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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The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation.
Alexa S. Green,Alexa S. Green,Nicolas Chapuis,Nicolas Chapuis,Thiago Trovati Maciel,Lise Willems,Lise Willems,Mireille Lambert,Mireille Lambert,Christophe Arnoult,Olivier Boyer,Valérie Bardet,Valérie Bardet,Sophie Park,Marc Foretz,Marc Foretz,Benoit Viollet,Benoit Viollet,Norbert Ifrah,François Dreyfus,Olivier Hermine,Ivan C. Moura,Catherine Lacombe,Catherine Lacombe,Patrick Mayeux,Patrick Mayeux,Didier Bouscary,Jerome Tamburini +27 more
TL;DR: The induction of the LKB1/AMPK/TSC tumor suppressor axis is functional in AML and can be activated by the biguanide molecule metformin, resulting in a specific inhibition of mammalian target of rapamycin catalytic activity.
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Antipsychotic-associated weight gain: management strategies and impact on treatment adherence
Madhubhashinee Dayabandara,Raveen Hanwella,S.S. Ratnatunga,Sudarshi Seneviratne,Chathurie Suraweera,Varuni de Silva +5 more
TL;DR: Tailoring antipsychotics according to the needs of the individual and close monitoring of weight and other metabolic parameters are the best preventive strategies at the outset.
Journal ArticleDOI
Successful aging: Advancing the science of physical independence in older adults.
Stephen D. Anton,Adam J. Woods,Tetsuo Ashizawa,Diana Barb,Thomas W. Buford,Christy S. Carter,David J. Clark,Ronald A. Cohen,Duane B. Corbett,Yenisel Cruz-Almeida,Vonetta M. Dotson,Natalie C. Ebner,Philip A. Efron,Roger B. Fillingim,Thomas C. Foster,David M. Gundermann,Anna Maria Joseph,Christy Karabetian,Christiaan Leeuwenburgh,Todd M. Manini,Michael Marsiske,Robert T. Mankowski,Heather Lee Mutchie,Michael G. Perri,Sanjay Ranka,Parisa Rashidi,Bhanuprasad Sandesara,Philip J. Scarpace,Kimberly T. Sibille,Laurence M. Solberg,Shinichi Someya,Connie Uphold,Stephanie E. Wohlgemuth,Samuel Shangwu Wu,Marco Pahor +34 more
TL;DR: An overview and discussion of specific health conditions, behavioral factors, and biological mechanisms that mark declining mobility and physical function and promising interventions to counter these effects are provided.
Journal ArticleDOI
Role of Mitochondria in the Mechanism(s) of Action of Metformin
TL;DR: Both historical and more recent findings are discussed on the central role played by the interaction between metformin and the mitochondria in its cellular mechanism of action.
Journal ArticleDOI
Metformin ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice.
Guo-Shun Xu,Hongying Wu,Junling Zhang,Deguan Li,Yueying Wang,Yingying Wang,Heng Zhang,Lu Lu,Chengcheng Li,Song Huang,Yonghua Xing,Daohong Zhou,Daohong Zhou,Aimin Meng +13 more
TL;DR: Findings demonstrate that resveratrol can protect HSCs from radiation at least in part via activation of Sirt1 and has the potential to be used as an effective therapeutic agent to ameliorate TBI-induced long-term BM injury.
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
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.
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.