The basic finding is that manipulating superoxide levels as close as possible to the ETC suggests that it is THE mediator of insulin resistance. Again, I'll skip a large amount of the extreme cleverness utilised and look at the bottom line and its implications. BTW the cleverness was very, very clever. How superoxide controls responsiveness to insulin, nobody knows (though George has some interesting ideas). But it appears to be a generic finding. They looked at steroids, they looked at TNF alpha, excess insulin (good old Somogyi) and, as you might expect, palmitic acid (as in the last post, on a background of 25mmol/l glucose). All cause insulin resistance in the models used. Also bear in mind that they are looking at myotubules and rather peculiar adipocyte-like cells. But I think they are probably correct in this basic conclusion.
Superoxide is core to insulin resistance.
It is very interesting to take this concept and look at various insulin resistance syndromes over the next few weeks.
Of course these folks are in obesity research so you have to be quite cautious when looking at their models and results. You also have to be very, very wary about their conclusions. This is the last sentence of the abstract:
"These data place mitochondrial superoxide at the nexus between intracellular metabolism [tick, agree] and the control of insulin action [tick, agree] potentially defining this as a metabolic sensor of energy excess [woaaaaah, care here]."
This is a slightly tricky sentence. It's that "excess" which bugs me. Look at section L from Fig 4 in the discussion to see how they are thinking:
Here we have a schematic of inactivity and overnutrition causing increased mitochondrial superoxide production. This clearly relates to the Denmark paper where people were paid to eat to excess while deliberately reducing their exercise. Fasting insulin spiked from 35pmol/l to 74pmol/l in 3 days. You can say that overnutrition certainly generates superoxide production. But is this what is happening in weight gain outside of paying people to over eat? That is not how most obese people become obese!
Inactivity and over nutrition are macroscopic changes and superoxide generation is a sub cellular mitochondrial effect. You have to be very careful in how you link the two features together. Superoxide may always signal insulin resistance but are there other drivers of superoxide production in addition to caloric excess?
The situation which keeps coming back to me is starvation.
There is no over nutrition during starvation. There is plenty of superoxide production. Why?
Humans have a brain which is rather dependent on glucose. Using glucose for non brain purposes during starvation would be potentially fatal. All tissues which can become insulin resistant should do so under these conditions.
Superoxide is utterly essential to the survival of starvation. Insulin resistance is a complete necessity.
It looks very much as if fat oxidation (especially palmitate) is directly set up to ensure this happens. It's the reason I was blogging about beta oxidation and FADH2 here. Fat supplies only two molecules of NADH for each of FADH2 and the beta oxidation derived FADH2 enters the electron transport chain through electron-transferring flavoprotein dehydrogenase, directly to the CoQ couple. This is a good situation to generate reverse electron transport, subsequent superoxide and trigger a specific refusal to process insulin. An overnight fasted human has total FFAs of around 0.5mmol/l and they stabilise at around 1.5mmol/l by four days of starvation. They stay there until some food, especially carbohydrate, is eaten.
This level (1.5mmol/l) should, by necessity, develop enough insulin resistance to stop GLUT4 dependent tissues from using glucose, to spare it for brain tissue.
Survival during starvation does not just necessitate using stored fat for energy. It necessitates the near complete abrogation of glucose usage for anything other than brain function. Not after that mere 14 hour fast before an oral glucose tolerance test, but certainly by four days without food. This abrogation cannot be reversed in a couple of hours during an OGTT. This is the "diabetes of starvation".
Superoxide is not always a marker of excess, though this is certainly one way of generating it. It is more accurately a marker of any situation in which insulin resistance is beneficial to survival.
Peter
And I really will get to emails some time soon (mea culpa!)
