Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis

作者：Traci E. LaMoia, Gina M. Butrico, Hasini A. Kalpage, Leigh Goedeke, Brandon T. Hubbard, Daniel F. Vatner, Rafael Calais Gaspar, Xian‐Man Zhang, Gary W. Cline, Keita Nakahara, Seungwan Woo, Atsuhiro Shimada, Maik Hüttemann, Gerald I. Shulman · 发表于：Proceedings of the National Academy of Sciences · 年份：2022 · DOI：10.1073/pnas.2122287119 · 被引用次数：102 · 研究领域：Metabolism, Diabetes, and Cancer、Pancreatic function and diabetes、Glycogen Storage Diseases and Myoclonus

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.