Abstract
IntroductionWe 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.MethodsHuman 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).ResultsIn 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.ConclusionsDepending on dose, metformin can cause mitochondrial dysfunction and lactate overproduction in human platelets in vitro and, possibly, in vivo.Trial registrationNCT 00942123.
Highlights
We have recently demonstrated that metformin intoxication causes mitochondrial dysfunction in several porcine tissues, including platelets
This study demonstrates that, depending on dose, metformin can cause mitochondrial dysfunction and lactate overproduction in human platelets
If analogue changes occur in other organs, they will likely contribute to the pathogenesis of metformin-induced lactic acidosis
Summary
We have recently demonstrated that metformin intoxication causes mitochondrial dysfunction in several porcine tissues, including platelets. Metformin is the drug of choice for adults with type 2 diabetes [1]. Metformin is a safe drug [4] but lactic acidosis can develop rarely, especially when renal failure leads to accidental intoxication [5,6,7]. The pathogenesis of lactic acidosis during metformin therapy remains poorly understood, when no other major risk factors (such as hypoxia, tissue hypoperfusion or liver failure) can be identified [9]. Growing evidence suggests that metformin intoxication may directly induce lactic acidosis [10], possibly by altering liver lactate metabolism. The fact that OCT-1 knock-out mice do not develop lactic acidosis in response to (non severe) metformin overdose does support this model [17]
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