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


ABSTRACT: 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.

SUBMITTER: LaMoia TE 

PROVIDER: S-EPMC8916010 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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

LaMoia Traci E TE   Butrico Gina M GM   Kalpage Hasini A HA   Goedeke Leigh L   Hubbard Brandon T BT   Vatner Daniel F DF   Gaspar Rafael C RC   Zhang Xian-Man XM   Cline Gary W GW   Nakahara Keita K   Woo Seungwan S   Shimada Atsuhiro A   Hüttemann Maik M   Shulman Gerald I GI  

Proceedings of the National Academy of Sciences of the United States of America 20220301 10


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  ...[more]

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