Metformin overdose causes platelet mitochondrial dysfunction in humans
1 Dipartimento di Anestesia, Rianimazione (Intensiva e Sub-Intensiva) e Terapia del Dolore, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università degli Studi di Milano, via F. Sforza 35, 20122 Milan, Italy
2 Centro Emofilia e Trombosi Angelo Bianchi Bonomi, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, via F. Sforza 35, 20122 Milan, Italy
3 Centro Dino Ferrari - Dipartimento di Scienze Neurologiche, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università degli Studi di Milano, via F. Sforza 35, 20122 Milan, Italy
4 Centro Trasfusionale e di Immunoematologia, Dipartimento di Medicina Rigenerativa, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, via F. Sforza 35, 20122 Milan, Italy
5 Centro Nazionale di Informazione Tossicologica - Centro Antiveleni, Fondazione IRCCS Salvatore Maugeri, via S. Maugeri 10/10A, 27100 Pavia, Italy
6 U.O. Anestesia e Rianimazione, A.O. San Paolo, Università degli Studi di Milano, via A. Di Rudiní 8, 20142 Milan, Italy
7 U.O. Rianimazione, A.O. San Carlo Borromeo, via Pio II 3, 20147 Milan, Italy
8 Servizio Anestesia e Rianimazione 1°, Ospedale Niguarda Ca' Granda, Piazza Ospedale Maggiore 3, 20162 Milan, Italy
Critical Care 2012, 16:R180 doi:10.1186/cc11663
See related commentary by Orban et al., http://ccforum.com/content/16/5/164Published: 3 October 2012
We have recently demonstrated that metformin intoxication causes mitochondrial dysfunction in several porcine tissues, including platelets. The aim of the present work was to clarify whether it also causes mitochondrial dysfunction (and secondary lactate overproduction) in human platelets, in vitro and ex vivo.
Human platelets were incubated for 72 hours with saline or increasing doses of metformin (in vitro experiments). Lactate production, respiratory chain complex activities (spectrophotometry), mitochondrial membrane potential (flow-cytometry after staining with JC-1) and oxygen consumption (Clark-type electrode) were then measured. Platelets were also obtained from ten patients with lactic acidosis (arterial pH 6.97 ± 0.18 and lactate 16 ± 7 mmol/L) due to accidental metformin intoxication (serum drug level 32 ± 14 mg/L) and ten healthy volunteers of similar sex and age. Respiratory chain complex activities were measured as above (ex vivo experiments).
In vitro, metformin dose-dependently increased lactate production (P < 0.001), decreased respiratory chain complex I activity (P = 0.009), mitochondrial membrane potential (P = 0.003) and oxygen consumption (P < 0.001) of human platelets. Ex vivo, platelets taken from intoxicated patients had significantly lower complex I (P = 0.045) and complex IV (P < 0.001) activity compared to controls.
Depending on dose, metformin can cause mitochondrial dysfunction and lactate overproduction in human platelets in vitro and, possibly, in vivo.