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

Mitochondrial membrane permeabilization in cell death
Kroemer, G., Galluzzi, L., & Brenner, C. (2007) · Physiological Reviews · doi:10.1152/physrev.00013.2006 · Cited by 3,598
“Also glucose, at high concentrations, may have proapoptotic effects due to the local generation of ROS (181).”
Background
Cellular and molecular mechanisms of metformin: an overview
Viollet, B., Guigas, B., Garcia, N. S., Leclerc, J., Foretz, M., & Andreelli, F. (2012) · Clinical Science · doi:10.1042/cs20110386 · Cited by 1,720
Self-citation
Metformin: from mechanisms of action to therapies
Foretz, M., Guigas, B., Bertrand, L., Pollak, M., & Viollet, B. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.09.018 · Cited by 1,501
Self-citation
Metformin: An Old Drug for the Treatment of Diabetes But a New Drug for the Protection of the Endothelium
Kinaan, M., Ding, H., & Triggle, C. R. (2015) · Medical Principles and Practice · doi:10.1159/000381643 · Cited by 1,515
Pharmacological and Clinical Aspects of Heme Oxygenase
Abraham, N. G., & Kappas, A. (2008) · Pharmacological Reviews · doi:10.1124/pr.107.07104 · Cited by 1,115
“, 2005) as well as to increased endothelial cell death and detachment (Detaille et al., 2005).”
The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level
Sahra, I. B., Laurent, K., Loubat, A., Giorgetti-Peraldi, S., Colosetti, P., Auberger, P., Tanti, J. F., Le Marchand-Brustel, Y., & Bost, F. (2008) · Oncogene · doi:10.1038/sj.onc.1211024 · Cited by 861
Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus
Foretz, M., Guigas, B., & Viollet, B. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0242-2 · Cited by 686
Self-citation
Metformin: An Old But Still the Best Treatment for Type 2 Diabetes
Rojas, L. B. A., & Gomes, M. B. (2013) · Diabetology & Metabolic Syndrome · doi:10.1186/1758-5996-5-6 · Cited by 567
Mitochondria and Endothelial Function
Kluge, M. A., Fetterman, J. L., & Vita, J. A. (2013) · Circulation Research · doi:10.1161/circresaha.111.300233 · Cited by 508
“Apoptosis is observed in cells exposed to high glucose and in animal models of diabetes mellitus, and under these conditions, apoptosis is inhibited by interventions that decrease ROS or inhibit MPT pore opening.(146,147) Hyperglycemia-induced apoptosis has been shown to involve activation of nuclear factor-κB and pro…”
Background
Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species
Yu, T., Sheu, S.-S., Robotham, J. L., & Yoon, Y. (2008) · Cardiovascular Research · doi:10.1093/cvr/cvn104 · Cited by 462
Endothelial Mitochondria: Contributing to Vascular Function and Disease
Davidson, S. M., & Duchen, M. R. (2007) · Circulation Research · doi:10.1161/01.res.0000261970.18328.1d · Cited by 381
Mitochondria, endothelial cell function, and vascular diseases
Tang, X., Luo, Y., Chen, H., & Liu, D. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00175 · Cited by 361
“Here we discuss mitochondria-directed antioxidants and interventions that improve mitochondria functions.”
Background
Role of mitochondria in the mechanism(s) of action of metformin
Vial, G., Detaille, D., & Guigas, B. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00294 · Cited by 303
Self-citation
The ROS production induced by a reverse-electron flux at respiratory-chain complex 1 is hampered by metformin
Batandier, C., Guigas, B., Detaille, D., El-Mir, M., Fontaine, E., Rigoulet, M., & Leverve, X. M. (2006) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-006-9003-8 · Cited by 279
Self-citation
High-Glucose Stimulation Increases Reactive Oxygen Species Production Through the Calcium and Mitogen-Activated Protein Kinase-Mediated Activation of Mitochondrial Fission
Yu, T., Jhun, B. S., & Yoon, Y. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3284 · Cited by 293
Metformin prevents experimental gentamicin-induced nephropathy by a mitochondria-dependent pathway
Morales, A. I., Détaille, D., Prieto, M., Puente, A., Briones, E., Arévalo, M. A., Leverve, X. M., López-Novoa, J. M., & El‐Mir, M. (2010) · Kidney International · doi:10.1038/ki.2010.11 · Cited by 284
Self-citation
Metformin Activates AMP-Activated Protein Kinase in Primary Human Hepatocytes by Decreasing Cellular Energy Status
Stephenne, X., Foretz, M., Taleux, N., van der Zon, G. C., Sokal, E., Hue, L., Viollet, B., & Guigas, B. (2011) · Diabetologia · doi:10.1007/s00125-011-2311-5 · Cited by 287
