Cited by 263Mitochondrial Function and PathologyCell death mechanisms and regulationMetabolism, Diabetes, and Cancer

The DOI matches its Crossref record; 40 of the 40 references it cites were found in a registry or an index.

Metformin Prevents High-Glucose–Induced Endothelial Cell Death Through a Mitochondrial Permeability Transition-Dependent Process

Detaille, Dominique, Guigas, Bruno, Chauvin, Christiane, Batandier, Cécile, Fontaine, Eric, Wiernsperger, Nicolas, Leverve, Xavier·2005·Diabetes

DOI 10.2337/diabetes.54.7.2179

Open this paper in CoChat — free account

Abstract

Hyperglycemia-induced oxidative stress is detrimental for endothelial cells, contributing to the vascular complications of diabetes. The mitochondrial permeability transition pore (PTP) is an oxidative stress–sensitive channel involved in cell death; therefore, we have examined its potential role in endothelial cells exposed to oxidative stress or high glucose level. Metformin, an antihyperglycemic agent used in type 2 diabetes, was also investigated because it inhibits PTP opening in transformed cell lines. Cyclosporin A (CsA), the reference PTP inhibitor, and a therapeutic dose of metformin (100 μmol/l) led to PTP inhibition in permeabilized human microvascular endothelial cells (HMEC-1). Furthermore, exposure of intact HMEC-1 or primary endothelial cells from either human umbilical vein or bovine aorta to the oxidizing agent tert-butylhydroperoxide or to 30 mmol/l glucose triggered PTP opening, cytochrome c decompartmentalization, and cell death. CsA or metformin prevented all of these effects. The antioxidant N-acetyl-l-cysteine also prevented hyperglycemia-induced apoptosis. We conclude that 1) elevated glucose concentration leads to an oxidative stress that favors PTP opening and subsequent cell death in several endothelial cell types and 2) metformin prevents this PTP opening–related cell death. We propose that metformin improves diabetes-associated vascular disease both by lowering blood glucose and by its effect on PTP regulation.

Integrity signals

Registry

Crossref · 10.2337/diabetes.54.7.2179

Cites

40 of 40 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)
(1998) · The Lancet · doi:10.1016/s0140-6736(98)07019-6 · Cited by 20,023
Biochemistry and molecular cell biology of diabetic complications
Brownlee, M. (2001) · Nature · doi:10.1038/414813a · Cited by 9,107
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)
(1998) · The Lancet · doi:10.1016/s0140-6736(98)07037-8 · Cited by 8,247
Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action
Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13505 · Cited by 5,652
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group.
(1998) · PubMed · Cited by 4,290
Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage
Nishikawa, T., Edelstein, D., Du, X. L., Yamagishi, S.-I., Matsumura, T., Kaneda, Y., Yorek, M. A., Beebe, D., Oates, P. J., Hammes, H.-P., et al. (2000) · Nature · doi:10.1038/35008121 · Cited by 4,277
Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain
OWEN, M. R., DORAN, E., & HALESTRAP, A. P. (2000) · Biochemical Journal · doi:10.1042/bj3480607 · Cited by 2,157
Mitochondria as the central control point of apoptosis
Desagher, S., & Martinou, J. (2000) · Trends in Cell Biology · doi:10.1016/s0962-8924(00)01803-1 · Cited by 1,935
Metformin
Bailey, C. J., & Turner, R. C. (1996) · New England Journal of Medicine · doi:10.1056/nejm199602293340906 · Cited by 1,726
Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I
El-Mir, M.-Y., Nogueira, V., Fontaine, E., Avéret, N., Rigoulet, M., & Leverve, X. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.1.223 · Cited by 1,399
Self-citation

