跑台试验测定的运动能力显著降低，而在HFD+吡格列酮组小鼠中，这种降低几乎完全改善。在HFD+溶剂组动物的SKM中，ADP依赖性线粒体呼吸、复合物I和III活性以及柠檬酸合酶活性显著降低，吡格列酮也减弱了这些降低。与ND+溶剂相比，HFD+溶剂中NAD（P）H氧化酶活性显著增加，并且这种增加在HFD+吡格列酮小鼠中得到改善。吡格列酮改善糖尿病小鼠的运动能力，这是由于线粒体功能的改善和SKM中氧化应激的减弱。我们的数据表明，吡格列酮可能是一种有用的药物治疗糖尿病。
We have reported that exercise capacity is reduced in high fat diet (HFD)-induced diabetic mice, and that this reduction is associated with impaired mitochondrial function in skeletal muscle (SKM). However, it remains to be clarified whether the treatment of diabetes ameliorates the reduced exercise capacity. Therefore, we examined whether an insulin-sensitizing drug, pioglitazone, could improve exercise capacity in HFD mice. C57BL/6J mice were fed a normal diet (ND) or HFD, then treated with or without pioglitazone (3 mg/kg/day) to yield the following 4 groups: ND+vehicle, ND+pioglitazone, HFD+vehicle, and HFD+pioglitazone (n=10 each). After 8 weeks, body weight, plasma glucose, and insulin in the HFD+vehicle were significantly increased compared to the ND+vehicle group. Pioglitazone normalized the insulin levels in HFD-fed mice, but did not affect the body weight or plasma glucose. Exercise capacity determined by treadmill tests was significantly reduced in the HFD+vehicle, and this reduction was almost completely ameliorated in HFD+pioglitazone mice. ADP-dependent mitochondrial respiration, complex I and III activities, and citrate synthase activity were significantly decreased in the SKM of the HFD+vehicle animals, and these decreases were also attenuated by pioglitazone. NAD(P)H oxidase activity was significantly increased in the HFD+vehicle compared with the ND+vehicle, and this increase was ameliorated in HFD+pioglitazone mice. Pioglitazone improved the exercise capacity in diabetic mice, which was due to the improvement in mitochondrial function and attenuation of oxidative stress in the SKM. Our data suggest that pioglitazone may be useful as an agent for the treatment of diabetes mellitus.