The DOI matches its Crossref record; 54 of the 55 references it cites were found in a registry or an index.
Metformin Suppresses Diabetes-Accelerated Atherosclerosis via the Inhibition of Drp1-Mediated Mitochondrial Fission
Open accessAbstract
Metformin is a widely used antidiabetic drug that exerts cardiovascular protective effects in patients with diabetes. How metformin protects against diabetes-related cardiovascular diseases remains poorly understood. Here, we show that metformin abated the progression of diabetes-accelerated atherosclerosis by inhibiting mitochondrial fission in endothelial cells. Metformin treatments markedly reduced mitochondrial fragmentation, mitigated mitochondrial-derived superoxide release, improved endothelial-dependent vasodilation, inhibited vascular inflammation, and suppressed atherosclerotic lesions in streptozotocin (STZ)-induced diabetic ApoE−/− mice. In high glucose–exposed endothelial cells, metformin treatment and adenoviral overexpression of constitutively active AMPK downregulated mitochondrial superoxide, lowered levels of dynamin-related protein (Drp1) and its translocation into mitochondria, and prevented mitochondrial fragmentation. In contrast, AMPK-α2 deficiency abolished the effects of metformin on Drp1 expression, oxidative stress, and atherosclerosis in diabetic ApoE−/−/AMPK-α2−/− mice, indicating that metformin exerts an antiatherosclerotic action in vivo via the AMPK-mediated blockage of Drp1-mediated mitochondrial fission. Consistently, mitochondrial division inhibitor 1, a potent and selective Drp1 inhibitor, reduced mitochondrial fragmentation, attenuated oxidative stress, ameliorated endothelial dysfunction, inhibited inflammation, and suppressed atherosclerosis in diabetic mice. These findings show that metformin attenuated the development of atherosclerosis by reducing Drp1-mediated mitochondrial fission in an AMPK-dependent manner. Suppression of mitochondrial fission may be a therapeutic approach for treating macrovascular complications in patients with diabetes.
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“In diabetes, mitochondrial dysfunction induces and aggravates macrovascular complications [218,219].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [218]
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“Wang et al., reported that treatment of streptozotocin (STZ)-induced diabetic mice with metformin (300 mg/kg/day) in their drinking water for 4 weeks suppressed mitochondrial fission through inhibition of dynamin-related protein (Drp1) via an AMPK-dependent process and enhanced mitochondrial fusion (186).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [186]
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2 retracted
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RetractedHypochlorous acid via peroxynitrite activates protein kinase Cθ and insulin resistance in adipocytes
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RetractedReport of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus
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Biochemistry and molecular cell biology of diabetic complications
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Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus
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Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to Mitophagy
Egan, D. F., Shackelford, D. B., Mihaylova, M. M., Gelino, S., Kohnz, R. A., Mair, W., Vasquez, D. S., Joshi, A., Gwinn, D. M., Taylor, R., et al. (2011) · Science · doi:10.1126/science.1196371 · Cited by 2,600
Mitochondrial fusion and fission in cell life and death
Westermann, B. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3013 · Cited by 2,002 · cited 1×
“Recent work has highlighted the importance of mitochondrial dynamics, particularly mitochondrial fusion and fission, in mitochondrial homeostasis (6).”
BackgroundYu, T., Robotham, J. L., & Yoon, Y. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0511154103 · Cited by 1,246
AMP-activated protein kinase mediates mitochondrial fission in response to energy stress
Toyama, E. Q., Herzig, S., Courchet, J., Lewis, T. L., Losón, O. C., Hellberg, K., Young, N. P., Chen, H., Polleux, F., Chan, D. C., et al. (2016) · Science · doi:10.1126/science.aab4138 · Cited by 1,085
Redox Homeostasis and Mitochondrial Dynamics
Willems, P. H. G. M., Rossignol, R., Dieteren, C. E. J., Murphy, M. P., & Koopman, W. J. H. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.06.006 · Cited by 876
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Forrester, S. J., Kikuchi, D. S., Hernandes, M. S., Xu, Q., & Griendling, K. K. (2018) · Circulation Research · doi:10.1161/circresaha.117.311401 · Cited by 2,081
Mitochondrial fusion and fission: The fine‐tune balance for cellular homeostasis
Adebayo, M., Singh, S., Singh, A. P., & Dasgupta, S. (2021) · The FASEB Journal · doi:10.1096/fj.202100067r · Cited by 733
Yuan, T., Yang, T., Chen, H., Fu, D., Hu, Y., Wang, J., Yuan, Q., Yu, H., Xu, W., & Xie, X. (2018) · Redox Biology · doi:10.1016/j.redox.2018.09.025 · Cited by 766
Mitochondrial dynamics in type 2 diabetes: Pathophysiological implications
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AMPK as a Therapeutic Target for Treating Metabolic Diseases
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Metadata
- Authors
- Wang, Q., Zhang, M., Torres, G., Wu, S., Ouyang, C., Xie, Z., & Zou, M.-H.
- Affiliations
- Georgia State University (US)
- University of Oklahoma Health Sciences Center (US)
- Corresponding author
- Xie, Zhonglin
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2016-10-13
- Volume
- 66
- Issue
- 1
- Pages
- 193-205
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC5204316
- OpenAlex
- W2531934030
- Cited by
- 370
- References
- 55
- Citations by year
- 2026: 21 · 2025: 34 · 2024: 30 · 2023: 38 · 2022: 53 · 2021: 56 · 2020: 43 · 2019: 40 · 2018: 35 · 2017: 18 · 2016: 1
- FWCI
- 16.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Diabetes (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung and Blood Institute (HL-128014, HL-132500, HL-079584, HL-080499, HL-089920, HL-110488)
- National Institute on Aging (AG-047776)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- metformin, mitochondrial fission, Drp1, AMPK, endothelial cells, mitochondrial superoxide, oxidative stress, endothelial dysfunction, vascular inflammation, ApoE-deficient mice, streptozotocin-induced diabetes, macrovascular complications
- MeSH terms
- Animals, Apolipoproteins E, Diabetes Mellitus, Experimental, Glucose, Humans, Male, Metformin, Superoxides, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, Dynamins, Atherosclerosis, Mice, Human Umbilical Vein Endothelial Cells, Mitochondrial Dynamics
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