Show all 40 references

Sorted by citations

Items 101–200 of 262

Endoplasmic reticulum stress is involved in myocardial apoptosis of streptozocin-induced diabetic rats
Li, Z., Zhang, T., Dai, H., Liu, G., Wang, H., Sun, Y., Zhang, Y. L., & Ge, Z. (2007) · Journal of Endocrinology · doi:10.1677/joe-07-0230 · Cited by 59
“…cardiomyocytes and endothelial cells have been observed in the heart of patient with diabetes and in STZ-induced diabetic rat (Cai & Kang 2003, Adeghate 2004), and exposing to high glucose also induced the same two types of cells to death in vitro (Detaille et al. 2005, Malhotra et al. 2005).”
Background
Retracted
Changes in Fat Mitochondrial DNA and Function in Subjects Randomized to Abacavir-Lamivudine or Tenofovir DF–Emtricitabine With Atazanavir-Ritonavir or Efavirenz: AIDS Clinical Trials Group Study A5224s, Substudy of A5202
McComsey, G. A., Daar, E. S., O’Riordan, M., Collier, A. C., Kosmiski, L. A., Santana, J., Fichtenbaum, C. J., Fink, H., Sax, P. E., Libutti, D. E., et al. (2012) · The Journal of Infectious Diseases · doi:10.1093/infdis/jis720 · Cited by 58
“[15], ethambutol [16], or linezolid [17], or in those exposed to excessive alcohol, a known mitochondrial toxin.”
Background
Atherosclerosis in diabetes and insulin resistance
Reusch, J. E. B., & Draznin, B. (2006) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2006.00620.x · Cited by 58
Effect of Transient and Permanent Permeability Transition Pore Opening on NAD(P)H Localization in Intact Cells
Dumas, J., Argaud, L., Cottet‐Rousselle, C., Vial, G., Dahout-Gonzalez, C., Détaille, D., Leverve, X. M., & Fontaine, E. M. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m900926200 · Cited by 61
Self-citation
AMP kinase activation improves angiogenesis in pulmonary artery endothelial cells with in utero pulmonary hypertension
Teng, R., Du, J., Afolayan, A. J., Eis, A., Shi, Y., & Konduri, G. G. (2012) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00200.2012 · Cited by 54
“Metformin prevents endothelial cell apoptosis via mild but specific inhibition of the mitochondrial respiratory chain complex I with decreased ROS formation (2, 9).”
Background
The regulatory effects of metformin on the [SNAIL/miR-34]:[ZEB/miR-200] system in the epithelial-mesenchymal transition(EMT) for colorectal cancer(CRC)
Wang, Y., Wu, Z., & Hu, L. (2018) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2018.07.006 · Cited by 57
Neferine prevented hyperglycemia-induced endothelial cell apoptosis through suppressing ROS/Akt/NF-κB signal
Guan, G., Han, H., Yang, Y., Jin, Y., Wang, X., & Liu, X.-M. (2014) · Endocrine · doi:10.1007/s12020-014-0186-1 · Cited by 55
Metformin influences cardiomyocyte cell death by pathways that are dependent and independent of caspase-3
An, D., Kewalramani, G., Chan, J. K. Y., Qi, D., Ghosh, S., Pulinilkunnil, T., Abrahani, A., Innis, S. M., & Rodrigues, B. B. (2006) · Diabetologia · doi:10.1007/s00125-006-0338-9 · Cited by 54
“In addition to its effect on substrate metabolism, metformin is also known to regulate endothelial cell death [20].”
Background
Ubiquinone Analogs: A Mitochondrial Permeability Transition Pore-Dependent Pathway to Selective Cell Death
Devun, F., Walter, L., Bellière, J., Cottet‐Rousselle, C., Leverve, X. M., & Fontaine, E. M. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011792 · Cited by 54
“The inhibition of respiratory chain complex 1 inhibits PTP opening in U937, KB and HMEC cells [31,32,33], whereas it does not have this effect in rat liver or rat heart mitochondria [6].”
Self-citation
Heme Oxygenase: A Target Gene for Anti-Diabetic and Obesity
Abraham, N. G., Tsenovoy, P. L., McClung, J. A., & Drummond, G. S. (2008) · Current Pharmaceutical Design · doi:10.2174/138161208783597371 · Cited by 51
“Diabetic complications have been related to abnormalities in mitochondrial function [68,71,72] as well as to increased endothelial cell death and detachment [73].”
Background
Metformin stimulates ischemia-induced revascularization through an eNOS dependent pathway in the ischemic hindlimb mice model
Takahashi, N. K., Shibata, R., Ouchi, N., Sugimoto, M., Murohara, T., & Komori, K. (2014) · Journal of Vascular Surgery · doi:10.1016/j.jvs.2013.09.061 · Cited by 51
Preservation of Cellular Glutathione Status and Mitochondrial Membrane Potential by N-Acetylcysteine and Insulin Sensitizers Prevent Carbonyl Stress-Induced Human Brain Endothelial Cell Apoptosis
Okouchi, M., Okayama, N., & Aw, T. Y. (2009) · Current Neurovascular Research · doi:10.2174/156720209789630348 · Cited by 49
“Interestingly, metformin was shown to inhibit mitochondrial respiratory chain complex I which has been suggested to prevent mPTP opening as an adaptive response to decreased mitochondrial ROS generation and attenuated oxidative stress (Detaille et al. 2005; Marchetti et al. 2004).”
BackgroundInfluential
Hypoglycemic pharmacological treatment of type 2 diabetes: Targeting the endothelium
Nathanson, D., & Nyström, T. (2008) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2008.11.016 · Cited by 48
“It eems that metformin may also exert antioxidative effects, in as uch as it protects against high-glucose induced oxidative stress n cultured ECs through a mitochondrial permeability transition ependent pathway (Detaille et al., 2005; Guigas et al., 2004).”
Background
Oxidative stress and endothelium influenced by metformin in type 2 diabetes mellitus
