E. Selvin, S. Bolen, H. Yeh, C. Wiley, L. Wilson et al., Cardiovascular Outcomes in Trials of Oral Diabetes Medications, Archives of Internal Medicine, vol.168, issue.19, pp.2070-2080, 2008.
DOI : 10.1001/archinte.168.19.2070

C. Lamanna, M. Monami, N. Marchionni, and E. Mannucci, Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials, Diabetes, Obesity and Metabolism, vol.46, issue.3, pp.221-228, 2011.
DOI : 10.1111/j.1463-1326.2010.01349.x

J. Gunton, P. Delhanty, S. Takahashi, and R. Baxter, Metformin Rapidly Increases Insulin Receptor Activation in Human Liver and Signals Preferentially through Insulin-Receptor Substrate-2, The Journal of Clinical Endocrinology & Metabolism, vol.88, issue.3, pp.1323-1332, 2003.
DOI : 10.1210/jc.2002-021394

A. Maida, B. Lamont, X. Cao, and D. Drucker, Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-?? in mice, Diabetologia, vol.59, issue.Suppl 1, pp.339-349, 2011.
DOI : 10.1007/s00125-010-1937-z

K. Cusi, A. Consoli, and R. Defronzo, Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus, J Clin Endocrinol Metab, vol.81, pp.4059-4067, 1996.

R. Hundal, M. Krssak, S. Dufour, D. Laurent, V. Lebon et al., Mechanism by which metformin reduces glucose production in type 2 diabetes, Diabetes, vol.49, issue.12, pp.2063-2069, 2000.
DOI : 10.2337/diabetes.49.12.2063

A. Natali and E. Ferrannini, Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review, Diabetologia, vol.27, issue.3, pp.434-441, 2006.
DOI : 10.1007/s00125-006-0141-7

D. Argaud, H. Roth, N. Wiernsperger, and X. Leverve, Metformin decreases gluconeogenesis by enhancing the pyruvate kinase flux in isolated rat hepatocytes, European Journal of Biochemistry, vol.119, issue.3, pp.1341-1348, 1993.
DOI : 10.1016/0014-5793(76)80865-4

URL : https://hal.archives-ouvertes.fr/inserm-00390262

V. Large and M. Beylot, Modifications of citric acid cycle activity and gluconeogenesis in streptozotocin-induced diabetes and effects of metformin, Diabetes, vol.48, issue.6, pp.1251-1257, 1999.
DOI : 10.2337/diabetes.48.6.1251

G. Mithieux, L. Guignot, J. Bordet, and N. Wiernsperger, Intrahepatic Mechanisms Underlying the Effect of Metformin in Decreasing Basal Glucose Production in Rats Fed a High-Fat Diet, Diabetes, vol.51, issue.1, pp.139-143, 2002.
DOI : 10.2337/diabetes.51.1.139

J. Radziuk, Z. Zhang, N. Wiernsperger, and S. Pye, Effects of Metformin on Lactate Uptake and Gluconeogenesis in the Perfused Rat Liver, Diabetes, vol.46, issue.9, pp.1406-1413, 1997.
DOI : 10.2337/diab.46.9.1406

Y. Shu, S. Sheardown, C. Brown, R. Owen, S. Zhang et al., Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action, Journal of Clinical Investigation, vol.117, issue.5, pp.1422-1431, 2007.
DOI : 10.1172/JCI30558DS1

C. Wilcock and C. Bailey, Accumulation of metformin by tissues of the normal and diabetic mouse, Xenobiotica, vol.37, issue.1, pp.49-57, 1994.
DOI : 10.1016/S0168-8227(88)80022-6

G. Zhou, R. Myers, Y. Li, Y. Chen, X. Shen et al., Role of AMP-activated protein kinase in mechanism of metformin action, Journal of Clinical Investigation, vol.108, issue.8, pp.1167-1174, 2001.
DOI : 10.1172/JCI13505

B. Viollet, B. Guigas, J. Leclerc, S. Hebrard, L. Lantier et al., AMP-activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives, Acta Physiologica, vol.108, issue.Pt 1, pp.81-98, 2009.
DOI : 10.1111/j.1748-1716.2009.01970.x

URL : https://hal.archives-ouvertes.fr/inserm-00363222

J. Oakhill, R. Steel, Z. Chen, J. Scott, N. Ling et al., AMPK Is a Direct Adenylate Charge-Regulated Protein Kinase, Science, vol.332, issue.6036, pp.1433-1435, 2011.
DOI : 10.1126/science.1200094

B. Xiao, M. Sanders, E. Underwood, R. Heath, F. Mayer et al., Structure of mammalian AMPK and its regulation by ADP, Nature, vol.50, issue.7342, pp.230-233, 2011.
DOI : 10.1038/nature09932

D. Hardie, Neither LKB1 Nor AMPK Are the Direct Targets of Metformin, Gastroenterology, vol.131, issue.3, pp.973-975, 2006.
DOI : 10.1053/j.gastro.2006.07.032

M. El-mir, V. Nogueira, E. Fontaine, N. Averet, M. Rigoulet et al., Dimethylbiguanide Inhibits Cell Respiration via an Indirect Effect Targeted on the Respiratory Chain Complex I, Journal of Biological Chemistry, vol.275, issue.1, pp.223-228, 2000.
DOI : 10.1074/jbc.275.1.223

URL : https://hal.archives-ouvertes.fr/inserm-00390049

M. Owen, E. Doran, and A. Halestrap, Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain, Biochemical Journal, vol.348, issue.3, pp.607-614, 2000.
DOI : 10.1042/bj3480607

