Metformin Prevents High-Glucose–Induced Endothelial Cell Death Through a Mitochondrial Permeability Transition-Dependent Process
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.
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Oxidative stress has been implicated in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.
“Oxidative stress has been implicated in a variety of neurological diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis disease [126].”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [126]
Cites
Biochemistry and molecular cell biology of diabetic complications
Brownlee, M. (2001) · Nature · doi:10.1038/414813a · Cited by 9,107 · see citing works
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 · see citing works
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 · see citing works
OWEN, M. R., DORAN, E., & HALESTRAP, A. P. (2000) · Biochemical Journal · doi:10.1042/bj3480607 · Cited by 2,157 · see citing works
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 1,915 · see citing works
Bailey, C. J., & Turner, R. C. (1996) · New England Journal of Medicine · doi:10.1056/nejm199602293340906 · Cited by 1,726 · see citing works
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 · see citing works
Self-citationHMEC-1: Establishment of an Immortalized Human Microvascular Endothelial Cell Line
Ades, E. W., Candal, F. J., Swerlick, R. A., George, V. G., Summers, S., Bosse, D. C., & Lawley, T. J. (1992) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12613748 · Cited by 1,265 · see citing works
Biochemical and molecular investigations in respiratory chain deficiencies
Rustin, P., Chrétien, D., Bourgeron, T., Gérard, B., Rötig, A., Saudubray, J., & Münnich, A. (1994) · Clinica Chimica Acta · doi:10.1016/0009-8981(94)90055-8 · Cited by 1,239 · see citing works
Gottlob, K., Majewski, N., Kennedy, S., Kandel, E., Robey, R. B., & Hay, N. (2001) · Genes & Development · doi:10.1101/gad.889901 · Cited by 961 · see citing works
R�sen, P., Nawroth, P., King, G. L., M�ller, W., Tritschler, H., & Packer, L. (2001) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.196 · Cited by 881 · see citing works
Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c
Rossé, T., Olivier, R., Monney, L., Rager, M., Conus, S., Fellay, I., Jansen, B., & Borner, C. (1998) · Nature · doi:10.1038/35160 · Cited by 870 · see citing works
Du, X., Matsumura, T., Edelstein, D., Rossetti, L., Zsengellér, Z. K., Szabó, C., & Brownlee, M. (2003) · Journal of Clinical Investigation · doi:10.1172/jci18127 · Cited by 832 · see citing works
Bernardi, P., Scorrano, L., Colonna, R., Petronilli, V., & Lisa, F. D. (1999) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.1999.00725.x · Cited by 755 · see citing works
Hawley, S. A., Gadalla, A. E., Olsen, G. S., & Hardie, D. G. (2002) · Diabetes · doi:10.2337/diabetes.51.8.2420 · Cited by 696 · see citing works
Petronilli, V., Miotto, G., Canton, M., Brini, M., Colonna, R., Bernardi, P., & Lisa, F. D. (1999) · Biophysical Journal · doi:10.1016/s0006-3495(99)77239-5 · Cited by 677 · see citing works
Bailey, C. J. (1992) · Diabetes Care · doi:10.2337/diacare.15.6.755 · Cited by 593 · see citing works
Mitochondria are morphologically and functionally heterogeneous within cells
Collins, T. J., Berridge, M. J., Lipp, P., & Bootman, M. D. (2002) · The EMBO Journal · doi:10.1093/emboj/21.7.1616 · Cited by 588 · see citing works
Thiazolidinediones, Like Metformin, Inhibit Respiratory Complex I
Brunmair, B., Staniek, K., Gras, F., Scharf, N., Althaym, A., Clara, R., Roden, M., Gnaiger, E., Nohl, H., Waldhäusl, W., et al. (2004) · Diabetes · doi:10.2337/diabetes.53.4.1052 · Cited by 521 · see citing works
Mitochondria, the killer organelles and their weapons
Ravagnan, L., Roumier, T., & Kroemer, G. (2002) · Journal of Cellular Physiology · doi:10.1002/jcp.10111 · Cited by 484 · see citing works
The Mitochondrial Permeability Transition, Release of Cytochrome c and Cell Death
Petronilli, V., Penzo, D., Scorrano, L., Bernardi, P., & Di Lisa, F. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010604200 · Cited by 472 · see citing works
Mitochondrial Dysfunction in the Pathogenesis of Necrotic and Apoptotic Cell Death
Lemasters, J. J., Qian, T., Bradham, C. A., Brenner, D. A., Cascio, W. E., Trost, L. C., Nishimura, Y., Nieminen, A., & Herman, B. A. (1999) · Journal of Bioenergetics and Biomembranes · doi:10.1023/a:1005419617371 · Cited by 406 · see citing works
Control of mitochondrial permeability by Bcl-2 family members
Sharpe, J. C., Arnoult, D., & Youle, R. J. (2004) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2003.10.016 · Cited by 367 · see citing works
Regulation of the Permeability Transition Pore in Skeletal Muscle Mitochondria
Fontaine, E. M., Eriksson, O., Ichas, F., & Bernardi, P. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.20.12662 · Cited by 347 · see citing works
Self-citationHyperglycemia-Induced Apoptosis in Human Umbilical Vein Endothelial Cells
Ido, Y., Carling, D., & Ruderman, N. B. (2002) · Diabetes · doi:10.2337/diabetes.51.1.159 · Cited by 323 · see citing works
Dumont, A., Hehner, S. P., Hofmann, T. G., Ueffing, M., Dröge, W., & Schmitz, M. L. (1999) · Oncogene · doi:10.1038/sj.onc.1202325 · Cited by 316 · see citing works
Guigas, B., Détaille, D., Chauvin, C., Batandier, C., Oliveira, F. D., Fontaine, E. M., & Leverve, X. M. (2004) · Biochemical Journal · doi:10.1042/bj20040885 · Cited by 148 · see citing works
Self-citationFontaine, E. M., & Bernardi, P. (1999) · Journal of Bioenergetics and Biomembranes · doi:10.1023/a:1005475802350 · Cited by 146 · see citing works
Self-citationApoptosis and necrosis in health and disease: Role of mitochondria
Nieminen, A. (2003) · International review of cytology · doi:10.1016/s0074-7696(05)24002-0 · Cited by 145 · see citing works
Rotenone Inhibits the Mitochondrial Permeability Transition-induced Cell Death in U937 and KB Cells
Chauvin, C., Oliveira, F. D., Ronot, X., Mousseau, M., Leverve, X. M., & Fontaine, E. M. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m106417200 · Cited by 142 · see citing works
Self-citationMitochondrial metabolism and type-2 diabetes: a specific target of metformin
Leverve, X. M., Guigas, B., Détaille, D., Batandier, C., Koceir, E.-A., Chauvin, C., Fontaine, E. M., & Wiernsperger, N. F. (2003) · Diabetes & Metabolism · doi:10.1016/s1262-3636(03)72792-x · Cited by 131 · see citing works
Self-citationDétaille, D., Guigas, B., Leverve, X. M., Wiernsperger, N. F., & Devos, P. E. (2002) · Biochemical Pharmacology · doi:10.1016/s0006-2952(02)00858-4 · Cited by 97 · see citing works
Self-citationMetformin: Intrinsic Vasculoprotective Properties
Wiernsperger, N. F. (2000) · Diabetes Technology & Therapeutics · doi:10.1089/15209150050025230 · Cited by 75 · see citing works
Self-citationOxidative stress: The special case of diabetes
Wiernsperger, N. F. (2003) · BioFactors · doi:10.1002/biof.5520190103 · Cited by 43 · see citing works
Self-citationGuidarelli, A., Brambilla, L., Clementi, E., Sciorati, C., & Cantoni, O. (1997) · Experimental Cell Research · doi:10.1006/excr.1997.3779 · Cited by 27 · see citing works
Sestili, P., Brambilla, L., & Cantoni, O. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)01027-3 · Cited by 16 · see citing works
What's in a risk factor? “He who strikes the ball”
Capron, L. (2003) · Diabetes & Metabolism · doi:10.1016/s1262-3636(07)70001-0 · Cited by 16 · see citing works
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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 · see citing works
“Also glucose, at high concentrations, may have proapoptotic effects due to the local generation of ROS (181).”
