Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state
Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state
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DOI：
10.1172/jci40671
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发表时间：
2010-07-01
影响因子：
15.9
通讯作者：
Viollet, Benoit
中科院分区：
文献类型：
--
作者：
Foretz, Marc;Hebrard, Sophie;Viollet, Benoit
二甲双胍广泛用于治疗2型糖尿病患者的高血糖症。最近，LKB 1/AMP活化蛋白激酶（LKB 1/AMPK）通路被认为介导二甲双胍对肝脏新生的作用。然而，这一途径运作的分子机制仍然难以捉摸。令人惊讶的是，我们发现在肝脏缺乏AMPK的小鼠中，血糖水平与野生型小鼠相当，二甲双胍的降血糖作用得以维持。与野生型肝细胞相比，缺乏AMPK的肝细胞显示正常的葡萄糖产生和致凋亡基因表达。与此相反，异生被上调。在LKB 1缺乏的肝细胞中。在野生型、AMPK缺陷型和LKB 1缺陷型肝细胞中，二甲双胍降低了编码葡萄糖-6-磷酸酶催化亚基（G6 β）的基因表达，而胞质磷酸烯醇丙酮酸羧激酶（Pepck）基因表达不受影响。令人惊讶的是，二甲双胍诱导的葡萄糖产生的抑制放大AMPK和LKB 1缺陷相比，野生型肝细胞。这种抑制以剂量依赖性方式与细胞内ATP含量的减少相关，这对葡萄糖产生至关重要。此外，二甲双胍诱导的葡萄糖生成抑制作用在通过过氧化物酶体增殖物激活物γ辅激活因子1 α（PGC-1 α）过表达的促血管生成基因强制表达下得以保留，表明二甲双胍通过转录非依赖性过程抑制血管生成。总之，我们证明二甲双胍通过降低肝脏能量状态以LKB 1和AMPK非依赖性方式抑制肝脏新生。
Metformin is widely used to treat hyperglycemia in individuals with type 2 diabetes. Recently the LKB1/AMP-activated protein kinase (LKB1/AMPK) pathway was proposed to mediate the action of metformin on hepatic gluconeogenesis. However, the molecular mechanism by which this pathway operates had remained elusive. Surprisingly, here we have found that in mice lacking AMPK in the liver, blood glucose levels were comparable to those in wild-type mice, and the hypoglycemic effect of metformin was maintained. Hepatocytes lacking AMPK displayed normal glucose production and gluconeogenic gene expression compared with wild-type hepatocytes. In contrast, gluconeogenesis was upregulated. in LKB1-deficient hepatocytes. Metformin decreased expression of the gene encoding the catalytic subunit of glucose-6-phosphatase (G6Pase), while cytosolic phosphoenolpyruvate carboxykinase (Pepck) gene expression was unaffected in wild-type, AMPK-deficient, and LKB1-deficient hepatocytes. Surprisingly, metformin-induced inhibition of glucose production was amplified in both AMPK- and LKB1-deficient compared with wild-type hepatocytes. This inhibition correlated in a dose-dependent manner with a reduction in intracellular ATP content, which is crucial for glucose production. Moreover, metformin-induced inhibition of glucose production was preserved under forced expression of gluconeogenic genes through PPAR gamma coactivator 1 alpha (PGC-1 alpha) overexpression, indicating that metformin suppresses gluconeogenesis via a transcription-independent process. In conclusion, we demonstrate that metformin inhibits hepatic gluconeogenesis in an LKB1- and AMPK-independent manner via a decrease in hepatic energy state.