B. Brunmair, K. Staniek, F. Gras, N. Scharf, A. Althaym et al., Thiazolidinediones, Like Metformin, Inhibit Respiratory Complex I: A Common Mechanism Contributing to Their Antidiabetic Actions?, Diabetes, vol.53, issue.4, pp.1052-1059, 2004.
DOI : 10.2337/diabetes.53.4.1052

D. Detaille, B. Guigas, C. Chauvin, C. Batandier, E. Fontaine et al., Metformin Prevents High-Glucose-Induced Endothelial Cell Death Through a Mitochondrial Permeability Transition-Dependent Process, Diabetes, vol.54, issue.7, pp.2179-2187, 2005.
DOI : 10.2337/diabetes.54.7.2179

URL : https://hal.archives-ouvertes.fr/inserm-00388755

S. Hinke, G. Martens, Y. Cai, J. Finsi, H. Heimberg et al., Methyl succinate antagonises biguanide-induced AMPK-activation and death of pancreatic ??-cells through restoration of mitochondrial electron transfer, British Journal of Pharmacology, vol.108, issue.Part 3, pp.1031-1043, 2007.
DOI : 10.1038/sj.bjp.0707189

M. El-mir, D. Detaille, G. Delgado-esteban, M. Guigas, B. Attia et al., Neuroprotective Role of Antidiabetic Drug Metformin Against Apoptotic Cell Death in Primary Cortical Neurons, Journal of Molecular Neuroscience, vol.279, issue.Suppl 4bis, pp.77-87, 2008.
DOI : 10.1007/s12031-007-9002-1

URL : https://hal.archives-ouvertes.fr/inserm-00388540

X. Stephenne, M. Foretz, N. Taleux, G. Van-der-zon, E. Sokal et al., Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status . Diabetologia . in the press, 2011.

D. Detaille, B. Guigas, X. Leverve, N. Wiernsperger, and P. Devos, Obligatory role of membrane events in the regulatory effect of metformin on the respiratory chain function, Biochemical Pharmacology, vol.63, issue.7, pp.1259-1272, 2002.
DOI : 10.1016/S0006-2952(02)00858-4

URL : https://hal.archives-ouvertes.fr/inserm-00389975

B. Guigas, D. Detaille, C. Chauvin, C. Batandier, D. Oliveira et al., study, Biochemical Journal, vol.382, issue.3, pp.877-884, 2004.
DOI : 10.1042/BJ20040885

URL : https://hal.archives-ouvertes.fr/inserm-00387151

H. Schafer, L. Mainka, G. Rathgeber, and G. Zimmer, Photoaffinity cross-linking of oligomycin-sensitive ATPase from beef heart mitochondria by 3???-arylazido-8-azido ATP, Biochemical and Biophysical Research Communications, vol.111, issue.2, pp.732-739, 1983.
DOI : 10.1016/0006-291X(83)90366-2

C. Batandier, B. Guigas, D. Detaille, M. El-mir, E. Fontaine et al., The ROS Production Induced by a Reverse-Electron Flux at Respiratory-Chain Complex 1 is Hampered by Metformin, Journal of Bioenergetics and Biomembranes, vol.79, issue.1, pp.33-42, 2006.
DOI : 10.1007/s10863-006-9003-8

URL : https://hal.archives-ouvertes.fr/inserm-00388702

D. Kane, E. Anderson, J. Price, T. Woodlief, C. Lin et al., Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats, Free Radical Biology and Medicine, vol.49, issue.6, pp.1082-1087, 2010.
DOI : 10.1016/j.freeradbiomed.2010.06.022

H. Freisleben, S. Ruckert, N. Wiernsperger, and G. Zimmer, The effects of glucose, insulin and metformin on the order parameters of isolated red cell membranes, Biochemical Pharmacology, vol.43, issue.6, pp.1185-1194, 1992.
DOI : 10.1016/0006-2952(92)90491-Z

S. Muller, S. Denet, H. Candiloros, R. Barrois, N. Wiernsperger et al., Action of metformin on erythrocyte membrane fluidity in vitro and in vivo, European Journal of Pharmacology, vol.337, issue.1, 1997.
DOI : 10.1016/S0014-2999(97)01287-9

S. Hawley, F. Ross, C. Chevtzoff, K. Green, A. Evans et al., Use of Cells Expressing ?? Subunit Variants to Identify Diverse Mechanisms of AMPK Activation, Cell Metabolism, vol.11, issue.6, pp.554-565, 2010.
DOI : 10.1016/j.cmet.2010.04.001

R. Shaw, K. Lamia, D. Vasquez, S. Koo, N. Bardeesy et al., The Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic Effects of Metformin, Science, vol.310, issue.5754, pp.1642-1646, 2005.
DOI : 10.1126/science.1120781

S. Koo, L. Flechner, L. Qi, X. Zhang, R. Screaton et al., The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism, Nature, vol.50, issue.7062, pp.1109-1111, 2005.
DOI : 10.1111/j.1432-1033.2004.04372.x

R. Dentin, S. Hedrick, J. Xie, J. Yates, and M. Montminy, Hepatic Glucose Sensing via the CREB Coactivator CRTC2, Science, vol.319, issue.5868, pp.1402-1405, 2008.
DOI : 10.1126/science.1151363

P. Caton, N. Nayuni, J. Kieswich, N. Khan, M. Yaqoob et al., Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5, Journal of Endocrinology, vol.205, issue.1, 2010.
DOI : 10.1677/JOE-09-0345

Y. Liu, R. Dentin, D. Chen, S. Hedrick, K. Ravnskjaer et al., A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange, Nature, vol.104, issue.7219, pp.269-273, 2008.
DOI : 10.1038/nature07349

L. He, A. Sabet, S. Djedjos, R. Miller, X. Sun et al., Metformin and Insulin Suppress Hepatic Gluconeogenesis through Phosphorylation of CREB Binding Protein, Cell, vol.137, issue.4, pp.635-646, 2009.
DOI : 10.1016/j.cell.2009.03.016