BackgroundCellular 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 · see citing works
Self-citationMetformin: 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 · see citing works
Self-citationKinaan, M., Ding, H., & Triggle, C. R. (2015) · Medical Principles and Practice · doi:10.1159/000381643 · Cited by 1,515 · see citing works
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 · see citing works
“, 2005) as well as to increased endothelial cell death and detachment (Detaille et al., 2005).”
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 · see citing works
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 · see citing works
Self-citationMetformin: 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 · see citing works
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 · see citing works
“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…”
BackgroundYu, T., Sheu, S.-S., Robotham, J. L., & Yoon, Y. (2008) · Cardiovascular Research · doi:10.1093/cvr/cvn104 · Cited by 462 · see citing works
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 · see citing works
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 345 · see citing works
“Here we discuss mitochondria-directed antioxidants and interventions that improve mitochondria functions.”
BackgroundRole 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 · see citing works
Self-citationBatandier, C., Guigas, B., Détaille, D., El-Mir, M. Y. A., Fontaine, E. M., Rigoulet, M., & Leverve, X. M. (2006) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-006-9003-8 · Cited by 306 · see citing works
Self-citationYu, T., Jhun, B. S., & Yoon, Y. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3284 · Cited by 286 · see citing works
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 · see citing works
Self-citationStephenne, 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 · see citing works
“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…”
BackgroundPaone, 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 277 · see citing works
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 · see citing works
Self-citationObesity-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 267 · see citing works
“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…”
BackgroundRomán-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 252 · see citing works
“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…”
BackgroundDiamanti‐Kandarakis, E., Christakou, C. D., Kandaraki, E., & Economou, F. (2009) · European Journal of Endocrinology · doi:10.1530/eje-09-0733 · Cited by 246 · see citing works
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 · see citing works
“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-citationPintana, H., Apaijai, N., Pratchayasakul, W., Chattipakorn, N., & Chattipakorn, S. C. (2012) · Life Sciences · doi:10.1016/j.lfs.2012.08.017 · Cited by 236 · see citing works
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 · see citing works
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 · see citing works
“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).”
BackgroundMitochondrial 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 216 · see citing works
“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 · see citing works
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 219 · see citing works
“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 218 · see citing works
“…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).”
BackgroundBhamra, 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 207 · see citing works
“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].”
BackgroundDual 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 204 · see citing works
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 184 · see citing works
“…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…”
InfluentialLee, H. J., Jung, Y., Choi, G., Kim, J. S., Chang, W.-C., Lim, J. R., Kim, S. Y., Yoon, J., Cho, J. H., Lee, S.-J., et al. (2020) · Cell Death and Differentiation · doi:10.1038/s41418-020-0593-1 · Cited by 1 · see citing works
Ullah, I., Ullah, N., Naseer, M. I., Lee, H., & Kim, M. (2012) · BMC Neuroscience · doi:10.1186/1471-2202-13-11 · Cited by 168 · see citing works
“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].”
BackgroundPop-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 · see citing works
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 155 · see citing works
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 150 · see citing works
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 · see citing works
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 149 · see citing works
“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,…”
BackgroundBertrand, 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 144 · see citing works
Self-citationMetformin 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 144 · see citing works
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 137 · see citing works
“cell death in isolated endothelial and vascular smooth muscle cells [81,85].”
BackgroundPop‐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 · see citing works
“, 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.”
