in this issue of critical care , protti and colleagues   report the effects of metformin on human platelets both in vitro and ex vivo . in vitro experiments
were performed on healthy platelets incubated with increasing doses of metformin , whereas ex vivo experiments were done on platelets from patients presenting accidental metformin - induced lactic acidosis . in both situations ,
platelets ' lactate production and mitochondrial functions were measured . in vitro , a dose - dependent relationship between metformin con centration and lactate production was found . in both conditions ,
high levels of metformin decreased mitochondrial respiratory chain complex i activity , mitochondria polarization , and oxygen consumption .
metformin is a biguanide that has been used as a first - line drug for type 2 diabetes treatment since 1957 in europe and 1995 in the us .
metformin was reputed to induce lactic acidosis , partly because phenformin , another biguanide , was withdrawn from the market because of an unacceptable rate of this complication .
however , numerous clinical studies reported a similar incidence of lactic acidosis in diabetic patients with or without metformin , leading some authors to deny the existence of metformin - associated lactic acidosis . however , in usual clinical practice , metformin contraindications are not often respected .
moreover , physicians do not really monitor adequately their prescription . as a result , numerous publications reported the association between metformin and lactic acidosis . when a cause of lactic acidosis such as shock state or acute renal failure is present , the responsibility of metformin could be questioned .
but when healthy patients without risk factors develop metformin poisoning leading to lactic acidosis , there is no doubt about this link .
however , metformin inhibits hepatic gluconeogenesis in different animal species and decreases mitochondrial respiratory chain complex i activity in different organs .
the clinical research on metformin - associated lactic acidosis was limited to retrospective studies describing incidence , risk factors , and supportive treatments .
a big step forward was made when the gattinoni group   reported a decrease in oxygen consumption after metformin poisoning in humans , strongly suggesting that metformin was able to induce mitochondrial dysfunction in humans .
the study by protti and colleagues elegantly confirms the implication of mitochondria in the pathophysiology of this disease .
of course , the importance of platelet mitochondrial dysfunction per se has to be put in perspective .
however , as demonstrated previously in the pig , platelet mitochondrial dysfunction mirrors the mitochondrial dysfunction in other vital organs .
platelets are more easily accessible than vital organs like the liver or kidney . for research purposes in humans
now that serious research on this rare disease has started , we can also imagine improving its care .
currently , the treatment is only supportive : increasing blood pressure with fluid infusion and catecholamines and promoting metformin elimination by renal replacement therapy . restoring atp production during energy failure due to mitochondria dysfunction is still challenging .
another condition associated with mitochondrial dysfunction , succinate can bypass respiratory chain complex i inhibition and restore oxygen consumption . in isolated cells
, succinate is reputed not to cross the plasma membrane , but methyl succinate ( a cellpermeant succinate ) has been used to bypass metformin blockade of respiratory chain complex i .
 does metformin - associated lactic acidosis really exist ? despite an old controversy , there is no doubt about it . but 
 do we understand what is going on ? 
 laboratory findings raised several hypotheses explaining the pathophysiology of this disease . 
 the main cause could be an inhibition of either gluconeogenesis or mitochondrial respiratory chain complex i. from bench to bedside , one hypothesis is now confirmed in humans . 
 metformin poisoning involves , at least partially , a mitochondrial dysfunction . 