Škrha, J., Prázný, M., Hilgertová, J., Kvasnička, J., Kalousová, M., & Zima, T. (2007) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-007-0378-1 · Cited by 48
“generation at different steps involving inhibition of nicotinamide dinucleotide phosphate (NADPH) oxidase [11], nuclear factor kappa B (NFκB) [12] and opening of the mitochondrial permeability transition pore [13].”
Background
Bright renoprotective properties of metformin: beyond blood glucose regulatory effects.
Nasri, H., Baradaran, A., Ardalan, M., Mardani, S., Momeni, A., & Rafieian‐Kopaei, M. (2013) · Iranian Journal of Kidney Diseases · Cited by 48
Endothelial cells' biophysical, biochemical, and chromosomal aberrancies in high‐glucose condition within the diabetic range
Rezabakhsh, A., Nabat, E., Yousefi, M., Montazersaheb, S., Cheraghi, O., Mehdizadeh, A., Fathi, F., Movassaghpour, A. A., Maleki‐Dizaji, N., Rahbarghazi‬, R., et al. (2017) · Cell Biochemistry and Function · doi:10.1002/cbf.3251 · Cited by 48
A Review on The Protective Effects of Metformin in Sepsis-Induced Organ Failure.
Hassan, F. I., Didari, T., Khan, F., Niaz, K., Mojtahedzadeh, M., & Abdollahi, M. R. (2020) · PubMed Central · doi:10.22074/cellj.2020.6286 · Cited by 48
“It exerts its effect by inhibiting complex I of the electron transport chain (ETC) which increases AMP/ATP ratio and subsequently induces AMPK activation (31).”
Background
Ganoderma atrum Polysaccharide Ameliorates Hyperglycemia-Induced Endothelial Cell Death via a Mitochondria-ROS Pathway
Li, W., Nie, S., Yao, Y.-F., Liu, X., Shao, D.-Y., Gong, D., Cui, S. W., Phillips, G. O., He, M., & Xie, M. (2015) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.5b03462 · Cited by 48
Hyperandrogenism and Insulin Resistance, Not Changes in Body Weight, Mediate the Development of Endothelial Dysfunction in a Female Rat Model of Polycystic Ovary Syndrome (PCOS)
Hurliman, A. K., Brown, J. K., Maille, N., Mandalà, M., Casson, P. R., & Osol, G. (2015) · Endocrinology · doi:10.1210/en.2015-1159 · Cited by 44
The Effects of Metformin on Age-Related Changes in the Liver Sinusoidal Endothelial Cell
Hunt, N. J., Lockwood, G. P., Kang, S. W. S., Pulpitel, T., Clark, X., Mao, H., McCourt, P., Cooney, G. J., Wali, J. A., Couteur, F. H. L., et al. (2019) · The Journals of Gerontology Series A · doi:10.1093/gerona/glz153 · Cited by 45
Adverse Effects of Metformin From Diabetes to COVID-19, Cancer, Neurodegenerative Diseases, and Aging: Is VDAC1 a Common Target?
Shoshan‐Barmatz, V., Anand, U., Crystal, E. N., Carlo, M. D., & Shteinfer‐Kuzmine, A. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.730048 · Cited by 42
Latrophilin-2 is a novel receptor of LRG1 that rescues vascular and neurological abnormalities and restores diabetic erectile function
Yin, G. N., Kim, D., Kang, J. I., Im, Y., Lee, D. S., Han, A. R., Ock, J., Choi, M. J., Kwon, M., Limanjaya, A., et al. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00773-5 · Cited by 44
Targeting oxidative stress in preeclampsia
Afrose, D., Alfonso-Sánchez, S., & McClements, L. (2024) · Hypertension in Pregnancy · doi:10.1080/10641955.2024.2445556 · Cited by 45
“Also, metformin prevents hyperglycemia-induced endothelial cell death by stabilizing the mitochondrial permeability transition, highlighting metformin’s protective role against oxidative injury to endothelial cells, which is relevant to preeclampsia (162).”
The pleiotropic effects of metformin: time for prospective studies
Bromage, D. I., & Yellon, D. M. (2015) · Cardiovascular Diabetology · doi:10.1186/s12933-015-0273-5 · Cited by 42
Coenzyme Q10 Attenuates High Glucose-Induced Endothelial Progenitor Cell Dysfunction through AMP-Activated Protein Kinase Pathways
Tsai, H., Lin, C.-P., Huang, P.-H., Li, S., Chen, J.-S., Lin, F., Chen, J., & Lin, S. (2015) · Journal of Diabetes Research · doi:10.1155/2016/6384759 · Cited by 40
“These findings are consistent with previous reports and suggest that activation of CoQ10 might reduce hyperglycemia-induced mitochondrial dysfunction and promote mitochondrial biogenesis in EPCs exposed to high glucose [27, 28].”
Result
Protective effect of metformin on testicular ischemia/reperfusion injury in rats
Asghari, A., Akbari, G., Meghdadi, A., & Mortazavi, P. (2016) · Acta Cirúrgica Brasileira · doi:10.1590/s0102-865020160060000008 · Cited by 40
Molecular Mechanisms of Class B GPCR Activation: Insights from Adrenomedullin Receptors
Garelja, M. L., Au, M., Brimble, M. A., Gingell, J. J., Hendrikse, E. R., Lovell, A., Prodan, N., Sexton, P. M., Siow, A., Walker, C. S., et al. (2020) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.9b00083 · Cited by 40
Two-year follow-up of 4 months metformin treatment vs. placebo in ST-elevation myocardial infarction: data from the GIPS-III RCT
Hartman, M. H. T., Prins, J. K. B., Schurer, R. A. J., Lipšic, E., Lexis, C. P. H., van der Horst‐Schrivers, A. N. A., van Veldhuisen, D. J., van der Horst, I. C. C., & van der Horst, I. C. C. (2017) · Clinical Research in Cardiology · doi:10.1007/s00392-017-1140-z · Cited by 40
Metformin Represses Glucose Starvation Induced Autophagic Response in Microvascular Endothelial Cells and Promotes Cell Death
Samuel, S. M., Ghosh, S., Majeed, Y., Arunachalam, G., Emara, M. M., Ding, H., & Triggle, C. R. (2017) · Biochemical Pharmacology · doi:10.1016/j.bcp.2017.03.001 · Cited by 37
AMP-kinase pathway is involved in tumor necrosis factor alpha-induced lipid accumulation in human hepatoma cells
