Metformin is a first-line drug for the treatment of individuals with type 2 diabetes, yet its precise mechanism of action remains unclear. Metformin exerts its antihyperglycemic action primarily through lowering hepatic glucose production (HGP). This suppression is thought to be mediated through inhibition of mitochondrial respiratory complex I, and thus elevation of 5'-adenosine monophosphate (AMP) levels and the activation of AMP-activated protein kinase (AMPK), though this proposition has been challenged given results in mice lacking hepatic AMPK. Here we report that the AMP-inhibited enzyme fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis, functions as a major contributor to the therapeutic action of metformin. We identified a point mutation in FBP1 that renders it insensitive to AMP while sparing regulation by fructose-2,6-bisphosphate (F-2,6-P₂), and knock-in (KI) of this mutant in mice significantly reduces their response to metformin treatment. We observe this during a metformin tolerance test and in a metformin-euglycemic clamp that we have developed. The antihyperglycemic effect of metformin in high-fat diet-fed diabetic FBP1-KI mice was also significantly blunted compared to wild-type controls. Collectively, we show a new mechanism of action for metformin and provide further evidence that molecular targeting of FBP1 can have antihyperglycemic effects.

中文翻译：

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二甲双胍通过抑制果糖-1-6-二磷酸酶来减少肝脏葡萄糖的产生。


二甲双胍是治疗2型糖尿病的一线药物，但其确切的作用机制尚不清楚。二甲双胍主要通过降低肝葡萄糖产生（HGP）发挥其抗高血糖作用。这种抑制被认为是通过抑制线粒体呼吸复合物 I 介导的，从而提高 5'-单磷酸腺苷 (AMP) 水平和激活 AMP 激活蛋白激酶 (AMPK)，尽管鉴于以下结果，这一主张受到了挑战缺乏肝 AMPK 的小鼠。在这里，我们报道了 AMP 抑制酶果糖-1,6-双磷酸酶-1 (FBP1)，一种糖异生中的速率控制酶，是二甲双胍治疗作用的主要贡献者。我们在 FBP1 中发现了一个点突变，使其对 AMP 不敏感，同时不受果糖-2,6-二磷酸 (F-2,6-P ₂ ) 的调节，并且该突变体在小鼠中的敲入 (KI) 显着降低了对二甲双胍治疗的反应。我们在二甲双胍耐受性测试和我们开发的二甲双胍正常血糖钳中观察到了这一点。与野生型对照相比，二甲双胍对高脂饮食喂养的糖尿病 FBP1-KI 小鼠的降血糖作用也显着减弱。总的来说，我们展示了二甲双胍的新作用机制，并提供了进一步的证据，证明 FBP1 的分子靶向可以具有抗高血糖作用。