Metformin induces lactate production in peripheral blood mononuclear cells and platelets through specific mitochondrial complex I inhibition

Acta Physiologica

Volumn 213, Issue 1, 2015, Pages 171-180

  Piel, S ^a,b   Ehinger, J K ^a,b,c   Elmer E ^a,b   Hansson, M J ^a,b  

^a LUND UNIVERSITY   (Sweden)

^b NeuroVive Pharmaceutical AB   (Sweden)

^c LUND UNIVERSITY HOSPITAL   (Sweden)

Author keywords

drug screening; human; metformin; mitochondrial toxicity; phenformin; respirometry

Indexed keywords

LACTIC ACID; METFORMIN; PHENFORMIN; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE DEHYDROGENASE (UBIQUINONE); ANTIDIABETIC AGENT;

ADULT; ARTICLE; CELL ISOLATION; CELL MEMBRANE PERMEABILITY; CONCENTRATION RESPONSE; CONTROLLED STUDY; DOSE RESPONSE; ENZYME INHIBITION; ENZYME SPECIFICITY; FEMALE; HUMAN; HUMAN CELL; IC50; LACTIC ACIDOSIS; MALE; MITOCHONDRIAL RESPIRATION; MITOCHONDRIAL TOXICITY; NORMAL HUMAN; PERIPHERAL BLOOD MONONUCLEAR CELL; PH; PRIORITY JOURNAL; RESPIROMETRY; THROMBOCYTE; BLOOD; DRUG EFFECTS; METABOLISM; MITOCHONDRION; MONONUCLEAR CELL; OXYGEN CONSUMPTION;

BLOOD PLATELETS; FEMALE; HUMANS; HYPOGLYCEMIC AGENTS; LACTIC ACID; LEUKOCYTES, MONONUCLEAR; MALE; METFORMIN; MITOCHONDRIA; OXYGEN CONSUMPTION;

EID: 84940845680     PISSN: 17481708     EISSN: 17481716     Source Type: Journal    
DOI: 10.1111/apha.12311     Document Type: Article

References (37)

