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Diabetologia
Published in: Diabetologia 7/2010

01-07-2010 | Article

Metformin suppresses hepatic gluconeogenesis and lowers fasting blood glucose levels through reactive nitrogen species in mice

Authors: Y. Fujita, M. Hosokawa, S. Fujimoto, E. Mukai, A. Abudukadier, A. Obara, M. Ogura, Y. Nakamura, K. Toyoda, K. Nagashima, Y. Seino, N. Inagaki

Published in: Diabetologia | Issue 7/2010

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Abstract

Aims/hypothesis

Metformin, the major target of which is liver, is commonly used to treat type 2 diabetes. Although metformin activates AMP-activated protein kinase (AMPK) in hepatocytes, the mechanism of activation is still not well known. To investigate AMPK activation by metformin in liver, we examined the role of reactive nitrogen species (RNS) in suppression of hepatic gluconeogenesis.

Methods

To determine RNS, we performed fluorescence examination and immunocytochemical staining in mouse hepatocytes. Since metformin is a mild mitochondrial complex I inhibitor, we compared its effects on suppression of gluconeogenesis, AMPK activation and generation of the RNS peroxynitrite (ONOO−) with those of rotenone, a representative complex I inhibitor. To determine whether endogenous nitric oxide production is required for ONOO− generation and metformin action, we used mice lacking endothelial nitric oxide synthase (eNOS).

Results

Metformin and rotenone significantly decreased gluconeogenesis and increased phosphorylation of AMPK in wild-type mouse hepatocytes. However, unlike rotenone, metformin did not increase the AMP/ATP ratio. It did, however, increase ONOO− generation, whereas rotenone did not. Exposure of eNOS-deficient hepatocytes to metformin did not suppress gluconeogenesis, activate AMPK or increase ONOO− generation. Furthermore, metformin lowered fasting blood glucose levels in wild-type diabetic mice, but not in eNOS-deficient diabetic mice.

Conclusions/interpretation

Activation of AMPK by metformin is dependent on ONOO−. For metformin action in liver, intra-hepatocellular eNOS is required.
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Metadata
Title
Metformin suppresses hepatic gluconeogenesis and lowers fasting blood glucose levels through reactive nitrogen species in mice
Authors
Y. Fujita
M. Hosokawa
S. Fujimoto
E. Mukai
A. Abudukadier
A. Obara
M. Ogura
Y. Nakamura
K. Toyoda
K. Nagashima
Y. Seino
N. Inagaki
Publication date
01-07-2010
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 7/2010
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-010-1729-5

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