New mechanisms of metformin action: Focusing on mitochondria and the gut
Open accessAbstract
The most well-known mechanism of metformin action, one of the most commonly prescribed antidiabetic drugs, is adenosine monophosphate-activated protein kinase activation; however, recent investigations have shown that adenosine monophosphate-activated protein kinase-independent pathways can explain some of metformin's beneficial metabolic effects as well as undesirable side-effects. Such novel pathways include induction of mitochondrial stress, inhibition of mitochondrial shuttles, alteration of intestinal microbiota, suppression of glucagon signaling, activation of autophagy, attenuation of inflammasome activation, induction of incretin receptors and reduction of terminal endoplasmic reticulum stress. Together, these studies have broadened our understanding of the mechanisms of antidiabetic agents as well as the pathogenic mechanism of diabetes itself. The results of such investigations might help to identify new target molecules and pathways for treatment of diabetes and metabolic syndrome, and could also have broad implications in diseases other than diabetes. Accordingly, new antidiabetic drugs with better efficacy and fewer adverse effects will likely result from these studies.
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Metformin acts through the mitochondrial electron transport chain (ETC) by inhibiting complex I.
“Given the evidence that metformin acts through the mitochondrial electron transport chain (ETC) by inhibiting complex I(46, 210–212) (Figure 8)”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [211]
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Romero, R., Erez, O., Hüttemann, M., Maymon, E., Panaitescu, B., Conde-Agudelo, A., Pacora, P., Yoon, B. H., & Grossman, L. I. (2017) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2017.06.003 · Cited by 253 · see citing works
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Rivera Vargas, T., Cai, Z., Shen, Y., Dosset, M., Benoit-Lizon, I., Martin, T., Roussey, A., Flavell, R. A., Ghiringhelli, F., & Apetoh, L. (2017) · Nature Communications · doi:10.1038/s41467-017-00468-w · Cited by 88 · see citing works
- Authors
- Hur, K. Y., & Lee, M.
- Affiliations
- Samsung Medical Center (KR)
- Corresponding author
- Lee, Myung‐Shik
- Venue
- Journal of Diabetes Investigation
- Publisher
- Wiley
- Published
- 2015-02-28
- Volume
- 6
- Issue
- 6
- Pages
- 600-609
- ISSN
- 2040-1116 (ISSN-L)
- 2040-1124
- PMC
- PMC4627534
- OpenAlex
- W2155185645
- Cited by
- 161
- References
- 97
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 5 · 2023: 7 · 2022: 15 · 2021: 14 · 2020: 17 · 2019: 19 · 2018: 27 · 2017: 19 · 2016: 18 · 2015: 2
- FWCI
- 2.13
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Diabetes Investigation (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Funders
- National Research Foundation of Korea (K21004000003‐10A0500‐00310)
- Ulsan National Institute of Science and Technology (2014M3A9D8034459)
- 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, mitochondrial stress, gut microbiota, glucagon signaling, autophagy, inflammasome activation, incretin receptors, endoplasmic reticulum stress, diabetes mellitus, metabolic syndrome, antidiabetic drugs
About these checks
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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