“The mitochondrial respiratory-chain complex 1 is the primary target of metformin The inhibition of the mitochondrial respiratory-chain complex 1 by metformin was first reported in perfused livers and isolated rat hepatocytes by Leverve’s group [12] and later confirmed in various other cellular models by us [21–25] and…”
Background
Endothelial cell apoptosis and the role of endothelial cell-derived extracellular vesicles in the progression of atherosclerosis
Paone, S., Baxter, A. A., Hulett, M. D., & Poon, I. K. H. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2983-9 · Cited by 281
Metformin-induced mitochondrial Complex I inhibition: facts, uncertainties, and consequences
Fontaine, E. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00753 · Cited by 269
Self-citation
Obesity-induced Insulin Resistance and Hyperglycemia
Martyn, J. A. J., Kaneki, M., Yasuhara, S., Warner, D. S., & Warner, M. A. A. (2008) · Anesthesiology · doi:10.1097/aln.0b013e3181799d45 · Cited by 278
“It has a well established, beneficial effect on peripheral tissues and mitochondrial function, in which it enhances the oxidation of fat and glucose presumably by activating adenosine monophosphate kinase.(106) The thiazolidinediones are a newer class of insulin-sensitizing drugs that not only increase peripheral util…”
Background
Diabetic Polyneuropathy in Type 2 Diabetes Mellitus: Inflammation, Oxidative Stress, and Mitochondrial Function
Román-Pintos, L. M., Villegas-Rivera, G., Rodríguez-Carrizález, A. D., Miranda‐Díaz, A. G., & Cardona-Muñóz, E. G. (2016) · Journal of Diabetes Research · doi:10.1155/2016/3425617 · Cited by 261
“Furthermore, another investigation of Metformin effects on mitochondria revealed that elevated glucose concentration leads to an oxidative stress that favors the mitochondrial permeability transition pore (PTP) opening and subsequent cell death in several endothelial cell types, and Metformin prevents this PTP opening…”
Background
Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome
Diamanti‐Kandarakis, E., Christakou, C. D., Kandaraki, E., & Economou, F. (2009) · European Journal of Endocrinology · doi:10.1530/eje-09-0733 · Cited by 251
Neuroprotective Role of Antidiabetic Drug Metformin Against Apoptotic Cell Death in Primary Cortical Neurons
El‐Mir, M., Détaille, D., R-Villanueva, G., Delgado‐Esteban, M., Guigas, B., Attia, S., Fontaine, E. M., Almeida, Á., & Leverve, X. M. (2007) · Journal of Molecular Neuroscience · doi:10.1007/s12031-007-9002-1 · Cited by 243
“As previously reported for human endothelial cells (Detaille et al. 2005), this kinetic constraint in complex I was accompanied by an inhibition of PTP opening in permeabilized neurons.”
InfluentialSelf-citation
Effects of metformin on learning and memory behaviors and brain mitochondrial functions in high fat diet induced insulin resistant rats
Pintana, H., Apaijai, N., Pratchayasakul, W., Chattipakorn, N., & Chattipakorn, S. C. (2012) · Life Sciences · doi:10.1016/j.lfs.2012.08.017 · Cited by 236
Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro
Dykens, J. A., Jamieson, J., Marroquin, L., Nadanaciva, S., Billis, P. A., & Will, Y. (2008) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2008.08.013 · Cited by 220
Metformin modulates hyperglycaemia‐induced endothelial senescence and apoptosis through SIRT1
Arunachalam, G., Samuel, S. M., Marei, I., Ding, H., & Triggle, C. R. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12496 · Cited by 221
“Metformin, 100 μM–10 mM, activates the AMPK/SIRT1 pathway and, via mitochondria complex 1, inhibits HG-induced apoptosis in human vascular endothelial cells (Detaille et al., 2005).”
Background
Mitochondrial Dynamics in Diabetes
Yoon, Y., Galloway, C. A., Jhun, B. S., & Yu, T. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3286 · Cited by 223
“Several reports also indicate that increased ROS in hyperglycemia directly induce apoptosis and oxidative stress, causing organ damage in diabetes (26, 47, 144) (Fig.”
Lactic Acidosis Induced by Metformin
Lalau, J. (2010) · Drug Safety · doi:10.2165/11536790-000000000-00000 · Cited by 221
Neuronal Apoptosis in Neurodegeneration
Okouchi, M., Ekshyyan, O. Y., Maracine, M., & Aw, T. Y. (2007) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.1511 · Cited by 222
“AMPK activation modulates mitochondrial hexokinase binding to the voltage dependent anion channel of MPT pore (76) and regulates MPT (385).”
The endothelium: influencing vascular smooth muscle in many ways
Triggle, C. R., Samuel, S. M., Ravishankar, S., Marei, I., Arunachalam, G., & Ding, H. (2012) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y2012-073 · Cited by 229
“…or indirectly activates SIRT1, possibly in part also involving AMPK, with subsequent multiple target actions that include improved endothelial function and an inhibition of hepatic gluconeogenesis (Mather et al. 2001; Zhou et al. 2001; Detaille et al. 2005; Caton et al. 2010; Foretz et al. 2010).”
Background
Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening
Bhamra, G. S., Hausenloy, D. J., Davidson, S. M., Carr, R. D., Paiva, M. S. A., Wynne, A. M., Mocanu, M. M., & Yellon, D. M. (2007) · Basic Research in Cardiology · doi:10.1007/s00395-007-0691-y · Cited by 211
“In this regard, recent studies have reported that metformin can inhibit the opening of the mitochondrial permeability transition pore (mPTP) induced by calcium and oxidative stress in a human carcinomaderived cell line [17] and human endothelial cells [14].”
Background
Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis
Isaković, A., Harhaji-Trajkovic, L. M., Stevanovic, D., Marković, Z. M., Šumarac-Dumanović, M., Starcevic, V. P., Micić, D., & Trajković, V. (2007) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-007-7080-4 · Cited by 210
Single-Cell RNA Sequencing Reveals Renal Endothelium Heterogeneity and Metabolic Adaptation to Water Deprivation
Dumas, S. J., Meta, E., Borri, M., Goveia, J., Rohlenová, K., Conchinha, N. V., Falkenberg, K. D., Teuwen, L.-A. M. N., de Rooij, L. P. M. H., Kalucka, J. M., et al. (2019) · Journal of the American Society of Nephrology · doi:10.1681/asn.2019080832 · Cited by 182
“…multi-functional compound that inhibits complex I of OXPHOS and oxygen consumption in ECs (Supplemental Figure 8C; consistent with previous reports 44,45 ), during dehydration elevated plasma urea levels, without altering plasma creatinine levels ( , 0.12 mg/dl), consistent with more severe…”
Influential
Urolithin A suppresses high glucose-induced neuronal amyloidogenesis by modulating TGM2-dependent ER-mitochondria contacts and calcium homeostasis
Lee, H. J., Jung, Y. H., Choi, G. E., Kim, J. S., Chae, C. W., Lim, J. R., Kim, S. Y., Yoon, J. H., Cho, J. H., Lee, S., et al. (2020) · Cell Death and Differentiation · doi:10.1038/s41418-020-0593-1 · Cited by 180
Neuroprotection with metformin and thymoquinone against ethanol-induced apoptotic neurodegeneration in prenatal rat cortical neurons
Ullah, I., Ullah, N., Naseer, M. I., Lee, H., & Kim, M. (2012) · BMC Neuroscience · doi:10.1186/1471-2202-13-11 · Cited by 170
“It was reported that the antidiabetic drug metformin (Met) prevents PTP opening and subsequent cell death in various endothelial cell types exposed to high glucose levels [17].”
Background
Impact of glycemic control strategies on the progression of diabetic peripheral neuropathy in the bypass angioplasty revascularization investigation 2 diabetes (BARI 2D) cohort
Pop-Busui, R., Lu, J., Brooks, M. M., Albert, S., Althouse, A. D., Escobedo, J., Green, J., Palumbo, P., Perkins, B. A., Whitehouse, F., et al. (2013) · Diabetes Care · doi:10.2337/dc13-0012 · Cited by 167
Therapeutic Concentrations of Metformin: A Systematic Review
Kajbaf, F., Broe, M. E. D., & Lalau, J. (2015) · Clinical Pharmacokinetics · doi:10.1007/s40262-015-0323-x · Cited by 160
The prevalence, patterns and predictors of diabetic peripheral neuropathy in a developing country
Katulanda, P., Ranasinghe, P. D., Jayawardena, R., Constantine, G. R., Sheriff, M. H. R., & Matthews, D. R. (2012) · Diabetology & Metabolic Syndrome · doi:10.1186/1758-5996-4-21 · Cited by 148
The prevalence and risk factors of peripheral neuropathy among patients with type 2 diabetes mellitus; the case of Jordan
Khawaja, N. M., Abu-Shennar, J. A., Saleh, M., Dahbour, S. S., Khader, Y. S., & Ajlouni, K. M. (2018) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-018-0309-6 · Cited by 148
Therapeutic Options Targeting Oxidative Stress, Mitochondrial Dysfunction and Inflammation to Hinder the Progression of Vascular Complications of Diabetes
Teodoro, J. S., Nunes, S., Rolo, A. P., Reis, F., & Palmeira, C. M. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2018.01857 · Cited by 150
“Giving further relevance to the role of mitochondrial function in EC are the numerous studies highlighting how hyperglycemia leads to calcium overload and elevated proapoptotic protein BAX content, which result in higher levels of mitochondrial permeability transition induction, ending in apoptosis (Kowluru and Abbas,…”
Background
AMPK activation restores the stimulation of glucose uptake in an in vitro model of insulin-resistant cardiomyocytes via the activation of protein kinase B
Bertrand, L., Ginion, A., Beauloye, C., Hebert, A. D., Guigas, B., Hue, L., & Vanoverschelde, J. (2006) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01269.2005 · Cited by 146
Self-citation
Metformin and other antidiabetic agents in renal failure patients
Lalau, J., Arnouts, P., Sharif, A., & Broe, M. E. D. (2014) · Kidney International · doi:10.1038/ki.2014.19 · Cited by 147
A CaPful of mechanisms regulating the mitochondrial permeability transition
Lisa, F. D., & Bernardi, P. (2009) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2009.03.006 · Cited by 143
“cell death in isolated endothelial and vascular smooth muscle cells [81,85].”
