title: Metformin overdose causes platelet mitochondrial dysfunction in humans.
abstract: BACKGROUND
  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.
  
  
  BACKGROUND
  NCT 00942123.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Protti
authors.forename: Anna
authors.initials: A
authors.lastname: Lecchi
authors.forename: Francesco
authors.initials: F
authors.lastname: Fortunato
authors.forename: Andrea
authors.initials: A
authors.lastname: Artoni
authors.forename: Noemi
authors.initials: N
authors.lastname: Greppi
authors.forename: Sarah
authors.initials: S
authors.lastname: Vecchio
authors.forename: Gigliola
authors.initials: G
authors.lastname: Fagiolari
authors.forename: Maurizio
authors.initials: M
authors.lastname: Moggio
authors.forename: Giacomo Pietro
authors.initials: GP
authors.lastname: Comi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Mistraletti
authors.forename: Barbara
authors.initials: B
authors.lastname: Lanticina
authors.forename: Loredana
authors.initials: L
authors.lastname: Faraldi
authors.forename: Luciano
authors.initials: L
authors.lastname: Gattinoni
mesh_terms: D000140:Acidosis, Lactic / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D062787:Drug Overdose / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008687:Metformin / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D008687:Metformin