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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Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription
Yaomin Chen,Kun Zhou,Ruishan Wang,Yun Liu,Young-Don Kwak,Tao Ma,Tao Ma,Robert C. Thompson,Yongbo Zhao,Layton H. Smith,Laura Gasparini,Zhijun Luo,Huaxi Xu,Francesca-Fang Liao +13 more
TL;DR: It is demonstrated that metformin, at doses that lead to activation of the AMP-activated protein kinase (AMPK), significantly increases the generation of both intracellular and extracellular Aβ species, suggesting a potentially harmful consequence of this widely prescribed antidiabetic drug when used as a monotherapy in elderly diabetic patients.
Journal ArticleDOI
Activation of AMP-Activated Protein Kinase by Metformin Improves Left Ventricular Function and Survival in Heart Failure
Susheel Gundewar,John W. Calvert,Saurabh Jha,Iris Toedt-Pingel,Sang Yong Ji,Denise Nunez,Arun Ramachandran,Mauricio Anaya-Cisneros,Rong Tian,David J. Lefer,David J. Lefer +10 more
TL;DR: It is demonstrated that metformin significantly improves left ventricular function and survival via activation of AMPK and its downstream mediators, eNOS and PGC-1&agr;, in a murine model of heart failure.
Journal ArticleDOI
AMP-activated protein kinase: the current landscape for drug development.
TL;DR: An overview of the physiological functions of AMPK is provided and the potential of this enzyme as a therapeutic target across diverse disease areas is discussed and Pharmacological activation of AM PK and the associated drug development challenges are assessed.
Journal ArticleDOI
Development of protein kinase activators: AMPK as a target in metabolic disorders and cancer.
Sarah Fogarty,D. G. Hardie +1 more
TL;DR: AMP-activated protein kinase, a cellular energy sensor activated by metabolic stresses that either inhibit ATP synthesis or accelerate ATP consumption, could have potential as novel therapeutics both for metabolic disorders and for cancer, which together constitute two of the most prevalent groups of diseases worldwide.
Journal ArticleDOI
AMPK inhibition in health and disease.
Benoit Viollet,Sandrine Horman,Jocelyne Leclerc,Louise Lantier,Marc Foretz,Marc Billaud,Shailendra Giri,Fabrizio Andreelli +7 more
TL;DR: This review discusses recent findings that support the role and function of AMPK inhibition under physiological and pathological states and discusses the importance of whole body energy homeostasis.
References
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Journal ArticleDOI
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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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.
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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.
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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.