Lv, Q., Zhen, Q., Liu, L., Gao, R., Yang, S., Huang, Z., Goswami, R., & Li, Q. (2015) · Life Sciences · doi:10.1016/j.lfs.2015.03.003 · Cited by 37
Metformin impairs Rho GTPase signaling to induce apoptosis in neuroblastoma cells and inhibits growth of tumors in the xenograft mouse model of neuroblastoma
Kumar, A., Al-Sammarraie, N., DiPette, D. J., & Singh, U. S. (2014) · Oncotarget · doi:10.18632/oncotarget.2606 · Cited by 38
Renoprotective effect of Caralluma fimbriata against high-fat diet-induced oxidative stress in Wistar rats
Gujjala, S., Putakala, M., Nukala, S., Manjunatha, B., Ramaswamy, R., & Desireddy, S. (2016) · Journal of Food and Drug Analysis · doi:10.1016/j.jfda.2016.01.013 · Cited by 36
Role of the Renal Microcirculation in Progression of Chronic Kidney Injury in Obesity
Chade, A., & Hall, J. E. (2016) · American Journal of Nephrology · doi:10.1159/000452365 · Cited by 36
Endoplasmic Reticulum-Mitochondria Crosstalk and Beta-Cell Destruction in Type 1 Diabetes
Vig, S., Lambooij, J. M., Zaldumbide, A., & Guigas, B. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.669492 · Cited by 38
Self-citation
Metformin attenuates adhesion between cancer and endothelial cells in chronic hyperglycemia by recovery of the endothelial glycocalyx barrier
Targosz‐Korecka, M., Malek-Zietek, K. E., Klóska, D., Rajfur, Z., Stępień, E. Ł., Grochot‐Przeczek, A., & Szymoński, M. (2020) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2020.129533 · Cited by 32
Endotheliopathy in the metabolic syndrome: Mechanisms and clinical implications
Furuta, K., Tang, X., Islam, S., Tapia, A., Chen, Z. B., & Ibrahim, S. H. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108372 · Cited by 36
Involvement of anion exchanger-2 in apoptosis of endothelial cells induced by high glucose through an mPTP-ROS-Caspase-3 dependent pathway
Huang, Q., Li, Q., Chen, Y., Li, L., Liu, L., Lei, S., Chen, H., Peng, W., & He, M. L. (2010) · APOPTOSIS · doi:10.1007/s10495-010-0477-9 · Cited by 33
Intestinal oxygen utilisation and cellular adaptation during intestinal ischaemia–reperfusion injury
Barakakis, P. A., Mavridis, T., Chlorogiannis, D., Barakakis, G., Laou, E., Sessler, D. I., Gkiokas, G., & Chalkias, A. F. (2024) · Clinical and Translational Medicine · doi:10.1002/ctm2.70136 · Cited by 32
Hydrogen sulfide exhibits cardioprotective effects by decreasing endoplasmic reticulum stress in a diabetic cardiomyopathy rat model
Li, F., Luo, J., Wu, Z., Xiao, T., Zeng, O., Li, L., Li, Y., & Yang, J. (2016) · Molecular Medicine Reports · doi:10.3892/mmr.2016.5289 · Cited by 33
“Moreover, the effect of myocardial apoptosis caused by hyperglycemia was also demonstrated in vitro (65,66).”
Icariin Attenuates High Glucose-Induced Apoptosis, Oxidative Stress, and Inflammation in Human Umbilical Venous Endothelial Cells
Sun, S., Liu, L., Tian, X., Guo, Y., Cao, Y., Mei, Y., & Wang, C. (2019) · Planta Medica · doi:10.1055/a-0837-0975 · Cited by 32
“Previous studies have evidenced that icariin and Met can keep the normal structure of the mitochondria membrane [18,27].”
Background
Metformin improves boar sperm quality via 5′-AMP-activated protein kinase-mediated energy metabolism in vitro
Li, R., 杨凌712100，中国, 西., Zhu, Z., Zheng, Y., Lv, Y., Tian, X., Wu, D., Wang, Y., Zeng, W., & 成都611100，中国, 四. (2020) · 动物学研究 · doi:10.24272/j.issn.2095-8137.2020.074 · Cited by 33
Metformin alleviates cholestasis-associated nephropathy through regulating oxidative stress and mitochondrial function
Ommati, M. M., Mohammadi, H., Mousavi, K., Azarpira, N., Farshad, O., Dehghani, R., Najibi, A., Kamran, S., Niknahad, H., & Heidari, R. (2020) · Liver Research · doi:10.1016/j.livres.2020.12.001 · Cited by 30
Protection by metformin against severe Covid-19: An in-depth mechanistic analysis
Wiernsperger, N. F., Al‐Salameh, A., Cariou, B., & Lalau, J. (2022) · Diabetes & Metabolism · doi:10.1016/j.diabet.2022.101359 · Cited by 31
“MET inhibited MTP opening and the release of cytochrome c in neurons [212], hyperglycaemia-cultured endothelial cells [213], pancre-”
Self-citation
Pericyte-derived extracellular vesicle-mimetic nanovesicles ameliorate erectile dysfunction via lipocalin 2 in diabetic mice
Limanjaya, A., Yin, G. N., Hong, S., Kang, J., Gho, Y. S., Suh, J., & Ryu, J. (2022) · International Journal of Biological Sciences · doi:10.7150/ijbs.72243 · Cited by 30
Evaluation of putative inhibitors of mitochondrial permeability transition for brain disorders — Specificity vs. toxicity
Morota, S., Månsson, R., Hansson, M. J., Kasuya, K., Shimazu, M., Hasegawa, E., Yanagi, S., Omi, A., Uchino, H., & Elmér, E. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.03.036 · Cited by 31
Protective effect of Caralluma fimbriata against high-fat diet induced testicular oxidative stress in rats
Gujjala, S., Putakala, M., Gangarapu, V., Nukala, S., Bellamkonda, R., Ramaswamy, R., & Desireddy, S. (2016) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2016.06.031 · Cited by 30
An investigation into the pleiotropic activity of metformin. A glimpse of haemostasis
Markowicz-Piasecka, M., Sadkowska, A., Huttunen, K. M., Podsiedlik, M., Mikiciuk‐Olasik, E., & Sikora, J. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.172984 · Cited by 31
Stem Cell Therapy in Diabetic Polyneuropathy: Recent Advancements and Future Directions
Akter, S., Choubey, M., Mohib, M. M., Arbee, S., Sagor, M. A. T., & Mohiuddin, M. S. (2023) · Brain Sciences · doi:10.3390/brainsci13020255 · Cited by 29
