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：
10.1042/0264-6021:3480607
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发表时间：
2000-06-15
影响因子：
4.1
通讯作者：
Halestrap, AP
中科院分区：
文献类型：
--
作者：
Owen, MR;Doran, E;Halestrap, AP
虽然二甲双胍被广泛用于治疗非胰岛素依赖型糖尿病，但其作用方式尚不清楚。在这里，我们提供的证据表明，其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 μ M）对肝癌细胞谷氨酸+苹果酸的线粒体氧化分别抑制了13%和30%，但琥珀酸的氧化不受影响。二甲双胍还在分离的线粒体中引起复合体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）。这些数据与线粒体基质中带正电荷的药物缓慢的膜电位驱动积累导致复合物1的抑制相一致。二甲双胍对离体大鼠肝细胞中l -乳酸糖异生的抑制作用也是时间和浓度依赖性的，并伴有代谢物水平的变化，类似于作用于复合物1的其他糖异生抑制剂所引起的变化。二甲双胍处理大鼠的冷冻夹肝在代谢物浓度方面也表现出类似的变化。我们的结论是，该药物的药理作用至少在一定程度上是通过对呼吸链的一种依赖于石灰的自限性抑制来介导的，这种抑制抑制了肝脏糖异生，同时增加了周围组织的葡萄糖利用。乳酸性酸中毒，一种偶然的副作用，也可以这样解释。
Although metformin is widely used for the treatment of noninsulin-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 mu M) inhibited mitochondrial oxidation of glutamate+malate in hepatoma cells by 13 and 30% after 24 and 60h exposure respectively, but succinate oxidation was unaffected. Metformin also caused time-dependent inhibition of complex 1 in isolated mitochondria, whereas in submitochondrial 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 lime-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, can also be explained in this way.