Introduction
Metformin improves glucose control by inhibiting hepatocyte mitochondrial complex I [1]. The pathogenesis of metforminassociated lactic acidosis is poorly understood and whether drug accumulation per se can cause hyperlactatemia remains unclear. The aim of the present study is to clarify whether metformin can increase cellular lactate production by inhibiting mitochondrial function in tissues other than the liver.
Methods
Platelet-rich-plasma (PRP) from healthy volunteers was incubated for 72 hours with different doses of metformin. The plasma lactate concentration was then measured. The proportion of normally polarized vs abnormally depolarized platelet mitochondria (FL2/FL1) was assessed by flow cytometry after staining with JC-1. Platelet respiratory chain complex I activity and citrate synthase (CS) activity, a marker of mitochondrial content, were measured by spectrophotometry. Data are presented as means ± SD. Analysis was performed with one-way ANOVA.
Results
Main results are reported in Table 1.
Table 1.
| No metformin | Metformin 0.01 mM | Metformin 1 mM | Metformin 100 mM | P value | |
|---|---|---|---|---|---|
| Lactate (mM) | 5 ± 1 | 5 ± 1 | 10 ± 2 | 21 ± 4 | <0.001 |
| FL2/FL1 | 5.6 ± 1.5 | 4.6 ± 1.1 | 4.6 ± 0.7 | 1.8 ± 0.7 | <0.001 |
| Complex I (nM/minute/mg) | 6.8 ± 2.5 | 6.8 ± 2.3 | 4.0 ± 1.6 | 1.6 ± 1.4 | <0.001 |
| CS (nM/minute/mg) | 102 ± 27 | 94 ± 15 | 99 ± 20 | 105 ± 10 | 0.74 |
PRP was incubated with metformin at the reported final concentrations (n = 4).
Conclusions
Metformin can cause hyperlactatemia by impairing platelet mitochondrial function.