Metformin is among the most prescribed antidiabetic drugs, but the primary molecular mechanism by which metformin lowers blood glucose levels is unknown. Previous studies have proposed numerous mechanisms by which acute metformin lowers blood glucose, including the inhibition of mitochondrial complex I of the electron transport chain (ETC). Here, we used transgenic mice that globally express the Saccharomyces cerevisiae internal alternative NADH dehydrogenase (NDI1) protein to determine whether the glucose-lowering effect of acute oral administration of metformin requires inhibition of mitochondrial complex I of the ETC in vivo. NDI1 is a yeast NADH dehydrogenase enzyme that complements the loss of mammalian mitochondrial complex I electron transport function and is insensitive to pharmacologic mitochondrial complex I inhibitors including metformin. We demonstrate that NDI1 expression attenuates metformin’s ability to lower blood glucose levels under standard chow and high-fat diet conditions. Our results indicate that acute oral administration of metformin targets mitochondrial complex I to lower blood glucose.

中文翻译：

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二甲双胍靶向线粒体复合物 I 以降低血糖水平


二甲双胍是处方最多的抗糖尿病药物之一，但二甲双胍降低血糖水平的主要分子机制尚不清楚。以前的研究提出了急性二甲双胍降低血糖的许多机制，包括抑制电子传递链 （ETC） 的线粒体复合物 I。在这里，我们使用了全球表达酿酒酵母内部替代 NADH 脱氢酶 （NDI1） 蛋白的转基因小鼠来确定急性口服二甲双胍的降糖作用是否需要在体内抑制 ETC 的线粒体复合物 I。NDI1 是一种酵母 NADH 脱氢酶，可补充哺乳动物线粒体复合物 I 电子传递功能的丧失，并且对包括二甲双胍在内的药理线粒体复合物 I 抑制剂不敏感。我们证明 NDI1 表达减弱了二甲双胍在标准食物和高脂肪饮食条件下降低血糖水平的能力。我们的结果表明，二甲双胍的急性口服给药针对线粒体复合物 I 以降低血糖。