Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase
Open accessAbstract
Metformin is considered to be one of the most effective therapeutics for treating type 2 diabetes because it specifically reduces hepatic gluconeogenesis without increasing insulin secretion, inducing weight gain or posing a risk of hypoglycaemia. For over half a century, this agent has been prescribed to patients with type 2 diabetes worldwide, yet the underlying mechanism by which metformin inhibits hepatic gluconeogenesis remains unknown. Here we show that metformin non-competitively inhibits the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase, resulting in an altered hepatocellular redox state, reduced conversion of lactate and glycerol to glucose, and decreased hepatic gluconeogenesis. Acute and chronic low-dose metformin treatment effectively reduced endogenous glucose production, while increasing cytosolic redox and decreasing mitochondrial redox states. Antisense oligonucleotide knockdown of hepatic mitochondrial glycerophosphate dehydrogenase in rats resulted in a phenotype akin to chronic metformin treatment, and abrogated metformin-mediated increases in cytosolic redox state, decreases in plasma glucose concentrations, and inhibition of endogenous glucose production. These findings were replicated in whole-body mitochondrial glycerophosphate dehydrogenase knockout mice. These results have significant implications for understanding the mechanism of metformin's blood glucose lowering effects and provide a new therapeutic target for type 2 diabetes.
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Metformin's antihyperglycemic action is attributed to suppression of hepatic gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase, modifying hepatocellular redox state to reduce glucose formation from lactate and glycerol.
“Metformin’s antihyperglycemic role is attributed to its action on glucose metabolism, specifically as a suppressor of hepatic gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase, thereby modifying the hepatocellular redox state to reduce glucose formation from lactate and glycerol”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Madiraju et al. 2014
Decreased hepatic gluconeogenesis is associated with metformin's direct inhibition of mitochondrial glycerophosphate dehydrogenase, which modulates cytosolic redox state.
“Decreased hepatic gluconeogenesis is also demonstrated to be associated with metformin’s direct inhibition of mitochondrial glycerophosphate dehydrogenase (mGPDH)- a flavin-linked respiratory chain-linked dehydrogenase, which in turn modulates cytosolic redox state”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Madiraju et al. 2014
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 [212]
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Self-citation
- Authors
- Madiraju, A. K., Erion, D. M., Rahimi, Y., Zhang, X.-M., Braddock, D. T., Albright, R. A., Prigaro, B. J., Wood, J. L., Bhanot, S., MacDonald, M. J., Jurczak, M. J., Camporez, J.-P., Lee, H.-Y., Cline, G. W., Samuel, V. T., Kibbey, R. G., & Shulman, G. I.
- Affiliations
- Howard Hughes Medical Institute (US)
- Yale University (US)
- Colorado State University (US)
- Baylor University (US)
- Ionis Pharmaceuticals (United States) (US)
- University of Wisconsin–Madison (US)
- University of Copenhagen (DK)
- Corresponding author
- Shulman, Gerald I.
- ORCID
- Venue
- Nature
- Published
- 2014-05-21
- Volume
- 510
- Issue
- 7506
- Pages
- 542-546
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4074244
- OpenAlex
- W2047516613
- Cited by
- 1,284
- References
- 33
- Citations by year
- 2026: 60 · 2025: 79 · 2024: 90 · 2023: 111 · 2022: 110 · 2021: 116 · 2020: 111 · 2019: 122 · 2018: 118 · 2017: 118 · 2016: 119 · 2015: 100 · 2014: 27 · 2012: 1
- FWCI
- 49.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (UL1TR000142)
- National Institute of Diabetes and Digestive and Kidney Diseases (K01DK099402, P30DK45735, R01-DK40936, R01DK040936, U24DK059635, R01DK028348, R01 DK-28348, R01DK092606, R24DK085638, P30DK034989, P30DK045735)
- National Center for Advancing Translational Sciences
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- metformin, hepatic gluconeogenesis, type 2 diabetes, redox state, biguanides, endogenous glucose production, antisense oligonucleotide knockdown, mitochondrial redox state, cytosolic redox state
- MeSH terms
- Insulin Secretion, Animals, Blood Glucose, Cells, Cultured, Diabetes Mellitus, Type 2, Gluconeogenesis, Glycerolphosphate Dehydrogenase, Humans, Hypoglycemic Agents, Insulin, Liver, Male, Metformin, Mitochondria, Oxidation-Reduction, Rats, Sprague-Dawley, Mice, Knockout, Lactic Acid, Rats
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