I've been meaning to post on this paper for a long time. It's old but not ancient (2006). The authors are interesting. Collier CA is first author and does not appear to have published anything else, ever. My guess is that it was her PhD which produced the paper and she dropped out of science at this point. Anyone who has tried to get funding for their first post doc will understand. Second author is Bruce CR and he has no other publications on metformin. Smith AC has one other publication on metformin but she wasn't looking at anything interesting from the Protons point of view. Last two authors are group leaders and have virtually zero publications on metformin.
So the lab dabbled in metformin for one PhD and lost either interest or funding. The paper has that feel to it. It looks preliminary, it has a few rough edges, the authors didn't appear to have known what the results were going to be before they started. Back in 2006 no one was thinking about mtG3Pdh or had any real idea of how metformin worked.
They used high doses of metformin and supra maximal doses of insulin on freshly isolated muscle tissue from healthy rats fed standard CIAB. So there is a simple black and white effect, nothing subtle. They looked at glucose oxidation and palmitate oxidation in acutely isolated soleus or epitrochlearis muscle. Soleus is a mixed fuel, oxidative muscle, epitrochlearis is glycolytic. Soleus is the one metformin works on. Here's the effect on palmitate oxidation:
One the left, metformin does nothing to suppress palmitate oxidation. No surprise there. On the right, insulin suppresses fatty acid oxidation.
That was one of the best findings in the paper. Never mind the lipophilic concept of obesity. Even if you keep your fatty acids outside of your adipocytes, insulin will suppress fatty acid oxidation in your soleus type muscles (i.e. an awful lot of them).
Metformin stops this happening and restores fatty acid oxidation. It does this for all of the reasons in the Protons thread which I won't repeat yet again except to say that, under metformin, insulin signalling can only be facilitated by fatty acid oxidation derived FADH2, not via mtG3Pdh FADH2.
The same happens for glucose oxidation:
Metformin alone does nothing to glucose oxidation in the absence of insulin but it blocks the small increase induced by supramaximal insulin.
If you want to suppress fatty acid oxidation in your muscles, insulin does this very nicely and metformin restores it. This was the most useful finding in the paper.
For whatever reason, they walked away from it.
Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle.