The next thing we have to think about is the glycerol 3 phosphate shuttle. This is a route in to the electron transport chain for cytoplasmic NADH, directly from the cytoplasm, no complex I involved.
There are two glycerol 3 phosphate dehydrogenases which make up the shuttle, just to confuse matters. Free in the cytosol there is cytosolic G3P dehydrogenase, which actually uses NADH to add a pair of hydrogens to a glycolysis intermediate (dihydroxyacetone phosphate) to form G3P.
The other G3P dehydrogenase really does dehydrogenate G3P, back to dihydroxyacetone phosphate. But this second G3P dehydrogenase is embedded in the outer surface of the inner mitochondrial membrane. And it contains an FAD/FADH2 moiety which takes these two hydrogens and uses them to reduce the CoQ couple, feeding electrons in to the electron transport chain.
So we are putting electrons from cytosolic NADH directly in to the ETC through FADH2. From the outside. And pumping no protons.
The G3P shuttle is very, very important.
In healthy cells the signal to reject excess calories picks on glucose, in the form of the development of insulin resistance, mediated by superoxide generated at complex I of the mitochondria. At iron sulphur cluster N-1a. The most simple way of doing this is to oxidise fully saturated fats (mmmmm, butter), generate a lot of FADH2, post a few electrons the wrong way through complex I and shut down glucose acceptance by the cell.
You can make glucose act as if it were butter through the G3P shuttle.
Think what happens if you are a Taterhead, just finishing your 4th plate of plain boiled, unsalted, unseasoned, unpeeled spuds.
Your FFAs, especially palmitate, are through the floor. Your glucose, given its own way, would be through the roof. Insulin is demanding that all cells accept glucose because no one wants a blood glucose of 30mmol/l. There is a shedload of NADH in both the cytoplasm and in the mitochondrial matrix. Electrons are pouring down the ETC but, in your post spud-prandial insulin induced stupor, you are not exactly sprinting to the gym.
You have to stop the supply of NADH pouring through complex I but, unless the NADH level is over three times the NAD+ level in mitochondria, you are not exactly going to get an electron on to N-1a excepting when there is a markedly reduced CoQ couple and a strong membrane potential. In the absence of palmitic acid (you're pigging out on fat-free spuds, don't forget) you need mitochondrial G3P dehydrogenase to pour electrons on to the CoQ couple, which allow the insulin/glucose induced membrane potential to push electrons back up the ETC to N-1a. And then SHUT DOWN THE BLOODY GLUCOSE SUPPLY.
You might just be able to do the same to deal with excess insulin. If insulin (from exogenous injection or an insulinoma) is allowing a free fall of glucose in to the cell and the cell really doesn't want all of this metabolic substrate, it has to say no. It was quite a while ago now but we have discussed insulin induced insulin resistance. Here's a possible metabolic mechanism. And the mechanism would kick in when the G3P shuttle goes in to overdrive, not when glucose becomes too low. Back to when we had the discussions about the Somogyi overswing... It's just a mimic of pigging out on spuds but without the spuds.
But the queen of insulin resistance generators is, of course, fructose. Fructose free falls through glycolysis to levels that the cells really cannot expect to use immediately. Of course a lot of it gets off loaded as lactate but there is still way more pyruvate than a cell can reasonably be expected to oxidise immediately. I consider this effect to be dose related. Eating the occasional apple might not kill you (gasp, there, I said it) but three Big Gulps per day probably has you well on your way.
Answer to fructose exposure is to shut down glucose supply to a level which compensates for the calories coming through from fructose. There can be no easier way than to reduce the CoQ couple using an FADH2 input. G3P dehydrogenase does this directly from the cytoplasm. It, like electron transferring flavoprotein dehydrogenase, is what I would describe as "complex II -like" in its action.
This smacks of physiological regulation to me.
Things get slightly more pathological where hyperglycaemia is overcoming insulin resistance. Or overcoming absolute insulin deficiency, as Sonksen and Sonksen pointed out. I'll come back to this in future posts.
There is quite a lot of support for this concept in Pubmed but here is an abstract I particularly enjoyed. Anyone thinking of indulging in a bit of Taterism should have a read first. A real giggle while you boil your spuds.
The wild type mice were funniest. For your delectation:
"The high carbohydrate diet induced hyperglycaemia, hyperinsulinaemia, and islet hyperplasia in the wild-type [mice]"
Oh, for the love of Taterism, does anyone remember the discussion of Barnard's victims and their progression of diabetes under a low sugar, high complex carbohydrate diet? Well, mice are not so different from people! In people we call this Taterism. Well, some of us do.
And look at the tweaked physiology in the same abstract. If you knock out mG3P dehydrogenase (ie you eliminate this "complex II-like" FADH2 reduction of the CoQ couple) you get increased insulin sensitivity (no reverse electron flow as there is no FADH2 route in to the ETC except complex II and we're not feeding fat).
Is this a good or a bad state to be in? That depends on degree and whether you are happy to push far more electrons down your ETC than you could possibly have a use for. An interesting question. I'm not in the queue to trial a mG3P dehydrogenase inhibitor (actually, it's called diazoxide and it does seem to help). Not eating carbs seems a rather safer bet.
[BTW if anyone has this high carb paper it would be nice to know which mice they used and what the diet was actually made of... Ta.]
Edit: Got it, many thanks Paul and Purposelessness. End edit
Which leads straight on to neurons.