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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LKB1 is the upstream kinase in the AMP-activated protein kinase cascade
Angela Woods,Stephen R. Johnstone,Kristina Dickerson,Fiona C. Leiper,Lee G.D. Fryer,Dietbert Neumann,Uwe Schlattner,Theo Wallimann,Marian Carlson,David Carling +9 more
TL;DR: The results identify a link between two protein kinases, previously thought to lie in unrelated, distinct pathways, that are associated with human diseases.
Journal ArticleDOI
A Placebo-Controlled Trial of Pioglitazone in Subjects with Nonalcoholic Steatohepatitis
Renata Belfort,Stephen A. Harrison,Kenneth A. Brown,Celia Darland,Joan Finch,Jean Hardies,Bogdan Balas,Amalia Gastaldelli,Amalia Gastaldelli,Fermin O. Tio,Joseph P. Pulcini,Rachele Berria,Jennie Z. Ma,Sunil Dwivedi,Russell Havranek,Chris Fincke,Ralph A. DeFronzo,George A. Bannayan,Steven Schenker,Kenneth Cusi +19 more
TL;DR: In this proof-of-concept study, the administration of pioglitazone led to metabolic and histologic improvement in subjects with nonalcoholic steatohepatitis and larger controlled trials of longer duration are warranted to assess the long-term clinical benefit.
Journal ArticleDOI
Complexes between the LKB1 tumor suppressor, STRADα/β and MO25α/β are upstream kinases in the AMP-activated protein kinase cascade
Simon A. Hawley,Jérôme Boudeau,Jennifer L Reid,Kirsty J. Mustard,Lina Udd,Tomi P. Mäkelä,Dario R. Alessi,D. Grahame Hardie +7 more
TL;DR: These results provide the first description of a physiological substrate for the LKB1 tumor suppressor and suggest that it functions as an upstream regulator of AMPK.
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The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress
Reuben J. Shaw,Monica Kosmatka,Nabeel Bardeesy,Rebecca L. Hurley,Lee A. Witters,Ronald A. DePinho,Lewis C. Cantley +6 more
TL;DR: In this article, the LKB1 serine/threonine kinase, the gene inactivated in the Peutz-Jeghers familial cancer syndrome, is the dominant regulator of AMPK activation in several mammalian cell types.
Journal ArticleDOI
AMPK in Health and Disease
TL;DR: This review looks at how AMPK integrates stress responses such as exercise as well as nutrient and hormonal signals to control food intake, energy expenditure, and substrate utilization at the whole body level and the possible role of AMPK in multiple common diseases.
References
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Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain
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Mohamad Y. El-Mir,Véronique Nogueira,Eric Fontaine,Nicole Avéret,Michel Rigoulet,Xavier Leverve +5 more
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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.