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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Antidiabetic activities of triterpenoids isolated from bitter melon associated with activation of the AMPK pathway.
Minjia Tan,Ji-Ming Ye,Nigel Turner,Cordula Hohnen-Behrens,Chang-Qiang Ke,Chunping Tang,Tong Chen,Hans-Christoph Weiss,Ernst-Rudolf Gesing,Alex Rowland,David E. James,Yang Ye +11 more
TL;DR: Findings indicate that cucurbitane triterpenoids, the characteristic constituents of M. charantia, may provide leads as a class of therapeutics for diabetes and obesity.
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Upstream of the mammalian target of rapamycin: do all roads pass through mTOR?
TL;DR: This review highlights recent advances in the mTOR signaling field that relate to how the two mTOR complexes are regulated, and discusses stress conditions linked to the m TOR signaling network that have not been extensively covered in other reviews.
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Metformin prevents tobacco carcinogen--induced lung tumorigenesis.
Regan M. Memmott,Jose Mercado,Colleen R. Maier,Shigeru Kawabata,Stephen D. Fox,Phillip A. Dennis +5 more
TL;DR: It is shown that metformin prevents tobacco carcinogen–induced lung tumorigenesis and support clinical testing of met formin as a chemopreventive agent.
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Dietary Anthocyanin-Rich Bilberry Extract Ameliorates Hyperglycemia and Insulin Sensitivity via Activation of AMP-Activated Protein Kinase in Diabetic Mice
TL;DR: It is found that dietary BBE ameliorates hyperglycemia and insulin sensitivity in type 2 diabetic mice via activation of AMP-activated protein kinase (AMPK), which provides a biochemical basis for the use of bilberry fruits and has important implications for the prevention and treatment of type 2 diabetes.
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Conditional Disruption of the Peroxisome Proliferator-Activated Receptor γ Gene in Mice Results in Lowered Expression of ABCA1, ABCG1, and apoE in Macrophages and Reduced Cholesterol Efflux
Taro E. Akiyama,Shuichi Sakai,Gilles Lambert,Christopher J. Nicol,Kimihiko Matsusue,Satish Pimprale,Ying-Hue Lee,Mercedes Ricote,Christopher K. Glass,H. Bryan Brewer,Frank J. Gonzalez +10 more
TL;DR: Data indicate that PPARγ plays a critical role in the regulation of cholesterol homeostasis by controlling the expression of a network of genes that mediate cholesterol efflux from cells and its transport in plasma.
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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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.