Bart's and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University, London, UK.
J Endocrinol. 2010 Apr;205(1):97-106. doi: 10.1677/JOE-09-0345. Epub 2010 Jan 21.
Abnormal elevation of hepatic gluconeogenesis is central to the onset of hyperglycaemia in patients with type 2 diabetes mellitus (T2DM). Metformin corrects hyperglycaemia through inhibition of gluconeogenesis, but its mechanism of action is yet to be fully described. SIRT1 and GCN5 (listed as KAT2A in the MGI Database) have recently been identified as regulators of gluconeogenic gene expression through modulation of levels and activity of the coactivators cAMP-response element binding protein-regulated transcription coactivator 2 (TORC2 or CRTC2 as listed in the MGI Database) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1alpha or PPARGC1A as listed in the MGI Database). We report that in db/db mice, metformin (250 mg/kg per day; 7 days) increases hepatic levels of GCN5 protein and mRNA compared with the untreated db/db mice, as well as increases levels of SIRT1 protein and activity relative to controls and untreated db/db mice. These changes were associated with reduced TORC2 protein level and decreased gene expression and activation of the PGC1alpha gene target phosphoenolpyruvate carboxykinase, and lower plasma glucose and insulin. Inhibition of SIRT1 partially blocked the effects of metformin on gluconeogenesis. SIRT1 was increased through an AMP-activated protein kinase-mediated increase in gene expression of nicotinamide phosphoribosyltransferase, the rate-limiting enzyme of the salvage pathway for NAD(+). Moreover, levels of GCN5 were dramatically reduced in db/db mice compared with the controls. This indicates that loss of GCN5-mediated inhibition of gluconeogenesis appears to constitute a major mechanism for the onset of abnormally elevated hepatic glucose production in db/db mice. In conclusion, induction of GCN5 and SIRT1 potentially represents a critical mechanism of action of metformin. In addition, these data identify induction of hepatic GCN5 as a potential therapeutic strategy for treatment of T2DM.
异常升高的肝糖异生是 2 型糖尿病（T2DM）患者高血糖发生的核心。二甲双胍通过抑制糖异生来纠正高血糖，但它的作用机制尚未完全描述。SIRT1 和 GCN5（在 MGI 数据库中列为 KAT2A）最近被鉴定为通过调节 cAMP 反应元件结合蛋白调节转录共激活因子 2（TORC2 或在 MGI 数据库中列为 CRTC2）和过氧化物酶体增殖物激活受体-γ共激活因子 1α（PGC1α 或在 MGI 数据库中列为 PPARGC1A）的共激活剂的水平和活性来调节糖异生基因表达的调节剂。我们报告说，在 db/db 小鼠中，与未治疗的 db/db 小鼠相比，二甲双胍（每天 250mg/kg；7 天）增加了肝 GCN5 蛋白和 mRNA 的水平，并且与对照和未治疗的 db/db 小鼠相比，SIRT1 蛋白和活性增加。这些变化与 TORC2 蛋白水平降低以及 PGC1α 基因靶标磷酸烯醇丙酮酸羧激酶的基因表达和激活降低以及血浆葡萄糖和胰岛素降低有关。SIRT1 的抑制部分阻断了二甲双胍对糖异生的作用。SIRT1 通过烟酰胺磷酸核糖基转移酶（NAD+补救途径的限速酶）的基因表达的 AMP 激活的蛋白激酶介导的增加而增加。此外，与对照组相比，db/db 小鼠中的 GCN5 水平显着降低。这表明 GCN5 介导的糖异生抑制的丧失似乎构成了 db/db 小鼠中异常升高的肝葡萄糖产生的发生的主要机制。总之，GCN5 和 SIRT1 的诱导可能代表二甲双胍的关键作用机制。此外，这些数据表明诱导肝 GCN5 可能成为治疗 T2DM 的潜在治疗策略。
