Despite its position as the first-line drug for treatment of type 2 diabetes mellitus, the mechanisms underlying the plasma glucose level-lowering effects of metformin (1,1-dimethylbiguanide) still remain incompletely understood. Metformin is thought to exert its primary antidiabetic action through the suppression of hepatic glucose production. In addition, the discovery that metformin inhibits the mitochondrial respiratory chain complex 1 has placed energy metabolism and activation of AMP-activated protein kinase (AMPK) at the centre of its proposed mechanism of action. However, the role of AMPK has been challenged and might only account for indirect changes in hepatic insulin sensitivity. Various mechanisms involving alterations in cellular energy charge, AMP-mediated inhibition of adenylate cyclase or fructose-1,6-bisphosphatase 1 and modulation of the cellular redox state through direct inhibition of mitochondrial glycerol-3-phosphate dehydrogenase have been proposed for the acute inhibition of gluconeogenesis by metformin. Emerging evidence suggests that metformin could improve obesity-induced meta-inflammation via direct and indirect effects on tissue-resident immune cells in metabolic organs (that is, adipose tissue, the gastrointestinal tract and the liver). Furthermore, the gastrointestinal tract also has a major role in metformin action through modulation of glucose-lowering hormone glucagon-like peptide 1 and the intestinal bile acid pool and alterations in gut microbiota composition.

中文翻译：

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了解二甲双胍在2型糖尿病中的糖调节机制。

尽管其作为治疗2型糖尿病的一线药物的地位，对二甲双胍（1,1-二甲基双胍）降低血浆葡萄糖水平的作用机理仍未完全了解。二甲双胍被认为通过抑制肝葡萄糖的产生而发挥其主要的抗糖尿病作用。此外，二甲双胍抑制线粒体呼吸链复合物1的发现将能量代谢和AMP激活的蛋白激酶（AMPK）的激活置于其提议的作用机制的中心。但是，AMPK的作用已受到挑战，可能仅解释了肝胰岛素敏感性的间接变化。涉及细胞能量电荷变化，AMP介导的腺苷酸环化酶或果糖1抑制的各种机制，已经提出了6-二磷酸酶1和通过直接抑制线粒体甘油-3-磷酸脱氢酶来调节细胞氧化还原状态，以通过二甲双胍来急性抑制糖异生。越来越多的证据表明，二甲双胍可以通过对代谢器官（即脂肪组织，胃肠道和肝脏）中组织驻留免疫细胞的直接和间接作用来改善肥胖症引起的间质炎症。此外，胃肠道还通过调节降糖激素胰高血糖素样肽1和肠道胆汁酸池以及肠道菌群组成的改变，在二甲双胍的作用中也起主要作用。