Cited by 5,652Metabolism, Diabetes, and CancerPeroxisome Proliferator-Activated ReceptorsNatural Antidiabetic Agents Studies

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Role of AMP-activated protein kinase in mechanism of metformin action

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Zhou, Gaochao, Myers, Robert, Li, Ying, Chen, Yuli, Shen, Xiaolan, Fenyk-Melody, Judy, Wu, Margaret, Ventre, John, Doebber, Thomas, Fujii, Nobuharu, Musi, Nicolas, Hirshman, Michael F., Goodyear, Laurie J., Moller, David E.·2001·Journal of Clinical Investigation

DOI 10.1172/jci13505PMC PMC209533

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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.

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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: Zhou, Gaochao
Li, Ying
Shen, Xiaolan
Musi, Nicolas
Hirshman, Michael F.
Goodyear, Laurie J.
Moller, David E.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2001-10-15
Volume: 108
Issue: 8
Pages: 1167-1174
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci13505
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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Role of AMP-activated protein kinase in mechanism of metformin action

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