Published in:
Open Access
01-10-2012 | Research
Metformin overdose causes platelet mitochondrial dysfunction in humans
Authors:
Alessandro Protti, Anna Lecchi, Francesco Fortunato, Andrea Artoni, Noemi Greppi, Sarah Vecchio, Gigliola Fagiolari, Maurizio Moggio, Giacomo Pietro Comi, Giovanni Mistraletti, Barbara Lanticina, Loredana Faraldi, Luciano Gattinoni
Published in:
Critical Care
|
Issue 5/2012
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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.