This paper looked at a series of 10 hapless folk to whom this happened:
Metformin overdose causes platelet mitochondrial dysfunction in humans
The mean blood concentration which gets you an ITU bed was 32mg/l. Now this is a clinical paper, written by clinicians. Nothing wrong with that, except they use Noddy units which makes the metformin concentrations extremely difficult to relate to the vast body of metformin research, which uses units of millimolar or micromolar.
So we really need to take this image
and think of it in these terms when we're looking at research papers using mmol or micromol concentrations:
Bear in mind that these are very chronic exposure values and metformin is thought to be progressively cumulative within the mitochondria on chronic exposure. Of course, complex I is intra mitochondrial and there will be some dependency on cumulation in getting significant effects at this site. What we can say is that, in the above diagram, there is not enough inhibition of complex I to raise lactate production in platelets, an extra-hepatic tissue (hepatocytes may be slightly different), unless we are using near-death concentrations.
What is not hidden away inside the mitochondrial matrix is mtG3Pdh. It's on the outer surface of the inner mitochondrial membrane and will be exposed to whatever metformin concentration that manages to get inside the cell.
From the classic paper
Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase
we have this graph from Figure 3, using a slurry of mashed up mitochondria and some glycerol phosphate:
Here we have a significant effect on the oxidation of glycerol-3-phosphate at micromolar concentrations. Admittedly by 50μmol we are looking at very much the upper end of therapeutic concentrations but an effect is clearly visible at this level. We can say from the platelet paper that exposure to 250μmol (black circles at the bottom of the graph), if sustained, will put you in the ITU with potentially fatal lactic acidosis.
Because mtG3Pdh is exposed to cytoplasmic (non cumulative vs mitochondrial) metformin levels it will see the drug at plasma concentrations (or slightly less) and it will see these concentrations as soon as metformin enters the blood stream.
If you want a performance enhancing drug for endurance exercise, say a cycle race taking about three hours, you can pop a single metformin 500mg tablet before the start of the race and extend your time to exhaustion in a final sprint from 167 seconds to 191 seconds. That might make some difference to winning vs not winning.
Metformin improves performance in high-intensity exercise, but not anaerobic capacity in healthy male subjects
Equally, there is no acute effect on lactate levels in the same study. This is no surprise as I find it difficult to envisage acute complex I blockade, to lactate generating levels, as a performance enhancing ploy.
TLDR: metformin probably works in the cytolasm on mtG3Pdh. Rising lactate may well indicate mitochondrial cumulation and some degree of complex I inhibition. Extrapolating benefits from studies based around millimolar concentrations in-vitro may well put you in to the ITU if you try them in-vivo.
Peter