Cited by 479Metabolism, Diabetes, and CancerDiabetes Treatment and ManagementNatural Antidiabetic Agents Studies

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Molecular mechanism of action of metformin: old or new insights?

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Rena, Graham, Pearson, Ewan R., Sakamoto, Kei·2013·Diabetologia

DOI 10.1007/s00125-013-2991-0PMC PMC3737434

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Abstract

Metformin is the first-line drug treatment for type 2 diabetes. Globally, over 100 million patients are prescribed this drug annually. Metformin was discovered before the era of target-based drug discovery and its molecular mechanism of action remains an area of vigorous diabetes research. An improvement in our understanding of metformin's molecular targets is likely to enable target-based identification of second-generation drugs with similar properties, a development that has been impossible up to now. The notion that 5' AMP-activated protein kinase (AMPK) mediates the anti-hyperglycaemic action of metformin has recently been challenged by genetic loss-of-function studies, thrusting the AMPK-independent effects of the drug into the spotlight for the first time in more than a decade. Key AMPK-independent effects of the drug include the mitochondrial actions that have been known for many years and which are still thought to be the primary site of action of metformin. Coupled with recent evidence of AMPK-independent effects on the counter-regulatory hormone glucagon, new paradigms of AMPK-independent drug action are beginning to take shape. In this review we summarise the recent research developments on the molecular action of metformin.

