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 Anti-diabetic Drugs Rosiglitazone and Metformin Stimulate AMP-activated Protein Kinase through Distinct Signaling Pathways
TL;DR: It is shown that incubation of muscle cells with the thiazolidinedione, rosiglitazone, leads to a dramatic increase in this ratio with the concomitant activation of AMPK, which raises the possibility that a number of the beneficial effects of the th Diazolidinediones could be mediated via activated AMPK.
Journal ArticleDOI
Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug
Hao Wu,Eduardo Esteve,Eduardo Esteve,Valentina Tremaroli,Muhammad Tanweer Khan,Robert Caesar,Louise Mannerås-Holm,Marcus Ståhlman,Lisa M. Olsson,Matteo Serino,Mercè Planas-Fèlix,Gemma Xifra,Gemma Xifra,Josep M. Mercader,David Torrents,David Torrents,Rémy Burcelin,Rémy Burcelin,Wifredo Ricart,Wifredo Ricart,Rosie Perkins,José Manuel Fernández-Real,José Manuel Fernández-Real,Fredrik Bäckhed,Fredrik Bäckhed,Fredrik Bäckhed +25 more
TL;DR: It is shown that metformin affected pathways with common biological functions in species from two different phyla, and many of the met formin-regulated genes in these species encoded metalloproteins or metal transporters, which provides support for the notion that altered gut microbiota mediates some of metformIn's antidiabetic effects.
Journal ArticleDOI
New drug targets for type 2 diabetes and the metabolic syndrome
TL;DR: Emerging knowledge of key pathogenic mechanisms, such as the impairment of glucose-stimulated insulin secretion and the role of 'lipotoxicity' as a probable cause of hepatic and muscle resistance to insulin's effects on glucose metabolism, has led to a host of new molecular drug targets.
Journal ArticleDOI
New Users of Metformin Are at Low Risk of Incident Cancer: A cohort study among people with type 2 diabetes
Gillian Libby,Louise A. Donnelly,Peter T. Donnan,Dario R. Alessi,Dario R. Alessi,Andrew D. Morris,Josie M M Evans +6 more
TL;DR: Results suggest that metformin use may be associated with a reduced risk of cancer in people with type 2 diabetes, and a randomized trial is needed to assess whether met formin is protective in a population at high risk for cancer.
Journal ArticleDOI
Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism
Paul B. Yu,Charles C. Hong,Charles C. Hong,Chetana Sachidanandan,Jodie L. Babitt,Donna Y. Deng,Stefan A Hoyng,Herbert Y. Lin,Kenneth D. Bloch,Randall T. Peterson,Randall T. Peterson +10 more
TL;DR: The first known small-molecule inhibitor of BMP signaling-dorsomorphin is described, which was identified in a screen for compounds that perturb dorsoventral axis formation in zebrafish and found that dorsomorphin selectively inhibits the BMP type I receptors ALK2, ALK3 and ALK6 and thus blocks BMP-mediated SMAD1/5/8 phosphorylation, target gene transcription and osteogenic differentiation.
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.
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.