Email updates

Keep up to date with the latest news and content from Critical Care and BioMed Central.

Open Access Highly Accessed Research

Metformin overdose causes platelet mitochondrial dysfunction in humans

Alessandro Protti1*, Anna Lecchi2, Francesco Fortunato3, Andrea Artoni2, Noemi Greppi4, Sarah Vecchio5, Gigliola Fagiolari3, Maurizio Moggio3, Giacomo Pietro Comi3, Giovanni Mistraletti6, Barbara Lanticina7, Loredana Faraldi8 and Luciano Gattinoni1

Author Affiliations

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

For all author emails, please log on.

Critical Care 2012, 16:R180  doi:10.1186/cc11663


See related commentary by Orban et al., http://ccforum.com/content/16/5/164

Published: 3 October 2012

Abstract

Introduction

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.

Methods

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).

Results

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.

Conclusions

Depending on dose, metformin can cause mitochondrial dysfunction and lactate overproduction in human platelets in vitro and, possibly, in vivo.

Trial registration

NCT 00942123.