Y. Kim, K. Park, Y. Lee, Y. Park, D. Kim et al., Metformin Inhibits Hepatic Gluconeogenesis Through AMP-Activated Protein Kinase-Dependent Regulation of the Orphan Nuclear Receptor SHP, Diabetes, vol.57, issue.2, pp.306-314, 2008.
DOI : 10.2337/db07-0381

M. Takashima, W. Ogawa, K. Hayashi, H. Inoue, S. Kinoshita et al., Role of KLF15 in Regulation of Hepatic Gluconeogenesis and Metformin Action, Diabetes, vol.59, issue.7, pp.1608-1615, 2010.
DOI : 10.2337/db09-1679

M. Foretz, S. Hebrard, J. Leclerc, E. Zarrinpashneh, M. Soty et al., Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state, Journal of Clinical Investigation, vol.120, issue.7, pp.2355-2369, 2010.
DOI : 10.1172/JCI40671DS1

URL : https://hal.archives-ouvertes.fr/inserm-00495746

R. Miller and M. Birnbaum, An energetic tale of AMPK-independent effects of metformin, Journal of Clinical Investigation, vol.120, issue.7, pp.2267-2270, 2010.
DOI : 10.1172/JCI43661

H. Lin, S. Yang, C. Chuckaree, F. Kuhajda, G. Ronnet et al., Metformin reverses fatty liver disease in obese, leptin-deficient mice, Nat Med, vol.6, pp.998-1003, 2000.

G. Raso, E. Esposito, A. Iacono, M. Pacilio, S. Cuzzocrea et al., Comparative therapeutic effects of metformin and vitamin E in a model of non-alcoholic steatohepatitis in the young rat, European Journal of Pharmacology, vol.604, issue.1-3, pp.125-131, 2009.
DOI : 10.1016/j.ejphar.2008.12.013

G. Marchesini, M. Brizi, G. Bianchi, S. Tomassetti, M. Zoli et al., Metformin in non-alcoholic steatohepatitis, The Lancet, vol.358, issue.9285, pp.893-894, 2001.
DOI : 10.1016/S0140-6736(01)06042-1

S. Nair, A. Diehl, M. Wiseman, G. Farr, . Jr et al., Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial, Alimentary Pharmacology and Therapeutics, vol.49, issue.1, pp.23-28, 2004.
DOI : 10.1073/pnas.95.25.14751

M. Zang, A. Zuccollo, X. Hou, D. Nagata, K. Walsh et al., AMP-activated Protein Kinase Is Required for the Lipid-lowering Effect of Metformin in Insulin-resistant Human HepG2 Cells, Journal of Biological Chemistry, vol.279, issue.46, pp.47898-47905, 2004.
DOI : 10.1074/jbc.M408149200

M. Foretz, N. Ancellin, F. Andreelli, Y. Saintillan, P. Grondin et al., Short-Term Overexpression of a Constitutively Active Form of AMP-Activated Protein Kinase in the Liver Leads to Mild Hypoglycemia and Fatty Liver, Diabetes, vol.54, issue.5, pp.1331-1339, 2005.
DOI : 10.2337/diabetes.54.5.1331

M. Foretz, D. Carling, C. Guichard, P. Ferre, and F. Foufelle, AMP-activated Protein Kinase Inhibits the Glucose-activated Expression of Fatty Acid Synthase Gene in Rat Hepatocytes, Journal of Biological Chemistry, vol.273, issue.24, pp.14767-14771, 1998.
DOI : 10.1074/jbc.273.24.14767

Y. Hong, U. Varanasi, W. Yang, and T. Leff, AMP-activated Protein Kinase Regulates HNF4?? Transcriptional Activity by Inhibiting Dimer Formation and Decreasing Protein Stability, Journal of Biological Chemistry, vol.278, issue.30, pp.27495-27501, 2003.
DOI : 10.1074/jbc.M304112200

T. Kawaguchi, K. Osatomi, H. Yamashita, T. Kabashima, and K. Uyeda, Mechanism for Fatty Acid "Sparing" Effect on Glucose-induced Transcription: REGULATION OF CARBOHYDRATE-RESPONSIVE ELEMENT-BINDING PROTEIN BY AMP-ACTIVATED PROTEIN KINASE, Journal of Biological Chemistry, vol.277, issue.6, pp.3829-3835, 2002.
DOI : 10.1074/jbc.M107895200

I. Leclerc, C. Lenzner, L. Gourdon, S. Vaulont, A. Kahn et al., Hepatocyte Nuclear Factor-4?? Involved in Type 1 Maturity-Onset Diabetes of the Young Is a Novel Target of AMP-Activated Protein Kinase, Diabetes, vol.50, issue.7, pp.1515-1521, 2001.
DOI : 10.2337/diabetes.50.7.1515

W. Yang, Y. Hong, X. Shen, C. Frankowski, H. Camp et al., Regulation of Transcription by AMP-activated Protein Kinase: PHOSPHORYLATION OF p300 BLOCKS ITS INTERACTION WITH NUCLEAR RECEPTORS, Journal of Biological Chemistry, vol.276, issue.42, pp.38341-38344, 2001.
DOI : 10.1074/jbc.C100316200

E. Kim, N. Liu, I. Yu, H. Lin, Y. Lee et al., Metformin Inhibits Nuclear Receptor TR4-Mediated Hepatic Stearoyl-CoA Desaturase 1 Gene Expression With Altered Insulin Sensitivity, Diabetes, vol.60, issue.5, pp.1493-1503, 2011.
DOI : 10.2337/db10-0393

