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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The ancient drug salicylate directly activates AMP-activated protein kinase
Simon A. Hawley,Morgan D. Fullerton,Fiona A. Ross,Jonathan D. Schertzer,Cyrille Chevtzoff,Katherine J. Walker,Mark Peggie,Darya Zibrova,Kevin A. Green,Kirsty J. Mustard,Bruce E. Kemp,Kei Sakamoto,Gregory R. Steinberg,Gregory R. Steinberg,D. Grahame Hardie +14 more
TL;DR: The results suggest that AMPK activation could explain some beneficial effects of salsalate and aspirin in humans, and a possible molecular mechanism of action for a metabolite of aspirin is described.
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TL;DR: The hypothesis that dysregulation of AMPK is both a pathogenic factor for metabolic syndrome-related disorders in humans and a target for their prevention and therapy is evaluated.
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Adiponectin: A novel adipokine linking adipocytes and vascular function.
TL;DR: Recent work on the vascular actions of adiponectin complements the growing body of information on its insulin-sensitizing effects in glucose and lipid metabolism and is now a recognized component of a novel signaling network among adipocytes, insulin-sensitive tissues, and vascular function that has important consequences for cardiovascular risk.
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The Antidiabetic Drug Metformin Activates the AMP-Activated Protein Kinase Cascade via an Adenine Nucleotide-Independent Mechanism
TL;DR: Evidence is presented that activation of AMPK in two different cell types is not a consequence of depletion of cellular energy charge via this mechanism, and the mechanism is different from that of the existing AMPK-activating agent, 5-aminoimidazole-4-carboxamide (AICA) riboside.
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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J. Denis McGarry,N. F. Brown +1 more
TL;DR: Key developments of the last 20 years that have led to the current understanding of the physiology of the CPT system, the structure of theCPT isoforms, the chromosomal localization of their respective genes, and the identification of mutations in the human population are reviewed.
Journal ArticleDOI
The AMP‐Activated Protein Kinase
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.
Journal ArticleDOI
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.
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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.