Open AccessMetformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis
Author(s) -
Traci E. LaMoia,
Gina M. Butrico,
Hasini A. Kalpage,
Leigh Goedeke,
Brandon T. Hubbard,
Daniel F. Vatner,
Rafael Calais Gaspar,
XianMan Zhang,
Gary W. Cline,
K Nakahara,
Seungwan Woo,
Atsuhiro Shimada,
Maik Hüttemann,
Gerald I. Shulman
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2122287119
Subject(s) - phenformin , gluconeogenesis , metformin , in vivo , glycerol , chemistry , medicine , endocrinology , pharmacology , in vitro , biochemistry , diabetes mellitus , biology , metabolism , microbiology and biotechnology
Significance Metformin 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.