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
Citations
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Metformin Inhibits Monocyte-to-Macrophage Differentiation via AMPK-Mediated Inhibition of STAT3 Activation: Potential Role in Atherosclerosis
Sathish Babu Vasamsetti,Santosh Karnewar,Anantha K Kanugula,Avinash Raj Thatipalli,Jerald Mahesh Kumar,Srigiridhar Kotamraju +5 more
TL;DR: It is concluded that the AMPK-STAT3 axis plays a pivotal role in regulating monocyte-to-macrophage differentiation and that by decreasing STAT3 phosphorylation through increased AMPK activity, AMPK activators inhibit monocyte’s differentiation.
Journal ArticleDOI
Pathophysiological implications of insulin resistance on vascular endothelial function.
TL;DR: Lifestyle measures and drug therapies which improve insulin sensitivity and ameliorate endothelial dysfunction may be important in delaying the progression to overt cardiovascular disease in at risk individuals.
Journal ArticleDOI
Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2
Wouter De Haes,Lotte Frooninckx,Roel Van Assche,Arne Smolders,Geert Depuydt,Johan Billen,Bart P. Braeckman,Liliane Schoofs,Liesbet Temmerman +8 more
TL;DR: It is shown that metformin extends lifespan through the process of mitohormesis and a signaling cascade in which met formin-induced production of reactive oxygen species increases overall life expectancy is revealed.
Journal ArticleDOI
Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial
Sirwan Hadad,Takayuki Iwamoto,Lee B. Jordan,Colin A. Purdie,Susan E. Bray,Lee Baker,Gera Jellema,Steve Deharo,D. Grahame Hardie,Lajos Pusztai,Stacy Moulder-Thompson,John Dewar,Alastair M. Thompson,Alastair M. Thompson +13 more
TL;DR: In this article, the authors examined the effects of metformin on Ki67 and gene expression in primary breast cancer and found that the mean percentage of cells staining for Ki67 was significantly reduced following met-formin treatment in both the pilot cohort (P = 0.041, paired t-test) and in the non-diabetic women with no drug and 2 weeks later had core biopsy at surgery.
Journal ArticleDOI
Activation of AMPK attenuates neutrophil proinflammatory activity and decreases the severity of acute lung injury
Xia Zhao,Jaroslaw W. Zmijewski,Emmanuel Lorne,Gang Liu,Young-Jun Park,Yuko Tsuruta,Edward Abraham +6 more
TL;DR: Results suggest that AMPK activation reduces TLR4-induced neutrophil activation and diminishes the severity of neutrophIL-driven proinflammatory processes, including acute lung injury.
References
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Journal ArticleDOI
Metabolic effects of metformin in non-insulin-dependent diabetes mellitus.
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