Background
Prevalence of diabetic peripheral neuropathy and relation to glycemic control therapies at baseline in the BARI 2D cohort
Pop‐Busui, R., Lu, J., Lopes, N., & Jones, T. L. Z. (2009) · Journal of the Peripheral Nervous System · doi:10.1111/j.1529-8027.2009.00200.x · Cited by 133
“, 1990), prevention of oxidative stress-induced endothelial cell death (Detaille et al., 2005), and direct neuroprotective effects via inhibition of oxidative stress-related apoptotic cell death in primary neurons (El-Mir et al.”
Background
High Glucose Disrupts Mitochondrial Morphology in Retinal Endothelial Cells
Trudeau, K. M., Molina, A. J. A., Guo, W., & Roy, S. (2010) · American Journal Of Pathology · doi:10.2353/ajpath.2010.091029 · Cited by 132
Endothelial Function and Dysfunction: Impact of Metformin
Nafisa, A., Gray, S. G., Cao, Y., Wang, T., Xu, S., Wattoo, F. H., Barras, M., Cohen, N., Kamato, D., & Little, P. J. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.07.007 · Cited by 128
Translational Significance of Heme Oxygenase in Obesity and Metabolic Syndrome
Abraham, N. G., Junge, J. M., & Drummond, G. S. (2015) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2015.09.003 · Cited by 126
“Diabetic complications have also been related to abnormalities in mitochondrial function [186,187] aswell as to increased endothelial cell death and detachment [188].”
Metformin in cardiovascular diabetology: a focused review of its impact on endothelial function
Ding, Y., Zhou, Y., Ling, P., Feng, X., Luo, S., Zheng, X., Little, P. J., Xu, S., & Weng, J. (2021) · Theranostics · doi:10.7150/thno.64706 · Cited by 121
AMP-activated protein kinase-independent inhibition of hepatic mitochondrial oxidative phosphorylation by AICA riboside
Guigas, B., Taleux, N., Foretz, M., Détaille, D., Andréelli, F., Viollet, B., & Hue, L. (2007) · Biochemical Journal · doi:10.1042/bj20070105 · Cited by 122
Self-citation
AMPK-mediated GSK3β inhibition by isoliquiritigenin contributes to protecting mitochondria against iron-catalyzed oxidative stress
Choi, S. H., Kim, Y. W., & Kim, S. G. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.12.011 · Cited by 118
“, 5-aminoimidazole-4carboxamide-1-b-D-ribofuranoside (AICAR) and metformin] increases cell viability under the conditions of stress [32,33].”
The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma
McBride, M. A., Owen, A. M., Stothers, C. L., Hernandez, A., Luan, L., Burelbach, K. R., Patil, T. K., Bohannon, J. K., Sherwood, E. R., & Patil, N. K. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01043 · Cited by 120
Simvastatin impairs ADP-stimulated respiration and increases mitochondrial oxidative stress in primary human skeletal myotubes
Kwak, H.-B., Thalacker-Mercer, A., Anderson, E. J., Lin, C.-T., Kane, D. A., Lee, N.-S., Cortright, R. N., Bamman, M. M., & Neufer, P. D. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.10.449 · Cited by 114
“Additionally, we observed impaired complex I-linked maximal ADP-stimulated respiration, increased mitochondrial oxidative stress, and increased pro-apoptotic Bax protein levels, all of which are indicative of increased susceptibility to PTP opening[41, 50] [50, 51] [48].”