BackgroundHigh 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 · see citing works
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 · see citing works
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 123 · see citing works
“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 · see citing works
Guigas, B., Taleux, N., Foretz, M., Détaille, D., Andréelli, F., Viollet, B., & Hue, L. (2007) · Biochemical Journal · doi:10.1042/bj20070105 · Cited by 117 · see citing works
Self-citationChoi, S. H., Kim, Y. W., & Kim, S. G. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.12.011 · Cited by 116 · see citing works
“, 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 116 · see citing works
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 · see citing works
“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].”
BackgroundPicone, 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 114 · see citing works
Durham, A. E., Rendle, D. I., & Newton, J. R. (2008) · Equine Veterinary Journal · doi:10.2746/042516408x273648 · Cited by 113 · see citing works
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 111 · see citing works
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 110 · see citing works
“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.”
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 107 · see citing works
Self-citationHan, G., Gong, H., Wang, Y., Guo, S., & Liu, K. (2014) · Cancer Biology & Therapy · doi:10.4161/15384047.2014.987021 · Cited by 107 · see citing works
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 104 · see citing works
“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.”
BackgroundLin, 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 103 · see citing works
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 · see citing works
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 100 · see citing works
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 · see citing works
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 · see citing works
“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].”
BackgroundInfluentialDetaille, 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 · see citing works
Self-citationTriggle, C. R., & Ding, H. (2015) · Acta Physiologica · doi:10.1111/apha.12644 · Cited by 99 · see citing works
“…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).”
BackgroundCan 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 · see citing works
“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].”
BackgroundMechanisms 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 96 · see citing works
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 · see citing works
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 · see citing works
“[124] Detaille D, Guigas B, Chauvin C, Batandier C, Fontaine E,”
BackgroundPicard, 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 90 · see citing works
“Similar measurements have been previously reported in permeabilized hepatocytes and various cell lines (13, 17, 23).”
ResultOresta, 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 · see citing works
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 · see citing works
“…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).”
BackgroundMetformin 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 86 · see citing works
“Mol Cell Biochem (2008) 308:75‐83 DOI 10.1007/s11010-007-9614-3 cells (HMEC-1) [ 9 ].”
InfluentialMitochondrial function and substrate availability
Leverve, X. M. (2007) · Critical Care Medicine · doi:10.1097/01.ccm.0000278044.19217.73 · Cited by 85 · see citing works
Self-citationMitochondrial 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 83 · see citing works
“, 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.”
BackgroundInfluentialIsmaiel, 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 · see citing works
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 79 · see citing works
“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-citationFabbri, 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 · see citing works
“For this preliminary experiment we used a concentration of 1 µM [ 39 ].”
MethodTang, 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 73 · see citing works
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 73 · see citing works
“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.”
BackgroundMaillard 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 72 · see citing works
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 70 · see citing works
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 70 · see citing works
“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.”
BackgroundSub-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 · see citing works
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 · see citing works
“Metformin prevented high-glucose-induced cell death in endothelium [5].”
BackgroundMetformin 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 67 · see citing works
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 66 · see citing works
“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].”
ResultReed, S., Taka, E., Darling‐Reed, S., & Soliman, K. F. A. (2025) · Cells · doi:10.3390/cells14141064 · Cited by 71 · see citing works
“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 · see citing works
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 · see citing works
Self-citationMetformin 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 · see citing works
“In vitro, it dose-dependently inhibits mitochondrial function even in cells other than hepatocytes [27-32].”
BackgroundDrahota, 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 63 · see citing works
“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).”
BackgroundVDAC: 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 62 · see citing works
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 61 · see citing works
“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).”
BackgroundWu, 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 61 · see citing works
Katila, N., Bhurtel, S., Park, P., & Choi, D. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.105120 · Cited by 59 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
“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)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2005-07-01
- Volume
- 54
- Issue
- 7
- Pages
- 2179-2187
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- 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
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