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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Cardiac Metabolism and its Interactions With Contraction, Growth, and Survival of Cardiomyocytes
TL;DR: An overview of the cardiac metabolic network is provided and alterations observed in cardiac pathologies as well as strategies used as metabolic therapies in heart failure are highlighted.
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Metformin, Independent of AMPK, Induces mTOR Inhibition and Cell-Cycle Arrest through REDD1
Isaam Ben Sahra,Claire Regazzetti,Guillaume Robert,Kathiane Laurent,Yannick Le Marchand-Brustel,Patrick Auberger,Jean-François Tanti,Sophie Giorgetti-Peraldi,Frédéric Bost +8 more
TL;DR: RedD1 (also known as DDIT4 and RTP801), a negative regulator of mTOR, is identified as a new molecular target of metformin and inhibition of REDD1 reverses meetformin-induced cell-cycle arrest and significantly protects from the deleterious effects of met formin on cell transformation.
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Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction
Kei Sakamoto,Afshan McCarthy,Darrin P. Smith,Kevin A. Green,D. Grahame Hardie,Alan Ashworth,Dario R. Alessi +6 more
TL;DR: These studies establish the importance of LKB1 in regulating AMPK activity and cellular energy levels in response to contraction and phenformin and reduce phosphorylation and activation of AMPKα2.
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Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness.
TL;DR: Comparison and contrast the role of VSMCs in driving calcification in both atherosclerosis and in the vessel media focusing on the major drivers of calcification, including aging, uraemia, mechanical stress, oxidative stress, and inflammation are compared.
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Obesity and cancer—mechanisms underlying tumour progression and recurrence
TL;DR: Recent advances in understanding the contributions of obesity to cancer and their implications for tumour treatment are discussed.
References
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Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain
TL;DR: It is concluded that the drug's pharmacological effects are mediated, at least in part, through a time-dependent, self-limiting inhibition of the respiratory chain that restrains hepatic gluconeogenesis while increasing glucose utilization in peripheral tissues.
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Journal ArticleDOI
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D. Grahame Hardie,David Carling +1 more
TL;DR: The central hypothesis is that the AMP-activated protein kinase cascade appears to be an ancient system which evolved to protect cells against the effects of nutritional or environmental stress, and protects the cell by switching off ATP-consuming pathways and switching on alternative pathways for ATP generation.
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Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I.
Mohamad Y. El-Mir,Véronique Nogueira,Eric Fontaine,Nicole Avéret,Michel Rigoulet,Xavier Leverve +5 more
TL;DR: The results suggest the existence of a new cell-signaling pathway targeted to the respiratory chain complex I with a persistent effect after cessation of the signaling process.
Journal ArticleDOI
Metabolic effects of metformin in non-insulin-dependent diabetes mellitus.
TL;DR: Metformin acts primarily by decreasing hepatic glucose output, largely by inhibiting gluconeogenesis, and also seems to induce weight loss, preferentially involving adipose tissue.