Metformin delays the manifestation of diabetes and vascular dysfunction in Goto-Kakizaki rats by reduction of mitochondrial oxidative stress
Metformin delays the manifestation of diabetes and vascular dysfunction in Goto-Kakizaki rats by reduction of mitochondrial oxidative stress
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DOI：
10.1002/dmrr.623
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发表时间：
2006-07-01
影响因子：
8
通讯作者：
Wiernsperger, Nicolas F.
中科院分区：
文献类型：
--
作者：
Roesen, Peter;Wiernsperger, Nicolas F.
背景和目的：本研究旨在验证高血糖诱导线粒体产生活性氧（ROS）的假设，二甲双胍治疗可减轻由此产生的氧化应激。以Goto-Kakizaki （GK）大鼠作为2型糖尿病模型，测定线粒体乌头酶活性作为线粒体ROS形成的参数。方法：在糖尿病（葡萄糖、胰岛素）发生的同时，通过测定过氧化脂质、蛋白质（羰基活性）和线粒体乌头酶活性，测定GK大鼠主动脉组织、心脏和肾脏氧化应激的产生情况。血管活性是通过测量内皮依赖性血管扩张对乙酰胆碱的反应和血管收缩对苯肾上腺素的反应来确定的。结果：在12-14周龄时，血糖水平从7.5急剧上升到16.2 mM，表明明显的糖尿病表现。此外，糖耐量受损。血糖升高不伴有血浆胰岛素的变化。血浆中脂质过氧化物仅呈增加趋势，而氧化蛋白（羰基部分）从4.6 μ mol/mg增加到10.9 μ mol/mg（2.4倍）。组织中脂质过氧化物含量增加。线粒体乌头酶活性在糖尿病动物的主动脉和肾脏中降低，但在心脏中没有。二甲双胍治疗几乎使高血糖正常化，并防止羰基、组织脂质过氧化物的上升和乌头酶活性的下降。而内皮依赖性血管扩张不受糖尿病的影响，主动脉对苯肾上腺素的反应强烈增强，二甲双胍治疗可防止这种变化。结论：这些观察结果提供了体内证据，表明ROS的产生在2型糖尿病GK大鼠糖尿病的发病和血管功能障碍的发展中起重要作用。版权所有(c) 2006约翰威利父子有限公司
Background and aim: This study was undertaken to test the hypothesis that hyperglycaemia induces the generation of reactive oxygen species (ROS) by mitochondria and that the oxidative stress thereby exerted is diminished by treatment with metformin. As a parameter of mitochondrial ROS formation, the activity of mitochondrial aconitase activity was determined using Goto-Kakizaki (GK) rats as model of type 2 diabetes.Methods: In parallel with the development of diabetes (glucose, insulin), the generation of oxidative stress was determined in aortic tissue, heart and kidney of GK rats by measurement of lipid peroxides oxidized, proteins (carbonyl activity) and mitochondrial aconitase activity. Vascular activity was determined in aortae by measuring the endothelium-dependent vasodilatation in response to acetylcholine, and vasoconstriction in response to phenylephrine.Results: At the age of 12-14 weeks, blood glucose levels rose dramatically from 7.5 up to 16.2 mM, indicating the manifestation of an overt diabetes. In addition, the glucose tolerance was impaired. The increase in blood glucose was not accompanied by changes in plasma insulin. Whereas the lipid peroxides in plasma only showed a tendency to increase, the amount of oxidized proteins (carbonyl moieties) increased from 4.6 to 10.9 mu mol/mg protein (2.4 fold). In addition, the lipid peroxides in tissue were increased. Mitochondrial aconitase activity was reduced in the aorta and kidney, but not in the heart of diabetic animals. Treatment with metformin nearly normalized the hyperglycaemia and prevented the rise in carbonyl, tissue lipid peroxides and the fall in aconitase activity. Whereas the endothelium-dependent vasodilatation was not affected by the diabetes, the reaction of aortae in response to phenylephrine was strongly enhanced, changes which were prevented by treatment with metformin.Conclusions: These observations provide in vivo evidence that the generation of ROS plays an important role in the onset of diabetes and the development of vascular dysfunction in GK rats with type 2 diabetes. Copyright (c) 2006 John Wiley & Sons, Ltd.