Y. Takiyama, T. Harumi, J. Watanabe, Y. Fujita, J. Honjo et al., Tubular Injury in a Rat Model of Type 2 Diabetes Is Prevented by Metformin, Diabetes, vol.60, issue.3, pp.981-992, 2011.
DOI : 10.2337/db10-0655

A. Morales, D. Detaille, M. Prieto, A. Puente, E. Briones et al., Metformin prevents experimental gentamicin-induced nephropathy by a mitochondria-dependent pathway, Kidney International, vol.77, issue.10, pp.861-869, 2010.
DOI : 10.1038/ki.2010.11

URL : https://hal.archives-ouvertes.fr/inserm-00628475

S. Cufi, A. Vazquez-martin, C. Oliveras-ferraros, B. Martin-castillo, J. Joven et al., Metformin against TGF??-induced epithelial-to-mesenchymal transition (EMT): From cancer stem cells to aging-associated fibrosis, Cell Cycle, vol.9, issue.22, pp.4461-4468, 2010.
DOI : 10.4161/cc.9.22.14048

A. Piwkowska, D. Rogacka, M. Jankowski, M. Dominiczak, J. Stepinski et al., Metformin induces suppression of NAD(P)H oxidase activity in podocytes, Biochemical and Biophysical Research Communications, vol.393, issue.2, pp.268-273, 2010.
DOI : 10.1016/j.bbrc.2010.01.119

T. Louro, P. Matafome, E. Nunes, F. Da-cunha, and R. Seica, Insulin and metformin may prevent renal injury in young type 2 diabetic Goto???Kakizaki rats, European Journal of Pharmacology, vol.653, issue.1-3, 2011.
DOI : 10.1016/j.ejphar.2010.11.029

W. Wang, X. Guo, H. Wu, N. Wang, and X. Xu, Effect of fenofibrate and metformin on lipotoxicity in OLETF rat kidney, Beijing Da Xue Xue Bao, vol.38, pp.170-175, 2006.

V. Takiar, S. Nishio, P. Seo-mayer, J. King, . Jr et al., Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis, Proceedings of the National Academy of Sciences, vol.108, issue.6, pp.2462-2467, 2011.
DOI : 10.1073/pnas.1011498108

H. Pilmore, Review: Metformin: Potential benefits and use in chronic kidney disease, Nephrology, vol.14, issue.3, pp.412-418, 2010.
DOI : 10.1111/j.1440-1797.2010.01328.x

H. Nye and W. Herrington, Metformin: The Safest Hypoglycaemic Agent in Chronic Kidney Disease?, Nephron Clinical Practice, vol.118, issue.4, pp.380-383, 2011.
DOI : 10.1159/000323739

A. Frid, G. Sterner, M. Londahl, C. Wiklander, A. Cato et al., Novel Assay of Metformin Levels in Patients With Type 2 Diabetes and Varying Levels of Renal Function: Clinical recommendations, Diabetes Care, vol.33, issue.6, pp.1291-1293, 2010.
DOI : 10.2337/dc09-1284

R. Hurst and R. Lee, Increased Incidence of Coronary Atherosclerosis in Type 2 Diabetes Mellitus: Mechanisms and Management, Annals of Internal Medicine, vol.139, issue.10, pp.824-834, 2003.
DOI : 10.7326/0003-4819-139-10-200311180-00010

J. Johnson, S. Simpson, E. Toth, and S. Majumdar, Reduced cardiovascular morbidity and mortality associated with metformin use in subjects with Type 2 diabetes, Diabetic Medicine, vol.281, issue.Series B, pp.497-502, 2005.
DOI : 10.1111/j.1464-5491.2005.01448.x

J. Johnson, S. Majumdar, S. Simpson, and E. Toth, Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes . Diabetes Care, pp.2244-2248, 2002.

M. Yin, I. Van-der-horst, J. Van-melle, C. Qian, W. Van-gilst et al., Metformin improves cardiac function in a non-diabetic rat model of post-MI heart failure, Am J Physiol Heart Circ Physiol, 2011.

E. Kravchuk, E. Grineva, A. Bairamov, M. Galagudza, and T. Vlasov, The Effect of Metformin on the Myocardial Tolerance to Ischemia-Reperfusion Injury in the Rat Model of Diabetes Mellitus Type II, Experimental Diabetes Research, vol.3, issue.4, p.907496, 2011.
DOI : 10.2337/diabetes.54.7.2227

C. Yeh, T. Chen, Y. Wang, Y. Lin, and S. Fang, AMP-Activated Protein Kinase Activation during Cardioplegia-Induced Hypoxia/Reoxygenation Injury Attenuates Cardiomyocytic Apoptosis via Reduction of Endoplasmic Reticulum Stress, Mediators of Inflammation, vol.270, issue.4, p.130636, 2010.
DOI : 10.1038/sj.cdd.4401984

S. Scolletta and B. Biagioli, Energetic myocardial metabolism and oxidative stress: Let's make them our friends in the fight against heart failure, Biomedicine & Pharmacotherapy, vol.64, issue.3, pp.203-207, 2010.
DOI : 10.1016/j.biopha.2009.10.002

G. Lopaschuk, Optimizing Cardiac Fatty Acid and Glucose Metabolism as an Approach to Treating Heart Failure, Seminars in Cardiothoracic and Vascular Anesthesia, vol.10, issue.3, pp.228-230, 2006.
DOI : 10.1177/1089253206291150

J. Benes, L. Kazdova, Z. Drahota, J. Houstek, D. Medrikova et al., Effect of metformin therapy on cardiac function and survival in a volume-overload model of heart failure in rats, Clinical Science, vol.277, issue.1, pp.29-41, 2011.
DOI : 10.1097/HJH.0b013e3282f9b58a

R. Khurana and I. Malik, Metformin: safety in cardiac patients, Postgraduate Medical Journal, vol.86, issue.1016, pp.99-102, 2010.
DOI : 10.1136/hrt.2009.173773

D. Eurich, S. Majumdar, F. Mcalister, R. Tsuyuki, and J. Johnson, Improved clinical outcomes associated with metformin in patients with diabetes and heart failure . Diabetes Care, pp.2345-2351, 2005.

