Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions?
Level 5 - mechanism / opinion, no new human data
In vitro and ex vivo bench/animal mechanism study
PubMed 15047621 · doi:10.2337/diabetes.53.4.1052
What was done
The study evaluated the direct effects of metformin and thiazolidinediones (rosiglitazone and pioglitazone) on mitochondrial complex I activity and cellular respiration. Researchers measured complex I enzyme activity in disrupted skeletal muscle tissue homogenates, assessed state 3 respiration in isolated mitochondria consuming glutamate plus malate (complex I substrates) versus succinate (complex II substrate), and measured glucose oxidation and lactate release in isolated rat soleus muscle after 24 hours of drug incubation.
What was found
In skeletal muscle homogenates, complex I activity was significantly inhibited by 30 mmol/l metformin (-15 ± 2%), 100 µmol/l rosiglitazone (-54 ± 7%), and 100 µmol/l pioglitazone (-12 ± 4%) (P < 0.05 each). State 3 mitochondrial respiration supported by complex I substrates decreased with metformin (-77 ± 1%), rosiglitazone (-24 ± 4%), and pioglitazone (-18 ± 5%) (P < 0.05 each), whereas complex II-driven respiration was unaffected. In isolated rat soleus muscle, 24-hour drug exposure decreased glucose oxidation (metformin 270 µmol/l: -30 ± 9%; rosiglitazone 9 µmol/l: -25 ± 8%; pioglitazone 9 µmol/l: -45 ± 3%; P < 0.05) and increased lactate production (metformin: +84 ± 12%; rosiglitazone: +38 ± 6%; pioglitazone: +64 ± 11%; P < 0.05).
Why it matters
The findings demonstrate that thiazolidinediones share metformin's ability to inhibit mitochondrial complex I and promote glycolytic flux. This suggests that some antidiabetic actions of thiazolidinediones may occur through mitochondrial inhibition independently of or alongside PPAR-gamma receptor activation.
Limits
This was an in vitro and ex vivo study using isolated rat muscle and organelle preparations without human clinical evaluation. Replicate numbers and sample sizes are not reported in the abstract. In addition, the experimental drug concentrations used in cell-free and tissue assays are substantially higher than typical therapeutic plasma levels in humans.
Cited by
- context Metformin causes mitochondrial stress by inhibiting complex I or complex II of the electron transport chain.