Metformin and respiratory chain complex I: the last piece of the puzzle?
Fontaine, E. M. (2014) · Biochemical Journal · doi:10.1042/bj20141020 · Cited by 29
Self-citation
Role of mitochondrial dysfunction in hyperglycaemia-induced coronary microvascular dysfunction: Protective role of resveratrol
Joshi, M. S., Williams, D., Horlock, D., Samarasinghe, T. D., Andrews, K. L., Jefferis, A., Berger, P. J., Chin-Dusting, J. P. F., & Kaye, D. M. (2015) · Diabetes and Vascular Disease Research · doi:10.1177/1479164114565629 · Cited by 29
Cardiac-specific overexpression of GTP cyclohydrolase 1 restores ischaemic preconditioning during hyperglycaemia
Ge, Z., Ionova, I. A., Vladic, N., Pravdić, D., Hirata, N., Vasquez-Vivar, J. M., Pratt, P. F., Warltier, D. C., Pieper, G. M., & Kersten, J. R. (2011) · Cardiovascular Research · doi:10.1093/cvr/cvr079 · Cited by 28
Review: 50 years later: is metformin a vascular drug with antidiabetic properties?
Wiernsperger, N. F. (2007) · The British Journal of Diabetes · doi:10.1177/14746514070070050201 · Cited by 28
“Indeed metformin inhibits opening of the mitochondrial transition pore and cytochrome C release into the cytoplasm.(65,66)”
BackgroundSelf-citation
Metformin Modulates High Glucose-Incubated Human Umbilical Vein Endothelial Cells Proliferation and Apoptosis Through AMPK/CREB/BDNF Pathway
Han, X., Wang, B., Sun, Y., Huang, J., Wang, X., Ma, W., Zhu, Y., Xu, R., Jin, H. L., & Liu, N. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.01266 · Cited by 28
“Studies have indicated that diabetes or highglucose (HG) levels trigger multiple endothelial dysfunctions, such as dysregulated endothelial cell proliferation, migration, and apoptosis (Baumgartner-Parzer et al., 1995; Tousoulis et al., 2013; Dong et al., 2017).”
Exploring new mechanisms of Imeglimin in diabetes treatment: Amelioration of mitochondrial dysfunction
Li, Y., Lou, N., Liu, X., Zhuang, X., & Chen, S. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116755 · Cited by 27
Sulfenamide and Sulfonamide Derivatives of Metformin – A New Option to Improve Endothelial Function and Plasma Haemostasis
Markowicz-Piasecka, M., Huttunen, K. M., Broncel, M., & Sikora, J. (2019) · Scientific Reports · doi:10.1038/s41598-019-43083-z · Cited by 27
Sugar Composition Analysis of Fuzi Polysaccharides by HPLC-MSn and Their Protective Effects on Schwann Cells Exposed to High Glucose
Wang, B., Wang, J., Jiang, Y. G., Quan, Q., Ji, R., Tan, P., Han, J., & Liu, Y. (2016) · Molecules · doi:10.3390/molecules21111496 · Cited by 27
“However, AMPK activators could increase cell survival, such as metformin and dithiolethiones [38,39].”
Background
Alpha-mangostin decreased cellular senescence in human umbilical vein endothelial cells
Tousian, H., Razavi, B. M., & Hosseinzadeh, H. (2019) · DARU Journal of Pharmaceutical Sciences · doi:10.1007/s40199-019-00305-z · Cited by 26
The Hormetic Effect of Metformin: “Less Is More”?
Panfoli, I., Puddu, A., Bertola, N., Ravera, S., & Maggi, D. C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126297 · Cited by 29
“For example, MTF used at micromolar concentration inhibits the mPTP opening by an AKT-dependent pathway [36], preventing the associated ROS generation and the release of cytochrome c [37].”
Background
Investigation of the potential effects of metformin on atherothrombotic risk factors in hyperlipidemic rats
Ghatak, S. B., Dhamecha, P. S., Bhadada, S. V., & Panchal, S. J. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2011.03.029 · Cited by 26
“, 2006), antioxidant effects like prevention of mitochondrial permeability transition pore opening (Detaille et al., 2005), reduction in radical oxygen species production (Gallo et al.”
Background
Impact of metformin use on the prognostic value of lactate in sepsis
Green, J. P., Berger, T., Garg, N., Suarez, A. E., Hagar, Y., Radeos, M. S., & Panacek, E. A. (2012) · The American Journal of Emergency Medicine · doi:10.1016/j.ajem.2012.01.014 · Cited by 25
Metformin and Glaucoma—Review of Anti-Fibrotic Processes and Bioenergetics
Hurley, D. J., Irnaten, M., & O'Brien, C. J. (2021) · Cells · doi:10.3390/cells10082131 · Cited by 24
Metformin prevents endothelial oxidative stress and microvascular insulin resistance during obesity development in male rats
Liu, J., Aylor, K. W., Chai, W., Barrett, E. J., & Liu, Z. (2022) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00240.2021 · Cited by 27
Establishment of in vitro model of erectile dysfunction for the study of high‐glucose‐induced angiopathy and neuropathy
Yin, G. N., Park, S., Song, K., Limanjaya, A., Ghatak, K., Minh, N. N., Ock, J., Ryu, J., & Suh, J. ‐. (2016) · Andrology · doi:10.1111/andr.12307 · Cited by 25
“…model for diabetes-induced angiopathy, primary cultured MCECs and MCPs were serum-starved for 24 h and were exposed to the normal-glucose (5 mmoL, Sigma- Aldrich) or high-glucose (30 mmoL) condition for 48 h as previously described (Poczatek et al., 2000; Li et al., 2003; Detaille et al., 2005).”
Method
Use of metformin for prevention of ovarian hyperstimulation syndrome: a novel approach
Khattab, S., Foutouh, I. A., Mohesn, I. A., Metwally, M. A., & Moaz, M. (2006) · Reproductive BioMedicine Online · doi:10.1016/s1472-6483(10)60614-1 · Cited by 24
Metformin Effect on Endocan Biogenesis in Human Endothelial Cells Under Diabetic Condition
Zolali, E., Rezabakhsh, A., Nabat, E., Jaberi, H., Rahbarghazi‬, R., & Garjani, A. (2019) · Archives of Medical Research · doi:10.1016/j.arcmed.2019.08.012 · Cited by 23