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Additional file 8 of Glycemic control and neonatal outcomes in women with gestational diabetes mellitus treated using glyburide, metformin, or insulin: a pairwise and network meta-analysis
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Additional file 1 of Glycemic control and neonatal outcomes in women with gestational diabetes mellitus treated using glyburide, metformin, or insulin: a pairwise and network meta-analysis
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Additional file 12 of Glycemic control and neonatal outcomes in women with gestational diabetes mellitus treated using glyburide, metformin, or insulin: a pairwise and network meta-analysis
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Additional file 3 of Glycemic control and neonatal outcomes in women with gestational diabetes mellitus treated using glyburide, metformin, or insulin: a pairwise and network meta-analysis
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Additional file 13 of Glycemic control and neonatal outcomes in women with gestational diabetes mellitus treated using glyburide, metformin, or insulin: a pairwise and network meta-analysis
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Additional file 7 of Glycemic control and neonatal outcomes in women with gestational diabetes mellitus treated using glyburide, metformin, or insulin: a pairwise and network meta-analysis
Yu, D.-Q., Xu, G.-X., Teng, X.-Y., Xu, J.-W., Tang, L.-F., Feng, C., Rao, J.-P., Jin, M., & Wang, L.-Q. (2021) · Figshare · doi:10.6084/m9.figshare.16800532
Additional file 2 of Glycemic control and neonatal outcomes in women with gestational diabetes mellitus treated using glyburide, metformin, or insulin: a pairwise and network meta-analysis
Yu, D.-Q., Xu, G.-X., Teng, X.-Y., Xu, J.-W., Tang, L.-F., Feng, C., Rao, J.-P., Jin, M., & Wang, L.-Q. (2021) · Figshare · doi:10.6084/m9.figshare.16800517
Additional file 6 of Glycemic control and neonatal outcomes in women with gestational diabetes mellitus treated using glyburide, metformin, or insulin: a pairwise and network meta-analysis
Yu, D.-Q., Xu, G.-X., Teng, X.-Y., Xu, J.-W., Tang, L.-F., Feng, C., Rao, J.-P., Jin, M., & Wang, L.-Q. (2021) · Figshare · doi:10.6084/m9.figshare.16800529
Additional file 4 of Glycemic control and neonatal outcomes in women with gestational diabetes mellitus treated using glyburide, metformin, or insulin: a pairwise and network meta-analysis
Yu, D.-Q., Xu, G.-X., Teng, X.-Y., Xu, J.-W., Tang, L.-F., Feng, C., Rao, J.-P., Jin, M., & Wang, L.-Q. (2021) · Figshare · doi:10.6084/m9.figshare.16800523
Additional file 5 of Glycemic control and neonatal outcomes in women with gestational diabetes mellitus treated using glyburide, metformin, or insulin: a pairwise and network meta-analysis
Yu, D.-Q., Xu, G.-X., Teng, X.-Y., Xu, J.-W., Tang, L.-F., Feng, C., Rao, J.-P., Jin, M., & Wang, L.-Q. (2021) · Figshare · doi:10.6084/m9.figshare.16800526
Additional file 9 of Glycemic control and neonatal outcomes in women with gestational diabetes mellitus treated using glyburide, metformin, or insulin: a pairwise and network meta-analysis
Yu, D.-Q., Xu, G.-X., Teng, X.-Y., Xu, J.-W., Tang, L.-F., Feng, C., Rao, J.-P., Jin, M., & Wang, L.-Q. (2021) · Figshare · doi:10.6084/m9.figshare.16800538
Additional file 14 of Glycemic control and neonatal outcomes in women with gestational diabetes mellitus treated using glyburide, metformin, or insulin: a pairwise and network meta-analysis
Yu, D.-Q., Xu, G.-X., Teng, X.-Y., Xu, J.-W., Tang, L.-F., Feng, C., Rao, J.-P., Jin, M., & Wang, L.-Q. (2021) · Figshare · doi:10.6084/m9.figshare.16800508
Additional file 11 of Glycemic control and neonatal outcomes in women with gestational diabetes mellitus treated using glyburide, metformin, or insulin: a pairwise and network meta-analysis
Yu, D.-Q., Xu, G.-X., Teng, X.-Y., Xu, J.-W., Tang, L.-F., Feng, C., Rao, J.-P., Jin, M., & Wang, L.-Q. (2021) · Figshare · doi:10.6084/m9.figshare.16800499
Additional file 10 of Glycemic control and neonatal outcomes in women with gestational diabetes mellitus treated using glyburide, metformin, or insulin: a pairwise and network meta-analysis
Yu, D.-Q., Xu, G.-X., Teng, X.-Y., Xu, J.-W., Tang, L.-F., Feng, C., Rao, J.-P., Jin, M., & Wang, L.-Q. (2021) · Figshare · doi:10.6084/m9.figshare.16800496
Additional file 15 of Glycemic control and neonatal outcomes in women with gestational diabetes mellitus treated using glyburide, metformin, or insulin: a pairwise and network meta-analysis
Yu, D.-Q., Xu, G.-X., Teng, X.-Y., Xu, J.-W., Tang, L.-F., Feng, C., Rao, J.-P., Jin, M., & Wang, L.-Q. (2021) · Figshare · doi:10.6084/m9.figshare.16800511
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Authors: Rena, G., Pearson, E. R., & Sakamoto, K.
Affiliations: University of Dundee (GB)
École Polytechnique Fédérale de Lausanne (CH)
Corresponding author: Rena, Graham
Sakamoto, Kei
ORCID: Rena, Graham
Pearson, Ewan R.
Sakamoto, Kei
Venue: Diabetologia
Publisher: Springer Science and Business Media LLC
Published: 2013-07-09
Volume: 56
Issue: 9
Pages: 1898-1906
ISSN: 0012-186X (ISSN-L)
1432-0428
DOI: 10.1007/s00125-013-2991-0
PMC: PMC3737434
OpenAlex: W2025130292
Cited by: 479
References: 98
Citations by year: 2026: 9 · 2025: 22 · 2024: 20 · 2023: 33 · 2022: 22 · 2021: 52 · 2020: 33 · 2019: 38 · 2018: 58 · 2017: 51 · 2016: 37 · 2015: 52 · 2014: 43 · 2013: 8
FWCI: 4.39
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc
creativecommons.org/licenses/by-nc/2.0 (unspecified)
Locations: Diabetologia (publishedVersion, cc-by-nc)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
PubMed Central (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
reroDoc Digital Library (submittedVersion)
Discovery Research Portal (University of Dundee) (submittedVersion)
Funders: Medical Research Council (MR/K012924/1)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
Keywords: metformin, molecular mechanisms of action, type 2 diabetes, AMPK, glucagon, therapeutic target
MeSH terms: Diabetes Mellitus, Type 2, Energy Metabolism, Gluconeogenesis, Humans, Metformin, Models, Biological, AMP-Activated Protein Kinases

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Molecular mechanism of action of metformin: old or new insights?

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