Role of AMP-activated protein kinase in mechanism of metformin action
Gaochao Zhou,Robert W. Myers,Ying Li,Yuli Chen,Xiaolan Shen,Judy Fenyk-Melody,Margaret Wu,John Ventre,Thomas W. Doebber,Nobuharu Fujii,Nicolas Musi,Michael F. Hirshman,Laurie J. Goodyear,David E. Moller +13 more
TLDR
It is reported that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed.Abstract:
Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effect results from decreased hepatic glucose production and increased glucose utilization. Metformin's beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Here we report that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed. Activation of AMPK by metformin or an adenosine analogue suppresses expression of SREBP-1, a key lipogenic transcription factor. In metformin-treated rats, hepatic expression of SREBP-1 (and other lipogenic) mRNAs and protein is reduced; activity of the AMPK target, ACC, is also reduced. Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin's inhibitory effect on glucose production by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation. Activation of AMPK provides a unified explanation for the pleiotropic beneficial effects of this drug; these results also suggest that alternative means of modulating AMPK should be useful for the treatment of metabolic disorders.read more
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Synergistic Effects of Metformin Treatment in Combination with Gefitinib, a Selective EGFR Tyrosine Kinase Inhibitor, in LKB1 Wild-type NSCLC Cell Lines
Floriana Morgillo,Ferdinando Carlo Sasso,Carminia Maria Della Corte,Donata Vitagliano,Elena D'Aiuto,Teresa Troiani,Erika Martinelli,Ferdinando De Vita,Michele Orditura,Raffaele De Palma,Fortunato Ciardiello +10 more
TL;DR: Metformin and gefitinib are synergistic in LKB1 wild-type NSCLC cells, however, further studies are required to investigate better the effect of metformin action on the RAS/RAF/MAPK pathway and the best context in which to use met formin in combination with molecular targeted agents.
Journal ArticleDOI
AMP-Activated Protein Kinase Suppresses Endothelial Cell Inflammation Through Phosphorylation of Transcriptional Coactivator p300
TL;DR: It is demonstrated that transcriptional coactivator p300 phosphorylation at Ser89 by AMPK is critical for the therapeutic effect of AMPK and may be a potential target for pharmaceutical intervention in inflammatory diseases such as atherosclerosis.
Journal ArticleDOI
AMPK-mediated regulation of transcription in skeletal muscle.
Sean L. McGee,Mark Hargreaves +1 more
TL;DR: The present review examines the role of AMPK in skeletal muscle transcription and provides an overview of the known transcriptional substrates mediating the effects of AM PK on skeletal muscle phenotype.
Journal ArticleDOI
A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts
N. van Leeuwen,Giel Nijpels,Matthijs L. Becker,Harshal Deshmukh,Ke Zhou,B. H. Stricker,A.G. Uitterlinden,A. Hofman,E. van 't Riet,Christopher R. Palmer,Bruno Guigas,P.E. Slagboom,Paul N. Durrington,Roberto A. Calle,Andrew Neil,Graham A. Hitman,Shona J. Livingstone,Helen M. Colhoun,Rury R. Holman,Rury R. Holman,Mark I. McCarthy,Mark I. McCarthy,J.M. Dekker,Leen M 't Hart,Ewan R. Pearson +24 more
TL;DR: A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK, and is the first robustly replicated common susceptibility locus found to be associated with meetformIn treatment response.
Journal ArticleDOI
Ginsenoside Rb1 reduces fatty liver by activating AMP-activated protein kinase in obese rats.
Ling Shen,Ye Xiong,David Q.-H. Wang,Philip N. Howles,Joshua E. Basford,Jiang Wang,Yu Qing Xiong,David Y. Hui,Stephen C. Woods,Min Liu +9 more
TL;DR: It is concluded that Rb1 has a potent ability to reduce hepatic fat accumulation and might be useful as a therapeutic agent for fatty liver disorder.
References
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Journal ArticleDOI
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