D. Eurich and F. Mcalister, Wrongfully accused: metformin use in heart failure, Expert Review of Cardiovascular Therapy, vol.9, issue.2, pp.147-150, 2011.
DOI : 10.1586/erc.10.186

R. Roussel, F. Travert, B. Pasquet, P. Wilson, S. Smith et al., Metformin Use and Mortality Among Patients With Diabetes and Atherothrombosis<alt-title>Metformin Use With Diabetes and Atherothrombosis</alt-title>, Archives of Internal Medicine, vol.170, issue.21, pp.1892-1899, 2010.
DOI : 10.1001/archinternmed.2010.409

K. Pantalone, M. Kattan, C. Yu, B. Wells, S. Arrigain et al., The risk of overall mortality in patients with type 2 diabetes receiving glipizide, glyburide, or glimepiride monotherapy: a retrospective analysis . Diabetes Care, pp.1224-1229, 2010.

Z. Xie, K. Lau, B. Eby, P. Lozano, C. He et al., Improvement of Cardiac Functions by Chronic Metformin Treatment Is Associated With Enhanced Cardiac Autophagy in Diabetic OVE26 Mice, Diabetes, vol.60, issue.6, pp.1770-1778, 2011.
DOI : 10.2337/db10-0351

S. Gundewar, J. Calvert, S. Jha, I. Toedt-pingel, S. Ji et al., Activation of AMP-Activated Protein Kinase by Metformin Improves Left Ventricular Function and Survival in Heart Failure, Circulation Research, vol.104, issue.3, pp.403-411, 2009.
DOI : 10.1161/CIRCRESAHA.108.190918

H. Sasaki, H. Asanuma, M. Fujita, H. Takahama, M. Wakeno et al., Metformin Prevents Progression of Heart Failure in Dogs: Role of AMP-Activated Protein Kinase, Circulation, vol.119, issue.19, pp.2568-2577, 2009.
DOI : 10.1161/CIRCULATIONAHA.108.798561

C. Zhang, S. Pan, R. Meng, C. Peng, Z. Xiong et al., Metformin attenuates ventricular hypertrophy by activating the AMP-activated protein kinase-endothelial nitric oxide synthase pathway in rats, Clinical and Experimental Pharmacology and Physiology, vol.15, issue.1, pp.55-62, 2011.
DOI : 10.1111/j.1440-1681.2010.05461.x

G. Muller and H. Morawietz, Nitric Oxide, NAD(P)H Oxidase, and Atherosclerosis, Antioxidants & Redox Signaling, vol.11, issue.7, pp.1711-1731, 2009.
DOI : 10.1089/ars.2008.2403

E. Schulz, E. Anter, M. Zou, J. Keaney, and . Jr, Estradiol-Mediated Endothelial Nitric Oxide Synthase Association With Heat Shock Protein 90 Requires Adenosine Monophosphate-Dependent Protein Kinase, Circulation, vol.111, issue.25, pp.3473-3480, 2005.
DOI : 10.1161/CIRCULATIONAHA.105.546812

N. Ouslimani, J. Peynet, D. Bonnefont-rousselot, P. Therond, A. Legrand et al., Metformin decreases intracellular production of reactive oxygen species in aortic endothelial cells, Metabolism, vol.54, issue.6, pp.829-834, 2005.
DOI : 10.1016/j.metabol.2005.01.029

D. Kukidome, T. Nishikawa, K. Sonoda, K. Imoto, K. Fujisawa et al., Activation of AMP-Activated Protein Kinase Reduces Hyperglycemia-Induced Mitochondrial Reactive Oxygen Species Production and Promotes Mitochondrial Biogenesis in Human Umbilical Vein Endothelial Cells, Diabetes, vol.55, issue.1, pp.120-127, 2006.
DOI : 10.2337/diabetes.55.01.06.db05-0943

S. Rahbar, R. Natarajan, K. Yerneni, S. Scott, N. Gonzales et al., Evidence that pioglitazone, metformin and pentoxifylline are inhibitors of glycation, Clinica Chimica Acta, vol.301, issue.1-2, pp.65-77, 2000.
DOI : 10.1016/S0009-8981(00)00327-2

D. Jager, J. Kooy, A. Lehert, P. Bets, D. Wulffele et al., Effects of short-term treatment with metformin on markers of endothelial function and inflammatory activity in type 2 diabetes mellitus: a randomized, placebo-controlled trial, Journal of Internal Medicine, vol.29, issue.1, pp.100-109, 2005.
DOI : 10.1053/meta.2001.28078

M. Zou and Y. Wu, AMP-ACTIVATED PROTEIN KINASE ACTIVATION AS A STRATEGY FOR PROTECTING VASCULAR ENDOTHELIAL FUNCTION, Clinical and Experimental Pharmacology and Physiology, vol.277, issue.5-6, pp.535-545, 2008.
DOI : 10.1161/01.HYP.0000221429.94591.72

T. Tang, J. Lord, R. Norman, Y. E. Balen, and A. , nsulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility, Cochrane Database Syst Rev, p.3053, 2010.

E. Thessaloniki, P. Asrm-sponsored, . Consensus-workshop, and . Group, Consensus on infertility treatment related to polycystic ovary syndrome, Hum Reprod, vol.23, pp.462-477, 2008.

S. Palomba, A. Falbo, F. Zullo, F. Orio, and . Jr, Evidence-Based and Potential Benefits of Metformin in the Polycystic Ovary Syndrome: A Comprehensive Review, Endocrine Reviews, vol.30, issue.1, 2009.
DOI : 10.1210/er.2008-0030

R. Legro, H. Barnhart, W. Schlaff, B. Carr, M. Diamond et al., Gene, The Journal of Clinical Endocrinology & Metabolism, vol.93, issue.3, pp.792-800, 2008.
DOI : 10.1210/jc.2007-1736

E. Giovannucci, D. Harlan, M. Archer, R. Bergenstal, S. Gapstur et al., Diabetes and cancer: a consensus report . Diabetes Care, pp.1674-1685, 2010.

M. Jalving, J. Gietema, J. Lefrandt, S. De-jong, A. Reyners et al., Metformin: Taking away the candy for cancer?, European Journal of Cancer, vol.46, issue.13, pp.2369-2380, 2010.
DOI : 10.1016/j.ejca.2010.06.012

C. Currie, C. Poole, and E. Gale, The influence of glucose-lowering therapies on cancer risk in type 2 diabetes, Diabetologia, vol.23, issue.9, pp.1766-1777, 2009.
DOI : 10.1007/s00125-009-1440-6

J. Evans, L. Donnelly, A. Emslie-smith, D. Alessi, and A. Morris, Metformin and reduced risk of cancer in diabetic patients, BMJ, vol.330, issue.7503, pp.1304-1305, 2005.
DOI : 10.1136/bmj.38415.708634.F7

S. Bowker, Y. Yasui, P. Veugelers, and J. Johnson, Glucose-lowering agents and cancer mortality rates in type 2 diabetes: assessing effects of time-varying exposure, Diabetologia, vol.374, issue.5 Suppl B, pp.1631-1637, 2010.
DOI : 10.1007/s00125-010-1750-8

G. Landman, N. Kleefstra, K. Van-hateren, K. Groenier, R. Gans et al., Metformin Associated With Lower Cancer Mortality in Type 2 Diabetes: ZODIAC-16, Diabetes Care, vol.33, issue.2, pp.322-326, 2010.
DOI : 10.2337/dc09-1380

G. Libby, L. Donnelly, P. Donnan, D. Alessi, A. Morris et al., New Users of Metformin Are at Low Risk of Incident Cancer: A cohort study among people with type 2 diabetes, Diabetes Care, vol.32, issue.9, pp.1620-1625, 2009.
DOI : 10.2337/dc08-2175

M. Bodmer, C. Meier, S. Krahenbuhl, S. Jick, and C. Meier, Long-term metformin use is associated with decreased risk of breast cancer . Diabetes Care, pp.1304-1308, 2010.

D. Li, S. Yeung, M. Hassan, M. Konopleva, and J. Abbruzzese, Antidiabetic Therapies Affect Risk of Pancreatic Cancer, Gastroenterology, vol.137, issue.2, pp.482-488, 2009.
DOI : 10.1053/j.gastro.2009.04.013

J. Wright and J. Stanford, Metformin use and prostate cancer in Caucasian men: results from a population-based case???control study, Cancer Causes & Control, vol.164, issue.10, pp.1617-1622, 2009.
DOI : 10.1007/s10552-009-9407-y

B. Sahra, I. , L. Marchand-brustel, Y. Tanti, J. Bost et al., Metformin in Cancer Therapy: A New Perspective for an Old Antidiabetic Drug?, Molecular Cancer Therapeutics, vol.9, issue.5, pp.1092-1099, 2010.
DOI : 10.1158/1535-7163.MCT-09-1186

P. Goodwin, K. Pritchard, M. Ennis, M. Clemons, M. Graham et al., Insulin-Lowering Effects of Metformin in Women with Early Breast Cancer, Clinical Breast Cancer, vol.8, issue.6, pp.501-505, 2008.
DOI : 10.3816/CBC.2008.n.060

M. Schneider, H. Matsuzaki, J. Haorah, A. Ulrich, J. Standop et al., Prevention of pancreatic cancer induction in hamsters by metformin, Gastroenterology, vol.120, issue.5, pp.1263-1270, 2001.
DOI : 10.1053/gast.2001.23258

C. Algire, L. Amrein, M. Bazile, S. David, M. Zakikhani et al., Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo, Oncogene, vol.62, issue.10, pp.1174-1182, 2010.
DOI : 10.1158/1940-6207.CAPR-08-0081

N. Kalaany and D. Sabatini, Tumours with PI3K activation are resistant to dietary restriction, Nature, vol.42, issue.7239, pp.725-731, 2009.
DOI : 10.1038/nature07782

C. Franceschi, Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice, Exp Gerontol, vol.40, pp.685-693, 2005.

X. Huang, S. Wullschleger, N. Shpiro, V. Mcguire, K. Sakamoto et al., Important role of the LKB1???AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice, Biochemical Journal, vol.412, issue.2, pp.211-221, 2008.
DOI : 10.1042/BJ20080557

A. Tomimoto, H. Endo, M. Sugiyama, T. Fujisawa, K. Hosono et al., Metformin suppresses intestinal polyp growth in ApcMin/+ mice, Cancer Science, vol.333, issue.11, pp.2136-2141, 2008.
DOI : 10.1111/j.1349-7006.2008.00933.x

R. Dowling, M. Zakikhani, I. Fantus, M. Pollak, and N. Sonenberg, Metformin Inhibits Mammalian Target of Rapamycin Dependent Translation Initiation in Breast Cancer Cells, Cancer Research, vol.67, issue.22, pp.10804-10812, 2007.
DOI : 10.1158/0008-5472.CAN-07-2310

W. Gotlieb, J. Saumet, M. Beauchamp, J. Gu, S. Lau et al., In vitro metformin anti-neoplastic activity in epithelial ovarian cancer, Gynecologic Oncology, vol.110, issue.2, pp.246-250, 2008.
DOI : 10.1016/j.ygyno.2008.04.008

