Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain.
Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain.
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DOI：
10.1042/bj3480607
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发表时间：
2000-06
期刊：
影响因子：
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通讯作者：
Mark R. Owen;E. Doran;A. Halestrap
中科院分区：
文献类型：
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作者：
Mark R. Owen;E. Doran;A. Halestrap
虽然二甲双胍被广泛用于治疗非胰岛素依赖型糖尿病，但其作用模式尚不清楚。在这里，我们提供的证据表明，它的主要作用部位是通过直接抑制呼吸链的复合体1。二甲双胍(50微米)对肝癌细胞线粒体谷氨酸+苹果酸氧化的抑制作用在作用24 h和60 h后分别为13%和30%，琥珀酸氧化作用不受影响。在分离的线粒体中，二甲双胍还引起对复合体1的时间依赖性抑制，而在亚线粒体颗粒中，抑制是立即的，但需要非常高的二甲双胍浓度(K(0.5)，79 mM)。这些数据与由膜电位驱动的正电荷药物在线粒体基质中的缓慢蓄积导致对复合体1的抑制相一致。在体外培养的大鼠肝细胞中，二甲双胍对L乳酸盐糖异生的抑制作用也是时间和浓度依赖的，并伴随着类似于作用于复合体1的其他糖异生抑制剂所引起的代谢物水平的变化。我们的结论是，该药物的药理作用至少部分是通过对呼吸链的依赖和自限抑制来实现的，这种抑制作用抑制了肝脏的糖异生，同时增加了外周组织中葡萄糖的利用。乳酸中毒，偶尔会有副作用，所以就这样解释吧。
Although metformin is widely used for the treatment of non-insulin-dependent diabetes, its mode of action remains unclear. Here we provide evidence that its primary site of action is through a direct inhibition of complex 1 of the respiratory chain. Metformin(50 microM) inhibited mitochondrial oxidation of glutamate+malate in hepatoma cells by 13 and 30% after 24 and 60 h exposure respectively, but succinate oxidation was unaffected. Metformin also caused time-dependent inhibition of complex 1 in isolated mitochondria, whereas in sub-mitochondrial particles inhibition was immediate but required very high metformin concentrations (K(0.5),79 mM). These data are compatible with the slow membrane-potential-driven accumulation of the positively charged drug within the mitochondrial matrix leading to inhibition of complex 1. Metformin inhibition of gluconeogenesis from L-lactate in isolated rat hepatocytes was also time- and concentration-dependent, and accompanied by changes in metabolite levels similar to those induced by other inhibitors of gluconeogenesis acting on complex 1. Freeze-clamped livers from metformin-treated rats exhibited similar changes in metabolite concentrations. We conclude that the drug's pharmacological effects are mediated, at least in part, through a time-dependent, self-limiting inhibition of the respiratory chain that restrains hepatic gluconeogenesis while increasing glucose utilization in peripheral tissues. Lactic acidosis, an occasional side effect, canal so be explained in this way.