The activity of platelet respiratory chain (a) complex I (CI) (P = 0.045; rank sum test), …DiscussionThis study demonstrates that, depending on dose (and time), metformin Ganetespib msds can cause mitochondrial dysfunction and lactate overproduction in human platelets.In fact, human platelets incubated with a high (toxic) dose of metformin had progressively lower complex I activity, mitochondrial membrane potential and oxygen consumption and higher lactate production than those incubated with saline. These changes occurred independently from hypoxia and differences in platelet count and mitochondrial density. Human platelets incubated with a low (therapeutic) dose of metformin behaved as those incubated with saline.

This finding is consistent with the observation that metformin does not significantly increase the incidence of lactic acidosis, compared to other antidiabetic drugs [4], unless it accumulates.When lactic acid was used instead of metformin to induce severe lactic acidosis, human platelet oxygen consumption never significantly declined. Conversely, when sodium bicarbonate was used to mitigate metformin-induced acidosis, human platelet oxygen consumption never returned to normal. Therefore, human platelet respiration diminishes during metformin-induced lactic acidosis because of drug accumulation, rather than (lactic) acidosis. Accordingly, healthy pigs infused with a large dose of metformin consume less oxygen than sham controls, whereas those infused with lactic acid do not (despite similar severity of lactic acidosis) [18].

When human red blood cells (that lack mitochondria) were used instead of platelets, an extremely high dose of metformin did not alter cellular metabolism. Thus, it may be concluded that metformin can cause lactate overproduction by specifically altering mitochondrial function, in human platelets as well as in mouse pancreatic ? and connective tissue cells [20,29], rat hepatocytes and skeletal muscle [12,13,30] and human intestine [31].Aside from dose, metformin toxicity also depended on the duration of incubation. Slow drug diffusion into cells, due to inherent lipophilicity, is the most likely explanation. For this reason, patients who acutely ingest large doses of metformin may initially have very high serum drug levels but no, or only mild, lactic acidosis.

In contrast, those who inadvertently get intoxicated over a few days may have relatively low serum drug levels (but still above therapeutic limits) and extremely severe lactic acidosis [6].Our in vitro findings were, at least partially, replicated ex vivo. In fact, platelets taken from metformin-intoxicated patients had clear signs of mitochondrial dysfunction, including inhibition of complex I and IV and a lower proportion of normally polarized mitochondria (although this was only occasionally measured).On average, patients with metformin GSK-3 intoxication had a 20% decrease in platelet complex I activity.