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

The DOI matches its Crossref record; 99 of the 99 references it cites were found in a registry or an index.

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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Fig. 1 (a, b) Schematic diagram of the anti-hyperglycaemic action of metformin on the liver cell. Part (b) shows a simplified version of (a). Metformin is transported into hepatocytes mainly via OCT1, resulting in an inhibition of the mitochondrial respiratory chain (complex I) through a currently unknown mechanism(s). The resulting deficit in energy production is balanced by reducing the consumption of energy in the cell, particularly reduced gluconeogenesis in the liver. This is mediated in two main ways. First, a decrease in ATP and a concomitant increase in AMP concentration occur, which is thought to contribute to the inhibition of gluconeogenesis directly (because of the energy/ATP deficit). Second, increased AMP levels function as a key signalling mediator that has been proposed to (1) allosterically inhibit cAMP–PKA signalling through suppression of adenylate cyclase, (2) allosterically inhibit FBPase, a key gluconeogenic enzyme, and (3) activates AMPK. This leads to inhibition of gluconeogenesis (1 and 2) and lipid/cholesterol synthesis (3), which may contribute to the longer term metabolic and therapeutic responses to the drug. FBPase; fructose-1,6-bisphosphatase
Fig. 1 (a, b) Schematic diagram of the anti-hyperglycaemic action of metformin on the liver cell. Part (b) shows a simplified version of (a). Metformin is transported into hepatocytes mainly via OCT1, resulting in an inhibition of the mitochondrial respiratory chain (complex I) through a currently unknown mechanism(s). The resulting deficit in energy production is balanced by reducing the consumption of energy in the cell, particularly reduced gluconeogenesis in the liver. This is mediated in two main ways. First, a decrease in ATP and a concomitant increase in AMP concentration occur, which is thought to contribute to the inhibition of gluconeogenesis directly (because of the energy/ATP deficit). Second, increased AMP levels function as a key signalling mediator that has been proposed to (1) allosterically inhibit cAMP–PKA signalling through suppression of adenylate cyclase, (2) allosterically inhibit FBPase, a key gluconeogenic enzyme, and (3) activates AMPK. This leads to inhibition of gluconeogenesis (1 and 2) and lipid/cholesterol synthesis (3), which may contribute to the longer term metabolic and therapeutic responses to the drug. FBPase; fructose-1,6-bisphosphataseCC BY-NC · PubMed Central

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Research works printed but not linked: 2

  1. Ray RK, Kauffman GB (1999) Metal and non-metal biguanide complexes. New Age International Publishers, New Delhi
  2. Kazda CM, Garhyan P, Kelly RP et al (2012) 12-week treatment with glucagon receptor antagonist LY2409021 significantly lowers HbA1c and is well tolerated in patients with type 2 diabetes mellitus. Diabetologia 55(Suppl 1):S51, Abstr. 112

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Metadata

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
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
Licence
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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