Pleiotropic Activity of Metformin and Its Sulfonamide Derivatives on Vascular and Platelet Haemostasis
Markowicz-Piasecka, M., Huttunen, K. M., Sadkowska, A., & Sikora, J. (2019) · Molecules · doi:10.3390/molecules25010125 · Cited by 23
“Most of the current literature concentrates on the effects of metformin on the apoptosis of endothelial cells [40,41].”
Background
Pericyte-derived heme-binding protein 1 promotes angiogenesis and improves erectile function in diabetic mice
Yin, G. N. (2022) · Korean journal of urology · doi:10.4111/icu.20220038 · Cited by 20
“For glucose condition studies, the MCECs or MCPs were serum-starved for 24 hours and then exposed to normal glucose (NG, 5 mM glucose, Sigma-Aldrich) or HG (30 mM glucose) conditions for 3 days at 37°C in a humidified 5% CO2 atmosphere [14].”
Method
IGFBP5 antisense and short hairpin RNA (shRNA) constructs improve erectile function by inducing cavernosum angiogenesis in diabetic mice
Ock, J., Suh, J., Hong, S., Kang, J., Yin, G. N., & Ryu, J. (2022) · Andrology · doi:10.1111/andr.13234 · Cited by 19
Metformin prevents morphine-induced apoptosis in rats with diabetic neuropathy: a possible mechanism for attenuating morphine tolerance
Avcı, O., Özdemir, E., Taşkıran, A. Ş., İnan, Z. D. Ş., & Gürsoy, S. (2022) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-022-02283-7 · Cited by 19
Microcirculation and Mitochondria: The Critical Unit
Wang, G., Lian, H., Zhang, H., & Wang, X. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12206453 · Cited by 19
“Nevertheless, it must be used cautiously in patients with shock because of its potential for causing renal damage and serious side effects, such as hyperlactacidemia [82].”
Background
Anti-Inflammatory Potential of the Anti-Diabetic Drug Metformin in the Prevention of Inflammatory Complications and Infectious Diseases Including COVID-19: A Narrative Review
Plowman, T. J., Christensen, H., Aiges, M., Fernandez, E., Shah, M. H., & Ramana, K. V. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25105190 · Cited by 20
“Further, Detaille et al. [50] have shown that metformin prevents endothelial cell death by regulating the mitochondrial permeability transition pore.”
Background
Transcriptional profiling of mouse cavernous pericytes under high-glucose conditions: Implications for diabetic angiopathy
Yin, G. N., Wu, J., Cui, Y., Lin, C., Shi, L., Gao, Z., Suh, J., Ryu, J., & Jin, H. (2020) · Korean journal of urology · doi:10.4111/icu.20200272 · Cited by 18
Metformin Preserves VE–Cadherin in Choroid Plexus and Attenuates Hydrocephalus via VEGF/VEGFR2/p-Src in an Intraventricular Hemorrhage Rat Model
Shen, D., Ye, X., Li, J., Hao, X., Jin, L., Jin, Y., Tong, L., & Gao, F. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23158552 · Cited by 18
Metformin: A Promising Antidiabetic Medication for Cancer Treatment
Mu, W., Jiang, Y., Liang, G., Feng, Y., & Qu, F. (2022) · Current Drug Targets · doi:10.2174/1389450124666221104094918 · Cited by 18
Effect of metformin and detorsion treatment on serum anti-Müllerian hormonelevels and ovarian histopathology in a rat ovarian torsion model
Karakaş, S., Kaya, C., Güraslan, H., Sakız, D., Çaypınar, S. S., Cengiz, H., Ekin, M., & Yaşar, L. (2020) · TURKISH JOURNAL OF MEDICAL SCIENCES · doi:10.3906/sag-1803-196 · Cited by 18
“Previous ischemia-reperfusion studies performed with metformin in different tissues have shown that metformin protects tissues by reducing lipid peroxidase, MDA, ROS, and inflammatory cytokines [33,34].”
Background
Gene expression profiling of mouse cavernous endothelial cells for diagnostic targets in diabetes-induced erectile dysfunction
Yin, G. N., Ock, J., Choi, M. J., Limanjaya, A., Ghatak, K., Song, K., Kwon, M.-H., Suh, J., & Ryu, J. (2020) · Korean journal of urology · doi:10.4111/icu.20200119 · Cited by 18
Metformin and atorvastatin reduce adhesion formation in a rat uterine horn model
Yılmaz, B., Aksakal, O., Gungor, T., Şirvan, L., Süt, N., Kelekçi, S., Soysal, S., & Mollamahmutoğlu, L. (2009) · Reproductive BioMedicine Online · doi:10.1016/s1472-6483(10)60106-x · Cited by 18
Metformin and renal injury protection.
Rafieian-Kopaie, M. (2013) · PubMed Central · doi:10.12861/jrip.2013.29 · Cited by 17
“Various studies have suggested that AMPK activation by metformin is secondary to its effect on the mitochondria as the primary target of this agent (4-10).”
Background
Metformin prevented high glucose-induced endothelial reactive oxygen species via OGG1 in an AMPKα-Lin-28 dependent pathway
Tao, L., Fan, X., Sun, J., & Zhang, Z. (2021) · Life Sciences · doi:10.1016/j.lfs.2020.119015 · Cited by 18
Plant Compounds for the Treatment of Diabetes, a Metabolic Disorder: NF-κB as a Therapeutic Target
Ravi, S., Punabaka, J., Shanmugam, B., Ganjikunta, V. S., Shanmugam, K. R., & Kesireddy, S. R. (2020) · Current Pharmaceutical Design · doi:10.2174/1381612826666200730221035 · Cited by 15
N-Acetylcysteine Enhances the Recovery of Ischemic Limb in Type-2 Diabetic Mice
Zhu, Q., Liu, X., Zhu, Q., Liu, Z., Yang, C., Wu, H., Zhang, L., Xia, X., Wang, M., Hao, H., et al. (2022) · Antioxidants · doi:10.3390/antiox11061097 · Cited by 15
Effects of glycemic control on glucose utilization and mitochondrial respiration during resuscitated murine septic shock
Vogt, J. A., Wachter, U. A., Wagner, K., Calzia, E., Gröger, M., Weber, S., Stahl, B., Georgieff, M., Asfar, P., Fontaine, E. M., et al. (2014) · Intensive Care Medicine Experimental · doi:10.1186/2197-425x-2-19 · Cited by 15
