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 suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5
Paul W. Caton,Nanda K Nayuni,Julius Kieswich,Noorafza Q. Khan,Muhammed M. Yaqoob,Roger Corder +5 more
TL;DR: Induction of GCN5 and SIRT1 potentially represents a critical mechanism of action of metformin and is identified as a potential therapeutic strategy for treatment of type 2 diabetes mellitus.
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Metformin Targets Central Carbon Metabolism and Reveals Mitochondrial Requirements in Human Cancers.
TL;DR: An integrative metabolomics analysis of metformin action in ovarian cancer demonstrates with stable isotope tracing that a metabolic signature obtained from a patient with an exceptional clinical outcome mirrored that of a responsive animal tumor.
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Role of organic cation transporter 3 (SLC22A3) and its missense variants in the pharmacologic action of metformin
Ligong Chen,Bradley Pawlikowski,Avner Schlessinger,Swati S. More,Doug Stryke,Susan J. Johns,Michael A. Portman,Eugene Chen,Thomas E. Ferrin,Andrej Sali,Kathleen M. Giacomini +10 more
TL;DR: It is suggested that OCT3 plays a role in the therapeutic action of metformin and that genetic variants of OCT3 may modulate met formin and catecholamine action.
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5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside and metformin inhibit hepatic glucose phosphorylation by an AMP-activated protein kinase-independent effect on glucokinase translocation.
Bruno Guigas,Luc Bertrand,Nellie Taleux,Marc Foretz,Nicolas Wiernsperger,Didier Vertommen,Fabrizio Andreelli,Benoit Viollet,Louis Hue +8 more
TL;DR: AICAR, metformin, and oligomycin were found to inhibit the glucose-induced translocation of glucokinase from the nucleus to the cytosol by a mechanism that could be related to the decrease in intracellular ATP concentrations observed in these conditions.
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Nutrient–secretion coupling in the pancreatic islet β-cell: recent advances
TL;DR: Recent data indicate that glucose also enhances insulin secretion through mechanisms which do not involve a change in KATP channel activity, and seem likely to underlie the second, sustained phase of glucose-stimulated insulin secretion.
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.