Background
Metformin increases APP expression and processing via oxidative stress, mitochondrial dysfunction and NF-κB activation: Use of insulin to attenuate metformin's effect
Picone, P., Nuzzo, D., Caruana, L., Messina, E., Barera, A., Vasto, S., & Carlo, M. D. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.01.017 · Cited by 116
The effect of metformin on measurements of insulin sensitivity and β cell response in 18 horses and ponies with insulin resistance
Durham, A. E., Rendle, D. I., & Newton, J. R. (2008) · Equine Veterinary Journal · doi:10.2746/042516408x273648 · Cited by 117
Heme Oxygenase-1 Enhances Renal Mitochondrial Transport Carriers and Cytochrome c Oxidase Activity in Experimental Diabetes
Noia, M. A. D., Driesche, S. V., Palmieri, F., Yang, L. M., Quan, S., Goodman, A. I., & Abraham, N. G. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m510595200 · Cited by 110
Metformin reduces cisplatin-mediated apoptotic death of cancer cells through AMPK-independent activation of Akt
Janjetović, K., Vucicevic, L. M., Misirkic-Marjanovic, M., Vilimanovich, U., Tovilović-Kovačević, G., Zogovic, N. S., Nikolić, Z., Jovanović, S., Bumbasirevic, V. Z., Trajković, V., et al. (2010) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.11.005 · Cited by 115
“Namely, it has been shown thatmetformin can prevent high glucose-induced death of bovine endothelial cell (Detaille et al., 2005), reduce the lipotoxicity in human pancreatic islets (Lupi et al.”
Inhibition of complex I regulates the mitochondrial permeability transition through a phosphate-sensitive inhibitory site masked by cyclophilin D
Li, B., Chauvin, C., Paulis, D. D., Oliveira, F. D., Gharib, A., Vial, G., Lablanche, S., Leverve, X. M., Bernardi, P., Ovize, M., et al. (2012) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2012.05.011 · Cited by 112
Self-citation
AMPK/mTOR-mediated inhibition of survivin partly contributes to metformin-induced apoptosis in human gastric cancer cell
Han, G., Gong, H., Wang, Y., Guo, S., & Liu, K. (2014) · Cancer Biology & Therapy · doi:10.4161/15384047.2014.987021 · Cited by 107
Mitochondria and vascular pathology
Lisa, F. D., Kaludercic, N., Carpi, A., Menabò, R., & Giorgio, M. (2009) · Pharmacological Reports · doi:10.1016/s1734-1140(09)70014-3 · Cited by 106
“While data obtained in vitro indicate that PTP opening causes cell death in isolated endothelial and vascular smooth muscle cells [26, 28], no information on the effect of pharmacological or genetic inhibition of the PTP on atherogenesis in vivo is available.”
Background
Metformin Enhances Cisplatin Cytotoxicity by Suppressing Signal Transducer and Activator of Transcription–3 Activity Independently of the Liver Kinase B1–AMP-Activated Protein Kinase Pathway
Lin, C., Yeh, H.-H., Huang, W.-L., Yan, J.-J., Lai, W., Su, W., Chen, H. H. W., & Su, W. (2013) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2012-0244oc · Cited by 104
Enhanced apoptotic propensity in diabetic cardiac mitochondria: influence of subcellular spatial location
Williamson, C. L., Dabkowski, E. R., Baseler, W. A., Croston, T. L., Alway, S. E., & Hollander, J. M. (2009) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00668.2009 · Cited by 102
The potential effects of anti-diabetic medications on myocardial ischemia–reperfusion injury
Ye, Y., Perez-Polo, J. R., Aguilar, D. A., & Birnbaum, Y. (2011) · Basic Research in Cardiology · doi:10.1007/s00395-011-0216-6 · Cited by 101
Association of preadmission metformin use and mortality in patients with sepsis and diabetes mellitus: a systematic review and meta-analysis of cohort studies
Liang, H., Ding, X., Li, L., Wang, T., Kan, Q., Wang, L., & Sun, T. (2019) · Critical Care · doi:10.1186/s13054-019-2346-4 · Cited by 101
Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats
Kane, D. A., Anderson, E. J., Price, J. W., Woodlief, T. L., Lin, C.-T., Bikman, B. T., Cortright, R. N., & Neufer, P. D. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.06.022 · Cited by 99
“The PTP is a large conductance channel within the inner mitochondrial membrane that opens in response to a number of physiological factors and various forms of cellular stress (e.g., large increases in intracellular [Ca+2]), triggering collapse of the protonmotive force and release of pro-apoptotic factors [34].”
BackgroundInfluential
Imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration
Detaille, D., Vial, G., Borel, A.-L., Cottet-Rouselle, C., Hallakou-Bozec, S., Bolze, S., Fouqueray, P., & Fontaine, E. (2016) · Cell Death Discovery · doi:10.1038/cddiscovery.2015.72 · Cited by 99
Self-citation
Metformin is not just an antihyperglycaemic drug but also has protective effects on the vascular endothelium
Triggle, C. R., & Ding, H. (2015) · Acta Physiologica · doi:10.1111/apha.12644 · Cited by 101
“…effects, improved contribution of NO to EDV, effects on calcium handling, inhibition of mitochondrial complex 1 and activation of AMPK, and inhibition of apoptosis (Bhalla & Sharma 1996, Faure et al. 1999, Katakam et al. 2000, Zhou et al. 2001, Detaille et al. 2005, Arunachalam et al. 2014a).”
Background
Can Metformin Exert as an Active Drug on Endothelial Dysfunction in Diabetic Subjects
Salvatore, T., Pafundi, P. C., Galiero, R., Rinaldi, L., Caturano, A., Vetrano, E., Aprea, C., Albanese, G., Di Martino, A., Ricozzi, C., et al. (2020) · Biomedicines · doi:10.3390/biomedicines9010003 · Cited by 97
“induced oxidative stress in several endothelial cell types [203], and the biguanide given at the time of reperfusion may reduce myocardial infarct size in the heart of both non-diabetic and diabetic rats [204].”
Background
Mechanisms of Action of Metformin in Type 2 Diabetes and Associated Complications: An Overview
Correia, S. C., Carvalho, C., Santos, M. S., Seiça, R. M. F., Oliveira, C. R., & Moreira, P. I. (2008) · Mini-Reviews in Medicinal Chemistry · doi:10.2174/138955708786369546 · Cited by 98
Metformin prevents against oxidative stress-induced senescence in human periodontal ligament cells
Kuang, Y., Hu, B., Ge, F., Xiang, M., Deng, Y., Tan, M., Li, J., & Song, J. (2019) · Biogerontology · doi:10.1007/s10522-019-09838-x · Cited by 94
Effects of NO on mitochondrial function in cardiomyocytes: Pathophysiological relevance
Davidson, S. M., & Duchen, M. R. (2006) · Cardiovascular Research · doi:10.1016/j.cardiores.2006.01.019 · Cited by 91
“[124] Detaille D, Guigas B, Chauvin C, Batandier C, Fontaine E,”
Background
Resistance to Ca2+-induced opening of the permeability transition pore differs in mitochondria from glycolytic and oxidative muscles
Picard, M. A., Csukly, K., Robillard, M.-È., Godin, R., Ascah, A., Bourcier‐Lucas, C., & Burelle, Y. (2008) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.90357.2008 · Cited by 94
“Similar measurements have been previously reported in permeabilized hepatocytes and various cell lines (13, 17, 23).”
Result
Mitochondrial metabolic reprogramming controls the induction of immunogenic cell death and efficacy of chemotherapy in bladder cancer
Oresta, B., Pozzi, C., Braga, D., Hurle, R. F., Lazzeri, M., Colombo, P., Frego, N., Erreni, M., Faccani, C., Elefante, G. M., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.aba6110 · Cited by 89
AMPK activation by isorhamnetin protects hepatocytes against oxidative stress and mitochondrial dysfunction
Dong, G.-Z., Lee, J., Ki, S. H., Yang, J. H., Cho, I. J., Kang, S. H., Zhao, R., Kim, S. C., & Kim, Y. W. (2014) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2014.06.017 · Cited by 90
“…hypoxia (Sambandam and Lopaschuk, 2003), glucose deprivation (Xing et al., 2003) and osmotic stress (Tian et al., 2001), AMPK activators (e.g., metformin and dithiolethiones) increase cell survival by preventing changes in mitochondrial membrane potential (Detaille et al., 2005; Ido et al., 2002).”
Background
Metformin promotes isolated rat liver mitochondria impairment
Carvalho, C., Correia, S. C., Santos, M. S., Seiça, R. M. F., Oliveira, C. R., & Moreira, P. I. (2007) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-007-9614-3 · Cited by 88
“Mol Cell Biochem (2008) 308:75‐83 DOI 10.1007/s11010-007-9614-3 cells (HMEC-1) [ 9 ].”
Influential
Mitochondrial function and substrate availability
Leverve, X. M. (2007) · Critical Care Medicine · doi:10.1097/01.ccm.0000278044.19217.73 · Cited by 88
Self-citation
Mitochondrial function in vascular endothelial cell in diabetes
Pangare, M., & Makino, A. (2012) · Journal of Smooth Muscle Research · doi:10.1540/jsmr.48.1 · Cited by 87
“, 2004), opening of mPTP in endothelial cells (Detaille et al., 2005; Huang et al., 2010) and releasing the proapoptotic proteins from the mitochondria (Kowluru and Abbas, 2003; Detaille et al.”
BackgroundInfluential
Metformin, besides exhibiting strong in vivo anti-inflammatory properties, increases mptp-induced damage to the nigrostriatal dopaminergic system
Ismaiel, A. A., Espinosa‐Oliva, A. M., Santiago, M., García-Quintanilla, A., Oliva-Martín, M. J., Herrera, A. J., Venero, J. L., & de Pablos, R. M. (2016) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2016.03.004 · Cited by 81
Protection of pancreatic INS-1 β-cells from glucose- and fructose-induced cell death by inhibiting mitochondrial permeability transition with cyclosporin A or metformin
Lablanche, S., Cottet‐Rousselle, C., Lamarche, F., Benhamou, P., Halimi, S., Leverve, X. M., & Fontaine, E. M. (2011) · Cell Death and Disease · doi:10.1038/cddis.2011.15 · Cited by 84
“Hyperglycemia-induced oxidative stress has been shown to induce mitochondrial permeability transition and subsequent cell death in human endothelial cells.(11) Concerning pancreatic-derived cells, CsA has been shown to inhibit Ca2þ -induced PTP opening in permeabilized INS-1 and MIN-6 cells.”
Self-citation
Sequential events of apoptosis involving docetaxel, a microtubule-interfering agent: A cytometric study
Fabbri, F., Carloni, S., Brigliadori, G., Zoli, W., Lapalombella, R., & Marini, M. (2006) · BMC Cell Biology · doi:10.1186/1471-2121-7-6 · Cited by 75
“For this preliminary experiment we used a concentration of 1 µM [ 39 ].”
Method
Ginsenoside Rd ameliorates high glucose-induced retinal endothelial injury through AMPK-STRT1 interdependence
Tang, K., Qin, W., Wei, R.-Y., Jiang, Y.-Y., Fan, L., Wang, Z., & Tan, N. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106123 · Cited by 74
Treatment of the Fluoroquinolone‐Associated Disability: The Pathobiochemical Implications
Michalak, K. P., Sobolewska-Włodarczyk, A., Włodarczyk, M., Sobolewska, J., Woźniak, P., & Sobolewski, B. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/8023935 · Cited by 76
“Cyclosporine A and metformin are postulated to be able to close PTPs [102, 103] and protect against OS [102, 104–106]; thus, it is an interesting substance for possible FQAD treatment.”
Background
Maillard Reaction, mitochondria and oxidative stress: Potential role of antioxidants
Edeas, M. A., Attaf, D., Mailfert, A.-S., Nasu, M., & Joubet, R. (2009) · Pathologie Biologie · doi:10.1016/j.patbio.2009.09.011 · Cited by 74
Cognitive Impairment in Frail Hypertensive Elderly Patients: Role of Hyperglycemia
Mone, P., Gambardella, J., Pansini, A., Donato, A. D., Martinelli, G., Boccalone, E., Matarese, A., Frullone, S., & Santulli, G. (2021) · Cells · doi:10.3390/cells10082115 · Cited by 72
Metformin overdose causes platelet mitochondrial dysfunction in humans
Protti, A., Lecchi, A., Fortunato, F., Artoni, A., Greppi, N., Vecchio, S., Fagiolari, G., Moggio, M. G., Comi, G. P., Mistraletti, G., et al. (2012) · Critical Care · doi:10.1186/cc11663 · Cited by 71
“Others have observed, usually in vitro, that metformin overdose can alter mitochondrial activity in several other tissues including animal cerebral cortex [19], pancreatic beta cells [20], neutrophils [21] and oocytes [22] and human endothelial [23], carcinoma-derived (KB) [24] and adrenal [25] cells.”
Background
Sub-nanoliter metabolomics via mass spectrometry to characterize volume-limited samples
Li, Y., Bouza, M., Wu, C., Guo, H., Huang, D., Doron, G., Temenoff, J. S., Stecenko, A. A., Wang, Z. L., & Fernández, F. M. (2020) · Nature Communications · doi:10.1038/s41467-020-19444-y · Cited by 67
Metformin raises hydrogen sulfide tissue concentrations in various mouse organs
Wiliński, B., Wiliński, J., Somogyi, E., Piotrowska, J., & Opoka, W. (2013) · Pharmacological Reports · doi:10.1016/s1734-1140(13)71053-3 · Cited by 67
“Metformin prevented high-glucose-induced cell death in endothelium [5].”
Background
Metformin protects primary rat hepatocytes against oxidative stress‐induced apoptosis
de la Rosa, L. C., Vrenken, T. E., Buist‐Homan, M., Faber, K. N., & Moshage, H. J. (2015) · Pharmacology Research & Perspectives · doi:10.1002/prp2.125 · Cited by 66
Cardiovascular impact of drugs used in the treatment of diabetes
Triggle, C. R., & Ding, H. (2014) · Therapeutic Advances in Chronic Disease · doi:10.1177/2040622314546125 · Cited by 67
“A direct mitochondrial action may also explain the ability of metformin to inhibit glucose-induced endothelial cell death via inhibiting the opening of permeability transition pore; in this regard the effects of metformin are comparable to those of the antioxidant N-acetyl-cysteine [Detaille et al. 2005].”