“As a whole, these findings agree with various previous reports that hyperglycemia causes liver tissue apoptosis [39-42], which can be prevented by anti-diabetic drugs such as metformin [20,21,43], even during acute stress states [44].”
InfluentialSelf-citation
Microcirculation vs. Mitochondria—What to Target?
Merz, T., Denoix, N., Huber-Lang, M. S., Singer, M., Radermacher, P., & McCook, O. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.00416 · Cited by 15
“Metformin has been shown to be beneficial for the attenuation of mitochondrial transition pore opening (99), stimulation of mitochondrial biogenesis and reduction of mitochondrial ROS production, but has to be used with caution in shock patients due to its potentially severe side effects, i.”
Background
Insulin resistance in NSCLC: unraveling the link between development, diagnosis, and treatment
Zhan, S., Wang, L., Wang, W., & Li, R. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1328960 · Cited by 14
Metformin as a cellular protector; a synoptic view of modern evidences.
Wiernsperger, N. F. (2015) · Europe PMC (PubMed Central) · Cited by 13
Self-citation
Newly-found functions of metformin for the prevention and treatment of age-related macular degeneration
Dang, K., Hui, Y.-N., & Du, H. (2021) · International Journal of Ophthalmology · doi:10.18240/ijo.2021.08.20 · Cited by 14
Pancreas Β-Cells in Type 1 and Type 2 Diabetes: Cell Death, Oxidative Stress and Immune Regulation. Recently Appearing Changes in Diabetes Consequences
Novoselova, E. G. (2024) · Cellular Physiology and Biochemistry · doi:10.33594/000000690 · Cited by 13
Combination Therapy of Nifedipine and Sulphonylureas Exhibits a Mutual Antagonistic Effect on the Endothelial Cell Dysfunction Induced by Hyperglycemia Linked to Vascular Disease
Wang, L., Yu, J., Yang, H., Peng, C. Y., Zhang, C., Tao, X., & Xie, H. (2016) · Cellular Physiology and Biochemistry · doi:10.1159/000445587 · Cited by 12
Oxazolidinones and Human Immunodeficiency Virus
Madariaga, M. G., & Swindells, S. (2007) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01357-06 · Cited by 12
Metformin reduces vascular endothelial dysfunction caused by an acute glucose load in patients with hypertension
Zhang, T.-X., Xu, J., Peng, F., Chai, D., & Lin, J. (2012) · Blood Pressure · doi:10.3109/08037051.2012.732761 · Cited by 11
Association of Metformin Use With Risk of Venous Thromboembolism in Adults With Type 2 Diabetes: A General-Population–Based Cohort Study
Sha, T., Zhang, Y., Li, C., Lei, G., Wu, J., Li, X., Yang, Z., Zeng, C., & Wei, J. (2021) · American Journal of Epidemiology · doi:10.1093/aje/kwab291 · Cited by 12
Heat Shock Protein 70 in Penile Neurovascular Regeneration Requires Cystathionine Gamma-Lyase
Ghatak, K., Yin, G. N., Hong, S., Kang, J., Suh, J., & Ryu, J.-K. (2022) · The World Journal of Men s Health · doi:10.5534/wjmh.210249 · Cited by 10
Glucose and Its Metabolites Have Distinct Effects on the Calcium-Induced Mitochondrial Permeability Transition
Škrha, J., Gáll, J., Buchal, R., Sedláčková, E., & Plátenı́k, J. (2011) · Folia Biologica · doi:10.14712/fb2011057030096 · Cited by 11
“Even though the concentration required to produce these effects (30 mM) seems exceedingly high, previous studies modelling hyperglycaemic damage to cell cultures used the same glucose level (Detaille et al., 2005; Ksiazek et al., 2008).”
Background
Metformin suppresses the mitochondrial and transcriptional response to exercise, revealing a conserved BCL6B-associated angiogenic program
Bruss, M. D., Elliehausen, C. J., Clark, J. P., Minton, D. M., & Konopka, A. R. (2025) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00432.2025 · Cited by 11
Metformin induced expression of Hsp60 in human THP-1 monocyte cells
Tsuei, A.-C., & Martinus, R. D. (2011) · Cell Stress and Chaperones · doi:10.1007/s12192-011-0282-6 · Cited by 10
Dopamine D4 receptor protected against hyperglycemia-induced endothelial dysfunction via PI3K /eNOS pathway
Wang, H., Yao, Y., Liu, J., Cao, Y., Si, C., Zheng, R., Zeng, C., Huaimin, G., & Li, L. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.08.080 · Cited by 10
Photobiomodulation therapy for diabetic erectile dysfunction targeting neuroinflammation and neurovascular regeneration
Limanjaya, A., Choi, M. J., Yin, G. N., Ock, J., Kwon, M.-H., Hong, S., Kang, J., Suh, J., & Ryu, J. (2025) · Scientific Reports · doi:10.1038/s41598-025-04873-w · Cited by 9
Effects of alpha-mangostin on memory senescence induced by high glucose in human umbilical vein endothelial cells.
Tousian, H., Razavi, B. M., & Hosseinzadeh, H. (2020) · PubMed Central · doi:10.22038/ijbms.2020.40651.9612 · Cited by 9
“Hyperglycemia increases reactive oxygen species (ROS) production through mitochondria and induces angiopathy (2).”
Background
Renoprotective effects of metformin
Nasri, H. (2013) · DARU Journal of Pharmaceutical Sciences · doi:10.1186/2008-2231-21-36 · Cited by 8
“Various data indicates that AMPK activation by metformin is secondary to its effect on the mitochondria as the primary target of this agent [5,6,11].”
BackgroundResultInfluential
Energy metabolism modulation by biguanides in comparison with rotenone in rat liver and heart
Heinz, S., Freyberger, A., Lawrenz, B., Schladt, L., Schmuck, G., & Ellinger-Ziegelbauer, H. C. (2019) · Archives of Toxicology · doi:10.1007/s00204-019-02519-1 · Cited by 8