M. Zakikhani, R. Dowling, I. Fantus, N. Sonenberg, and M. Pollak, Metformin Is an AMP Kinase-Dependent Growth Inhibitor for Breast Cancer Cells, Cancer Research, vol.66, issue.21, pp.10269-10273, 2006.
DOI : 10.1158/0008-5472.CAN-06-1500

A. Green, N. Chapuis, T. Maciel, T. Willems, L. Lambert et al., The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation, Blood, vol.116, issue.20, pp.4262-4273, 2010.
DOI : 10.1182/blood-2010-02-269837

G. He, Y. Sung, J. Digiovanni, and S. Fischer, Thiazolidinediones Inhibit Insulin-Like Growth Factor-I-Induced Activation of p70S6 Kinase and Suppress Insulin-Like Growth Factor-I Tumor-Promoting Activity, Cancer Research, vol.66, issue.3, pp.1873-1878, 2006.
DOI : 10.1158/0008-5472.CAN-05-3111

K. Kisfalvi, G. Eibl, J. Sinnett-smith, and E. Rozengurt, Metformin Disrupts Crosstalk between G Protein-Coupled Receptor and Insulin Receptor Signaling Systems and Inhibits Pancreatic Cancer Growth, Cancer Research, vol.69, issue.16, pp.6539-6545, 2009.
DOI : 10.1158/0008-5472.CAN-09-0418

X. Xiang, A. Saha, R. Wen, N. Ruderman, and Z. Luo, AMP-activated protein kinase activators can inhibit the growth of prostate cancer cells by multiple mechanisms, Biochemical and Biophysical Research Communications, vol.321, issue.1, pp.161-167, 2004.
DOI : 10.1016/j.bbrc.2004.06.133

J. Grisouard, K. Dembinski, D. Mayer, U. Keller, B. Muller et al., Targeting AMP-activated protein kinase in adipocytes to modulate obesity-related adipokine production associated with insulin resistance and breast cancer cell proliferation, Diabetology & Metabolic Syndrome, vol.3, issue.1, p.16, 2011.
DOI : 10.1677/JME-09-0063

A. Salminen, J. Hyttinen, and K. Kaarniranta, AMP-activated protein kinase inhibits NF-kappaB signaling and inflammation: impact on healthspan and lifespan, J, 2011.

D. Xavier, L. Amaral, M. Gomes, M. Rocha, P. Campos et al., Metformin inhibits inflammatory angiogenesis in a murine sponge model, Biomedicine & Pharmacotherapy, vol.64, issue.3, pp.220-225, 2010.
DOI : 10.1016/j.biopha.2009.08.004

C. Ersoy, S. Kiyici, F. Budak, B. Oral, M. Guclu et al., The effect of metformin treatment on VEGF and PAI-1 levels in obese type 2 diabetic patients, Diabetes Research and Clinical Practice, vol.81, issue.1, pp.56-60, 2008.
DOI : 10.1016/j.diabres.2008.02.006

A. Vazquez-martin, C. Oliveras-ferraros, and J. Menendez, The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells, Cell Cycle, vol.8, issue.1, pp.88-96, 2009.
DOI : 10.4161/cc.8.1.7499

B. Sahra, I. Laurent, K. Loubat, A. Giorgetti-peraldi, S. Colosetti et al., The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level, Oncogene, vol.14, issue.25, pp.3576-3586, 2008.
DOI : 10.1172/JCI200113505

URL : https://hal.archives-ouvertes.fr/inserm-00277135

B. Sahra, I. Regazzetti, C. Robert, G. Laurent, K. et al., Metformin, Independent of AMPK, Induces mTOR Inhibition and Cell-Cycle Arrest through REDD1, Cancer Research, vol.71, issue.13, pp.4366-4372, 2011.
DOI : 10.1158/0008-5472.CAN-10-1769

Y. Zhuang and W. Miskimins, Cell cycle arrest in Metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1, and requires p27<sup>Kip1</sup> or p21<sup>Cip1</sup>, Journal of Molecular Signaling, vol.3, p.18, 2008.
DOI : 10.1186/1750-2187-3-18

A. Isakovic, L. Harhaji, D. Stevanovic, Z. Markovic, M. Sumarac-dumanovic et al., Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis, Cellular and Molecular Life Sciences, vol.64, issue.10, pp.1290-1302, 2007.
DOI : 10.1007/s00018-007-7080-4

B. Liu, Z. Fan, S. Edgerton, X. Deng, I. Alimova et al., Metformin induces unique biological and molecular responses in triple negative breast cancer cells, Cell Cycle, vol.8, issue.13, pp.2031-2040, 2009.
DOI : 10.4161/cc.8.13.8814

Y. Zhuang and W. Miskimins, Metformin Induces Both Caspase-Dependent and Poly(ADP-ribose) Polymerase-Dependent Cell Death in Breast Cancer Cells, Molecular Cancer Research, vol.9, issue.5, pp.603-615, 2011.
DOI : 10.1158/1541-7786.MCR-10-0343

B. Sahra, I. Laurent, K. Giuliano, S. Larbret, F. Ponzio et al., Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells, 2010.

