Departments of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
Department of Hepatology, Southern Medical University, Guangzhou, 510515, China.
Sci Rep. 2020 Jun 26;10(1):10482. doi: 10.1038/s41598-020-67030-5.
Metformin has been used to treat patients with type 2 diabetes for over 60 years, however, its mechanism of action is still not completely understood. Our previous reports showed that high-fat-diet (HFD)-fed mice with liver-specific knockout of both AMPK catalytic α1 and α2 subunits exhibited significantly higher fasting blood glucose levels and produced more glucose than floxed AMPK catalytic α1 and α2 mice after long-term metformin treatment, and that metformin promotes the formation of the functional AMPK αβγ heterotrimeric complex. We tested the importance of each regulatory γ subunit isoform to metformin action in this current study. We found that depletion of γ1, but not γ2 or γ3, drastically reduced metformin activation of AMPK. HFD-fed mice with depletion of the γ1 subunit are resistant to metformin suppression of liver glucose production. Furthermore, we determined the role of each regulatory cystathionine-β-synthase (CBS) domain in the γ1 subunit in metformin action and found that deletion of either CBS1 or CBS4 negated metformin's effect on AMPKα phosphorylation at T172 and suppression of glucose production in hepatocytes. Our data indicate that the γ1 subunit is required for metformin's control of glucose metabolism in hepatocytes. Furthermore, in humans and animal models, metformin treatment leads to the loss of body weight, we found that the decrease in body weight gain in mice treated with metformin is not directly attributable to increased energy expenditure.
二甲双胍已用于治疗 2 型糖尿病患者超过 60 年，但它的作用机制仍不完全清楚。我们之前的报告显示，高脂肪饮食（HFD）喂养的肝特异性敲除 AMPK 催化亚基 α1 和 α2 的小鼠在长期二甲双胍治疗后空腹血糖水平明显升高，产生的葡萄糖也比 floxed AMPK 催化亚基 α1 和 α2 小鼠多，并且二甲双胍促进功能性 AMPK αβγ 三聚体复合物的形成。在本研究中，我们测试了每个调节γ亚基同工型对二甲双胍作用的重要性。我们发现，γ1 的耗竭，而不是 γ2 或 γ3，大大降低了二甲双胍对 AMPK 的激活作用。HFD 喂养的 γ1 亚基耗竭的小鼠对二甲双胍抑制肝葡萄糖生成具有抗性。此外，我们确定了 γ1 亚基中每个调节半胱氨酸-β-合成酶（CBS）结构域在二甲双胍作用中的作用，发现 CBS1 或 CBS4 的缺失消除了二甲双胍对 AMPKα 在 T172 处磷酸化和抑制肝细胞葡萄糖生成的作用。我们的数据表明，γ1 亚基是二甲双胍控制肝细胞葡萄糖代谢所必需的。此外，在人类和动物模型中，二甲双胍治疗导致体重减轻，我们发现用二甲双胍治疗的小鼠体重增加减少不是直接归因于能量消耗增加。