Authors: Detaille, D., Guigas, B., Chauvin, C., Batandier, C., Fontaine, E., Wiernsperger, N., & Leverve, X.
Affiliations: Laboratoire de Bioénergétique Fondamentale et Appliquée, Institut National de la Santé et de la Recherche Médicale EMI-0221, Université Joseph Fourier, Grenoble, France
Inserm (FR)
Merck Serono S.A.S. (France) (FR)
ORCID: Guigas, Bruno
Fontaine, Eric
Wiernsperger, Nicolas
Venue: Diabetes
Publisher: American Diabetes Association
Published: 2005-07-01
Volume: 54
Issue: 7
Pages: 2179-2187
ISSN: 0012-1797 (ISSN-L)
1939-327X
DOI: 10.2337/diabetes.54.7.2179
OpenAlex: W2163301537
Cited by: 263
References: 40
Citations by year: 2026: 4 · 2025: 8 · 2024: 10 · 2023: 7 · 2022: 14 · 2021: 13 · 2020: 19 · 2019: 19 · 2018: 12 · 2017: 7 · 2016: 16 · 2015: 17 · 2014: 12 · 2013: 12 · 2012: 15
FWCI: 5.02
Type: journal article
Language: en
Open access: closed
Locations: Diabetes (publishedVersion)
PubMed (publishedVersion)
HAL (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords: metformin, mitochondrial permeability transition pore, endothelial cell death, hyperglycemia, oxidative stress, cyclosporine, cytochrome c release, apoptosis, tert-butyl hydroperoxide, N-acetylcysteine, diabetic vascular complications, type 2 diabetes, microvascular endothelial cells
MeSH terms: Cell Line, Endothelium, Vascular, Glucose, Humans, Metformin, Microcirculation, Mitochondria, Permeability, Skin, Cell Death

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 ›

Are you an author, or do you see a problem with this page? Request a review

Metformin Prevents High-Glucose–Induced Endothelial Cell Death Through a Mitochondrial Permeability Transition-Dependent Process

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks