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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Cross-Talk between PPARgamma and Insulin Signaling and Modulation of Insulin Sensitivity.
TL;DR: PPARγ activation in type 2 diabetic patients results in a marked improvement in insulin and glucose parameters, resulting from an improvement of whole-body insulin sensitivity, and is associated with beneficial effects on expression and secretion of a whole range of cytokines.
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The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy.
TL;DR: How MAPK-AMPK signalings interplay with each other in cancer biology is summarized, its implications in clinic cancer treatment with MAPK inhibition and AMPK modulators are discussed, and the exploitation of combinatory therapies targeting both MAPK and AM PK as a novel therapeutic intervention is discussed.
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Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of anti-cancer agents
Pamela J. Goodwin,Vuk Stambolic,Julie Lemieux,Bingshu E. Chen,Wendy R. Parulekar,Karen A. Gelmon,Dawn L. Hershman,Timothy J. Hobday,Jennifer A. Ligibel,Ingrid A. Mayer,Kathleen I. Pritchard,Timothy J. Whelan,Priya Rastogi,Lois E. Shepherd +13 more
TL;DR: The rationale for a modified approach to evaluation is reviewed and the key steps that will optimize development of this agent in breast cancer are outlined, including discussion of a Phase III adjuvant trial (NCIC MA.32) that has recently been initiated.
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Leptin regulates tau phosphorylation and amyloid through AMPK in neuronal cells.
TL;DR: The data implicate that AMPK is a key regulator of both AD-related pathways, and direct stimulation of AMPK with the cell-permeable activator, 5-aminoimidazole-4-carboxyamide ribonucleoside, replicated leptin's effects and conversely, Compound C, an inhibitor of AM PK, blocked leptin's action.
Journal ArticleDOI
Metformin reduces intracellular reactive oxygen species levels by upregulating expression of the antioxidant thioredoxin via the AMPK-FOXO3 pathway.
Xinguo Hou,Jun Song,Jun Song,Jun Song,Xiao-Nan Li,Xiao-Nan Li,Xiao-Nan Li,Lin Zhang,Lin Zhang,Xingli Wang,Xingli Wang,Li Chen,Ying H. Shen,Ying H. Shen +13 more
TL;DR: Results suggest that metformin reduces ROS levels by inducing Trx expression through activation of the AMPK-FOXO3 pathway.
References
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