Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520.
Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06520.
Proc Natl Acad Sci U S A. 2022 Mar 8;119(10):e2122287119. doi: 10.1073/pnas.2122287119. Epub 2022 Mar 1.
SignificanceMetformin is the most commonly prescribed drug for the treatment of type 2 diabetes mellitus, yet the mechanism by which it lowers plasma glucose concentrations has remained elusive. Most studies to date have attributed metformin's glucose-lowering effects to inhibition of complex I activity. Contrary to this hypothesis, we show that inhibition of complex I activity in vitro and in vivo does not reduce plasma glucose concentrations or inhibit hepatic gluconeogenesis. We go on to show that metformin, and the related guanides/biguanides, phenformin and galegine, inhibit complex IV activity at clinically relevant concentrations, which, in turn, results in inhibition of glycerol-3-phosphate dehydrogenase activity, increased cytosolic redox, and selective inhibition of glycerol-derived hepatic gluconeogenesis both in vitro and in vivo.
意义二甲双胍是治疗 2 型糖尿病最常用的药物，但它降低血浆葡萄糖浓度的机制一直难以捉摸。迄今为止的大多数研究都将二甲双胍的降血糖作用归因于对复合物 I 活性的抑制。与这一假说相反，我们表明，体外和体内抑制复合物 I 活性不会降低血浆葡萄糖浓度或抑制肝糖异生。我们接着表明，二甲双胍和相关的胍类/双胍类、苯乙双胍和蝙蝠葛碱在临床相关浓度下抑制复合物 IV 活性，这反过来又导致甘油-3-磷酸脱氢酶活性抑制、细胞内氧化还原增加以及甘油衍生的肝糖异生在体外和体内的选择性抑制。