1. Al-Abri, S.A., Hayashi, S., Thoren, K.L. & Olson, K.R. 2013. Metformin overdose-induced hypoglycemia in the absence of other antidiabetic drugs. Clin Toxicol (Phila) 51, 444–447.
2. Bailey, C.J. 1992. Biguanides and NIDDM. Diabetes Care 15, 755–772.
3. Boyum, A. 1968. Isolation of mononuclear cells and granulocytes from human blood. Isolation of mononuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl 97, 77–89.
4. Brunmair, B., Staniek, K., Gras, F., Scharf, N., Althaym, A., Clara, R., Roden, M., Gnaiger, E., Nohl, H., Waldhausl, W. & Furnsinn, C. 2004. Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? Diabetes 53, 1052–1059.
5. Carvalho, C., Correia, S., Santos, M.S., Seica, R., Oliveira, C.R. & Moreira, P.I. 2008. Metformin promotes isolated rat liver mitochondria impairment. Mol Cell Biochem 308, 75–83.
6. Chan, K., Truong, D., Shangari, N. & O'Brien, P.J. 2005. Drug-induced mitochondrial toxicity. Expert Opin Drug Metab Toxicol 1, 655–669.
7. Davidson, M.B. & Peters, A.L. 1997. An overview of metformin in the treatment of type 2 diabetes mellitus. Am J Med 102, 99–110.
8. Dykens, J.A. & Will, Y. 2007. The significance of mitochondrial toxicity testing in drug development. Drug Discov Today 12, 777–785.
9. Dykens, J.A., Jamieson, J., Marroquin, L., Nadanaciva, S., Billis, P.A. & Will, Y. 2008. Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro. Toxicol Appl Pharmacol 233, 203–210.
10. El-Mir, M.Y. 2000. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 275, 223–228.
11. Farina, J.A., Celotto, A.C., da Silva, M.F. & Evora, P.R.B. 2012. Guanylate cyclase inhibition by methylene blue as an option in the treatment of vasoplegia after a severe burn. A medical hypothesis. Med Sci Monit 18, Hy13–Hy17.
12. Fisher, J., Taori, G., Braitberg, G. & Graudins, A. 2014. Methylene blue used in the treatment of refractory shock resulting from drug poisoning. Clin Toxicol (Phila) 52, 63–65.
13. Gnaiger, E. 2008. Polarographic oxygen sensors, the oxygraph and high-resolution respirometry to assess mitochondrial function. In: J.A. Dykens & Y. Will (eds) Mitochondrial Dysfunction in Drug-Induced Toxicity, pp. 327–352. John Wiley & Sons, Inc., Hoboken, NJ.
14. Golan, D.E., Tashjian, A.H., Armstrong, E.J. & Armstrong, A.W. 2012. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy/David E. Golan. Wolters Kluwer/Lippincott Williams & Wilkins, cop., Philadelphia.
15. Graham, G.G., Punt, J., Arora, M., Day, R.O., Doogue, M.P., Duong, J.K., Furlong, T.J., Greenfield, J.R., Greenup, L.C., Kirkpatrick, C.M., Ray, J.E., Timmins, P. & Williams, K.M. 2011. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 50, 81–98.
16. Hinke, S.A., Martens, G.A., Cai, Y., Finsi, J., Heimberg, H., Pipeleers, D. & Van de Casteele, M. 2007. Methyl succinate antagonises biguanide-induced AMPK-activation and death of pancreatic beta-cells through restoration of mitochondrial electron transfer. Br J Pharmacol 150, 1031–1043.
17. Kane, D.A., Anderson, E.J., Price Iii, J.W., Woodlief, T.L., Lin, C.-T., Bikman, B.T., Cortright, R.N. & Neufer, P.D. 2010. Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats. Free Radic Biol Med 49, 1082–1087.
18. Kirpichnikov, D., McFarlane, S.I. & Sowers, J.R. 2002. Metformin: an update. Ann Intern Med 137, 25–33.
19. Kwong, S.C. & Brubacher, J. 1998. Phenformin and lactic acidosis: a case report and review. J Emerg Med 16, 881–886.
20. Lalau, J.D. 2010. Lactic acidosis induced by metformin: incidence, management and prevention. Drug Saf 33, 727–740.
21. Larsen, S., Rabøl, R., Hansen, C.N., Madsbad, S., Helge, J.W. & Dela, F. 2012. Metformin-treated patients with type 2 diabetes have normal mitochondrial complex I respiration. Diabetologia 55, 443–449.
22. Livshits, Z., Nelson, L.S., Hernandez, S.H., Smith, S.W., Howland, M.A. & Hoffman, R.S. 2010. Severe metformin toxicity: role of methylene blue and CVVHD as therapeutic adjuncts. Clin Toxicol 48, 611–612.
23. Owen, M.R., Doran, E. & Halestrap, A.P. 2000. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 348(Pt 3), 607–614.
24. Pesta, D. & Gnaiger, E. 2012. High-resolution respirometry: OXPHOS protocols for human cells and permeabilized fibers from small biopsies of human muscle. Methods Mol Biol 810, 25–58.
25. Plumb, B., Parker, A. & Wong, P. 2013. Feeling blue with metformin-associated lactic acidosis. BMJ Case Rep 2013, 008855
26. Protti, A., Russo, R., Tagliabue, P., Vecchio, S., Singer, M., Rudiger, A., Foti, G., Rossi, A., Mistraletti, G. & Gattinoni, L. 2010. Oxygen consumption is depressed in patients with lactic acidosis due to biguanide intoxication. Crit Care 14, R22.
27. Protti, A., Fortunato, F., Monti, M., Vecchio, S., Gatti, S., Comi, G.P., De Giuseppe, R. & Gattinoni, L. 2012a. Metformin overdose, but not lactic acidosis per se, inhibits oxygen consumption in pigs. Crit Care 16, R75.
28. Protti, A., Lecchi, A., Fortunato, F., Artoni, A., Greppi, N., Vecchio, S., Fagiolari, G., Moggio, M., Comi, G.P., Mistraletti, G., Lanticina, B., Faraldi, L. & Gattinoni, L. 2012b. Metformin overdose causes platelet mitochondrial dysfunction in humans. Crit Care 16, R180.
29. Regenthal, R., Krueger, M., Koeppel, C. & Preiss, R. 1999. Drug levels: therapeutic and toxic serum/plasma concentrations of common drugs. J Clin Monit Comput 15, 529–544.
30. Salpeter, S.R., Greyber, E., Pasternak, G.A. & Salpeter, E.E. 2010. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev CD002967.
31. Scheen, A.J. 1996. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 30, 359–371.
32. Schulz, M. & Schmoldt, A. 2003. Therapeutic and toxic blood concentrations of more than 800 drugs and other xenobiotics. Pharmazie 58, 447–474.
33. Sjövall, F., Ehinger, J.K., Marelsson, S.E., Morota, S., Frostner, E.A., Uchino, H., Lundgren, J., Arnbjornsson, E., Hansson, M.J., Fellman, V. & Elmer, E. 2013a. Mitochondrial respiration in human viable platelets–methodology and influence of gender, age and storage. Mitochondrion 13, 7–14.
34. Sjövall, F., Morota, S., Persson, J., Hansson, M.J. & Elmer, E. 2013b. Patients with sepsis exhibit increased mitochondrial respiratory capacity in peripheral blood immune cells. Crit Care 17, R152.
35. Sogame, Y., Kitamura, A., Yabuki, M. & Komuro, S. 2009. A comparison of uptake of metformin and phenformin mediated by hOCT1 in human hepatocytes. Biopharm Drug Dispos 30, 476–484.
36. Tanner, R.K., Fuller, K.L. & Ross, M.L. 2010. Evaluation of three portable blood lactate analysers: Lactate Pro, Lactate Scout and Lactate Plus. Eur J Appl Physiol 109, 551–559.
37. Wen, Y., Li, W.J., Poteet, E.C., Xie, L.K., Tan, C., Yan, L.J., Ju, X.H., Liu, R., Qian, H., Marvin, M.A., Goldberg, M.S., She, H., Mao, Z.X., Simpkins, J.W. & Yang, S.H. 2011. Alternative mitochondrial electron transfer as a novel strategy for neuroprotection. J Biol Chem 286, 16504–16515.