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Role of AMP-activated protein kinase in mechanism of metformin action
Open accessAbstract
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.
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“However, being a nonspecific inhibitor of oxidative phosphorylation [674, 675]”
From Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) 1 (2021) · cites this paper as [675]
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“AMPK is activated through metabolic stress and acts as a cellular regulator of lipid and glucose metabolism (102, 103).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [102]
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“It is also activated by the antidiabetic drugs metformin and rosiglitazone (21-23), and by the adipocyte-derived hormones leptin and adiponectin (24, 25).”
From CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations (2004) · cites this paper as [21]
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“it has even been shown to stimulate autophagy by an AMP-independent mechanism [675, 678]”
From Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) 1 (2021) · cites this paper as [675]
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Metadata
- Authors
- Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., Musi, N., Hirshman, M. F., Goodyear, L. J., & Moller, D. E.
- Affiliations
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Corresponding author
- Zhou, Gaochao
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2001-10-15
- Volume
- 108
- Issue
- 8
- Pages
- 1167-1174
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC209533
- OpenAlex
- W2138226825
- Cited by
- 5,652
- References
- 36
- Citations by year
- 2026: 149 · 2025: 182 · 2024: 198 · 2023: 234 · 2022: 270 · 2021: 312 · 2020: 272 · 2019: 310 · 2018: 306 · 2017: 304 · 2016: 296 · 2015: 331 · 2014: 307 · 2013: 295 · 2012: 291
- FWCI
- 26.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
- Keywords
- metformin, AMPK, type 2 diabetes, hepatic glucose production, acetyl-CoA carboxylase, SREBP1, lipogenesis, fatty acid oxidation, glucose uptake, skeletal muscle, hepatic lipid metabolism, AMPK inhibitors
- MeSH terms
- Aminoimidazole Carboxamide, Animals, Diabetes Mellitus, Type 2, DNA-Binding Proteins, Enzyme Activation, Fatty Acids, Glucose, Humans, Hypoglycemic Agents, Male, Metformin, Multienzyme Complexes, Protein Kinases, Pyrazoles, Pyrimidines, Ribonucleotides, RNA, Messenger, Transcription Factors, Gene Expression, Rats, Sprague-Dawley, Protein Serine-Threonine Kinases, Muscle, Skeletal, CCAAT-Enhancer-Binding Proteins, Hepatocytes, Protein Kinase Inhibitors, Rats, Sterol Regulatory Element Binding Protein 1, AMP-Activated Protein Kinases, In Vitro Techniques
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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