R. Jones, D. Plas, S. Kubek, M. Buzzai, J. Mu et al., AMP-Activated Protein Kinase Induces a p53-Dependent Metabolic Checkpoint, Molecular Cell, vol.18, issue.3, pp.283-293, 2005.
DOI : 10.1016/j.molcel.2005.03.027

M. Buzzai, R. Jones, R. Amaravadi, J. Lum, R. Deberardinis et al., Systemic Treatment with the Antidiabetic Drug Metformin Selectively Impairs p53-Deficient Tumor Cell Growth, Cancer Research, vol.67, issue.14, pp.6745-6752, 2007.
DOI : 10.1158/0008-5472.CAN-06-4447

B. Metzger, L. Lowe, A. Dyer, E. Trimble, U. Chaovarindr et al., Hyperglycemia and Adverse Pregnancy Outcomes, Obstetric Anesthesia Digest, vol.29, issue.1, pp.1991-2002, 2008.
DOI : 10.1097/01.aoa.0000344706.95925.dc

J. Balani, S. Hyer, D. Rodin, and H. Shehata, Pregnancy outcomes in women with gestational diabetes treated with metformin or insulin: a case-control study, Diabetic Medicine, vol.19, issue.8, 2009.
DOI : 10.1111/j.1464-5491.2009.02780.x

J. Rowan, W. Hague, W. Gao, M. Battin, and M. Moore, Metformin versus Insulin for the Treatment of Gestational Diabetes, New England Journal of Medicine, vol.358, issue.19, pp.2003-2015, 2008.
DOI : 10.1056/NEJMoa0707193

W. Knowler, E. Barrett-connor, S. Fowler, R. Hamman, J. Lachin et al., Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin, N Engl J Med, vol.346, pp.393-403, 2002.

G. Asher and U. Schibler, Crosstalk between Components of Circadian and Metabolic Cycles in Mammals, Cell Metabolism, vol.13, issue.2, pp.125-137, 2011.
DOI : 10.1016/j.cmet.2011.01.006

J. Um, S. Yang, S. Yamazaki, H. Kang, B. Viollet et al., Activation of 5'-AMP-activated Kinase with Diabetes Drug Metformin Induces Casein Kinase I?? (CKI??)-dependent Degradation of Clock Protein mPer2, Journal of Biological Chemistry, vol.282, issue.29, pp.20794-20798, 2007.
DOI : 10.1074/jbc.C700070200

B. Guigas, H. L. Mithieux, G. Wiernsperger, and N. , Metformin and the AMP-activated protein kinase . Metformin: mechanistic insights towards new applications . 81 -110 Transworld Research Network, 2008.

N. Kimura, S. Masuda, Y. Tanihara, H. Ueo, M. Okuda et al., Metformin is a Superior Substrate for Renal Organic Cation Transporter OCT2 rather than Hepatic OCT1, Drug Metabolism and Pharmacokinetics, vol.20, issue.5, pp.379-386, 2005.
DOI : 10.2133/dmpk.20.379

K. Umehara, T. Iwatsubo, K. Noguchi, and H. Kamimura, Functional involvement of organic cation transporter1 (OCT1/Oct1) in the hepatic uptake of organic cations in humans and rats, Xenobiotica, vol.51, issue.8, pp.818-831, 2007.
DOI : 10.1038/372549a0

M. Tzvetkov, S. Vormfelde, D. Balen, I. Meineke, T. Schmidt et al., The Effects of Genetic Polymorphisms in the Organic Cation Transporters OCT1, OCT2, and OCT3 on the Renal Clearance of Metformin, Clinical Pharmacology & Therapeutics, vol.1, issue.3, pp.299-306, 2009.
DOI : 10.1086/319501

Z. Wang, O. Yin, B. Tomlinson, and M. Chow, OCT2 polymorphisms and in-vivo renal functional consequence: studies with metformin and cimetidine, Pharmacogenetics and Genomics, vol.18, issue.7, 2008.
DOI : 10.1097/FPC.0b013e328302cd41

J. Distefano and R. Watanabe, Pharmacogenetics of Anti-Diabetes Drugs, Pharmaceuticals, vol.3, issue.8, pp.2610-2646, 2010.
DOI : 10.3390/ph3082610

K. Zhou, C. Bellenguez, C. Spencer, A. Bennett, R. Coleman et al., Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes, Nature Genetics, vol.352, issue.2, pp.117-120, 2011.
DOI : 10.1016/0014-5793(95)00172-6

C. Algire, M. Zakikhani, M. Blouin, J. Shuai, and M. Pollak, Metformin attenuates the stimulatory effect of a high-energy diet on in vivo LLC1 carcinoma growth, Endocrine Related Cancer, vol.15, issue.3, 2008.
DOI : 10.1677/ERC-08-0038

H. Hirsch, D. Iliopoulos, P. Tsichlis, and K. Struhl, Metformin Selectively Targets Cancer Stem Cells, and Acts Together with Chemotherapy to Block Tumor Growth and Prolong Remission, Cancer Research, vol.69, issue.19, pp.7507-7511, 2009.
DOI : 10.1158/0008-5472.CAN-09-2994

B. Bojkova, P. Orendas, M. Garajova, M. Kassayova, V. Kutna et al., Metformin in chemically-induced mammary carcinogenesis in rats, Neoplasma, vol.56, issue.3, pp.269-274, 2009.
DOI : 10.4149/neo_2009_03_269

R. Memmott, J. Mercado, C. Maier, S. Kawabata, S. Fox et al., Metformin Prevents Tobacco Carcinogen-Induced Lung Tumorigenesis, Cancer Prevention Research, vol.3, issue.9, pp.1066-1076, 2010.
DOI : 10.1158/1940-6207.CAPR-10-0055

K. Hosono, H. Endo, H. Takahashi, M. Sugiyama, T. Uchiyama et al., Metformin suppresses azoxymethane-induced colorectal aberrant crypt foci by activating AMP-activated protein kinase, Molecular Carcinogenesis, vol.57, issue.7, pp.662-671, 2010.
DOI : 10.1002/mc.20637

B. Viollet and M. Foretz, Metformin and cancer. From diabetes to cancer: New therapeutic perspectives for metformin . M decine des maladies M taboliques é é, pp.29-37, 2011.

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