Metformin, the universal first-line treatment for type 2 diabetes, exerts its therapeutic glucose-lowering effects by inhibiting hepatic gluconeogenesis. However, the primary molecular mechanism of this biguanide remains unclear, though it has been suggested to act, at least partially, by mitochondrial complex I inhibition. Here we show that clinically relevant concentrations of plasma metformin achieved by acute intravenous, acute intraportal or chronic oral administration in awake normal and diabetic rats inhibit gluconeogenesis from lactate and glycerol but not from pyruvate and alanine, implicating an increased cytosolic redox state in mediating metformin's antihyperglycemic effect. All of these effects occurred independently of complex I inhibition, evidenced by unaltered hepatic energy charge and citrate synthase flux. Normalizing the cytosolic redox state by infusion of methylene blue or substrates that contribute to gluconeogenesis independently of the cytosolic redox state abrogated metformin-mediated inhibition of gluconeogenesis in vivo. Additionally, in mice expressing constitutively active acetyl-CoA carboxylase, metformin acutely decreased hepatic glucose production and increased the hepatic cytosolic redox state without altering hepatic triglyceride content or gluconeogenic enzyme expression. These studies demonstrate that metformin, at clinically relevant plasma concentrations, inhibits hepatic gluconeogenesis in a redox-dependent manner independently of reductions in citrate synthase flux, hepatic nucleotide concentrations, acetyl-CoA carboxylase activity, or gluconeogenic enzyme protein expression.

中文翻译：

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二甲双胍在体内通过氧化还原依赖性机制抑制糖异生。

二甲双胍是2型糖尿病的通用一线治疗药物，它通过抑制肝糖异生来发挥其降低血糖的作用。然而，尽管已经表明这种双胍的主要分子机制尚至少部分地通过线粒体复合体I的抑制作用。在这里，我们显示，在清醒的正常和糖尿病大鼠中，通过急性静脉内，急性门内或慢性口服给药所达到的血浆二甲双胍的临床相关浓度抑制了乳酸和甘油的糖异生，但不抑制丙酮酸和丙氨酸的糖异生，这暗示了介导二甲双胍的降血糖药中细胞溶质氧化还原状态的增加。影响。所有这些作用均独立于复合物I抑制而发生，这由未改变的肝能电荷和柠檬酸合酶通量证明。通过输注亚甲基蓝或独立于胞质氧化还原状态而有助于糖异生的底物来标准化胞质氧化还原状态，从而消除了二甲双胍在体内对糖异生的抑制作用。此外，在表达组成性活性乙酰辅酶A羧化酶的小鼠中，二甲双胍可在不改变肝甘油三酯含量或糖异生酶表达的情况下，急剧降低肝脏葡萄糖的产生并增加肝脏胞质的氧化还原状态。这些研究表明，在临床相关的血浆浓度下，二甲双胍以氧化还原依赖性方式抑制肝糖异生，与柠檬酸合酶通量，肝核苷酸浓度，乙酰辅酶A羧化酶活性或糖异生酶蛋白表达的降低无关。