Metformin overdose causes platelet mitochondrial dysfunction in humans

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 h with saline or increasing dose 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