Result
Neuroprotective Effects of Metformin Through the Modulation of Neuroinflammation and Oxidative Stress
Reed, S., Taka, E., Darling‐Reed, S., & Soliman, K. F. A. (2025) · Cells · doi:10.3390/cells14141064 · Cited by 76
“By mitigating oxidative stress, metformin decreases lipid peroxidation, thereby preserving neuronal cell membranes’ integrity and preventing cell death [198].”
Metformin as an adjuvant in breast cancer treatment
Roshan, M. H. K., Shing, Y. K., & Pace, N. P. (2019) · SAGE Open Medicine · doi:10.1177/2050312119865114 · Cited by 63
The mechanism by which imeglimin inhibits gluconeogenesis in rat liver cells
Vial, G., Lamarche, F., Cottet‐Rousselle, C., Hallakou‐Bozec, S., Borel, A., & Fontaine, E. M. (2021) · Endocrinology Diabetes & Metabolism · doi:10.1002/edm2.211 · Cited by 65
Self-citation
Metformin overdose, but not lactic acidosis per se, inhibits oxygen consumption in pigs
Protti, A., Fortunato, F., Monti, M., Vecchio, S., Gatti, S., Comi, G. P., Giuseppe, R. D., & Gattinoni, L. (2012) · Critical Care · doi:10.1186/cc11332 · Cited by 64
“In vitro, it dose-dependently inhibits mitochondrial function even in cells other than hepatocytes [27-32].”
Background
Biguanides Inhibit Complex I, II and IV of Rat Liver Mitochondria and Modify Their Functional Properties
Drahota, Z., Páleníčková, E., Endlicher, R., Milerová, M., Brejchová, J., Vošahlíková, M., Svoboda, P., Kazdova, L., Kalous, M., Červinková, Z., et al. (2014) · Physiological Research · doi:10.33549/physiolres.932600 · Cited by 64
“Phenformin increases the resistance of mitochondrial permeability pore to Ca2+ Several reports indicate that biguanides can modify the function of the mitochondrial permeability transition pore (Detaille et al. 2005, Guigas et al. 2004).”
Background
VDAC: old protein with new roles in diabetes
Sasaki, K., Donthamsetty, R., Heldak, M., Cho, Y.-E., Scott, B. T., & Makino, A. (2012) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00087.2012 · Cited by 61
The beneficial effects of AMP kinase activation against oxidative stress are associated with prevention of PPARα-cyclophilin D interaction in cardiomyocytes
Barreto‐Torres, G., Hernández, J. S., Jang, S., Rodríguez‐Muñoz, A., Torres‐Ramos, C. A., Basnakian, A. G., & Javadov, S. A. (2015) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00414.2014 · Cited by 62
“Beneficial effects of AMPK activation by various pharmacological agents are mostly mediated through mitochondrial mechanisms, in particular, the inhibition of PTP opening (4, 6, 10).”
Background
Effects of the Nrf2 Protein Modulator Salvianolic Acid A Alone or Combined with Metformin on Diabetes-associated Macrovascular and Renal Injury
Wu, P., Yan, Y., Ma, L., Hou, B., He, Y., Zhang, L., Niu, Z., Song, J.-K., Pang, X.-C., Yang, X., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.712703 · Cited by 63
Metformin attenuates rotenone-induced oxidative stress and mitochondrial damage via the AKT/Nrf2 pathway
Katila, N., Bhurtel, S., Park, P., & Choi, D. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.105120 · Cited by 61
Antidiabetic drug metformin alleviates endotoxin-induced fulminant liver injury in mice
Yuan, H., Li, L., Zheng, W., Wan, J., Ge, P., Li, H., & Zhang, L. (2012) · International Immunopharmacology · doi:10.1016/j.intimp.2012.01.015 · Cited by 59
Effects of imeglimin on mitochondrial function, AMPK activity, and gene expression in hepatocytes
Hozumi, K., Sugawara, K., Ishihara, T., Ishihara, N., & Ogawa, W. (2023) · Scientific Reports · doi:10.1038/s41598-023-27689-y · Cited by 62
Red ginseng abrogates oxidative stress via mitochondria protection mediated by LKB1-AMPK pathway
Dong, G.-Z., Jang, E. J., Kang, S. H., Cho, I. J., Park, S., Kim, S. C., & Kim, Y. W. (2013) · BMC Complementary and Alternative Medicine · doi:10.1186/1472-6882-13-64 · Cited by 58
“This crucial role is supported by increases in cell survival upon treatment with the AMPK activators metformin and 5-aminoimidazole-4-carboxamide1-β-D-ribofuranoside (AICAR) [9,10].”
BackgroundMethod

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