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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Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk
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AMP activated protein kinase: a next generation target for total metabolic control.
TL;DR: The data suggest that AMPK may be a key player in the development of new treatments for obesity, Type 2 diabetes and the metabolic syndrome, with insight into the role of AMPK as a probable target for treatment of metabolic syndrome.
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Aβ-induced formation of autophagosomes is mediated by RAGE-CaMKKβ-AMPK signaling.
TL;DR: The results implicate the regulation of the Aβ-induced formation of AVs by the RAGE-calcium-CaMKKβ-AMPK pathway and suggest that modulation of autophagosome formation and the interaction between Aβ and RAGE are beneficial in the treatment and prevention of Alzheimer's disease.
Journal ArticleDOI
Metformin selectively targets redox control of complex I energy transduction.
Amy R. Cameron,Lisa Logie,Kashyap A. Patel,Stefan Erhardt,Sandra Bacon,Paul Middleton,Jean Harthill,Calum Forteath,Josh T. Coats,Calum Kerr,Heather Curry,Derek Stewart,Kei Sakamoto,Peter Repiščák,Martin J. Paterson,Ilmo E. Hassinen,Gordon J. McDougall,Graham Rena +17 more
TL;DR: The results suggest that metformin suppresses energy transduction by selectively inducing a state in complex I where redox and proton transfer domains are no longer efficiently coupled.
Journal ArticleDOI
Direct inhibition of hexokinase activity by metformin at least partially impairs glucose metabolism and tumor growth in experimental breast cancer
Cecilia Marini,Barbara Salani,Michela Massollo,Adriana Amaro,Alessia Isabella Esposito,Anna Maria Orengo,Selene Capitanio,Laura Emionite,Mattia Riondato,Gianluca Bottoni,Cinzia Massara,Simona Boccardo,Marina Fabbi,Cristina Campi,Silvia Ravera,Giovanna Angelini,Silvia Morbelli,Michele Cilli,Renzo Cordera,Mauro Truini,Davide Maggi,Ulrich Pfeffer,Gianmario Sambuceti +22 more
TL;DR: It is demonstrated that metformin directly inhibits the enzymatic function of hexokinase (HK) I and II in a cell line of triple-negative breast cancer (MDA-MB-231), and results strongly suggest that HK inhibition contributes to met formin therapeutic and preventive potential in breast cancer.
References
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