Hyperglycaemia and free radicals

I've been struggling through this paper for some time and refuse to give up on it as I think the group might have a point. This doesn't alter the fact that it is disjointed, interweaves hypeglycaemia and hypoxia as similar conditions with very little discussion of the subtle differences between them and has a major discussion paper associated which I cannot find. So the fact I've not binned it means I must want to read it! This seems to be what they are saying (I think):


Glycolysis produces two significant energy related molecules. ATP, which is directly useful, and NADH. NADH is a high energy molecule which can be used in the mitochondria to pump protons for the generation of ATP, as part of oxidative phosphorylation using the electron transport chain. NADH gets in to the mitochondria through the malate-aspartate shuttle. The shuttle won't run if there is not enough oxygen to allow oxidative phosphorylation.

Hyperglycaemia increases the rate of glycolysis and so increases the amount of NADH in the cell cytoplasm. This is no real problem provided the NADH can enter the mitochondria, which usually translates as so long as there is oxygen available. If there is no oxygen there is always the option of lactate formation in the cytosol. Pyruvate to lactate converts NADH back to the NAD+ which is needed to allow glycolysis to keep running.

Hyperglycaemia increases the amount of lactate per unit pyruvate. Blocking the polyol pathway (see below) stops this. As above, increased lactate formation is a technique for converting NADH to NAD+ when the NADH cannot get in to mitochondria, which suggest that hyperglycaemia mimics hypoxia, ie there is more NADH than can be used for oxidative phosphorylation and so a deficit in cytosolic NAD+, which needs correcting. The malate-aspartate shuttle obviously converts cytosolic NADH to NAD+ too.

There is a second pathway for glucose metabolism in cells which are insulin independent. These cells, which include the retina, neurons, renal cells and a few others, cannot become insulin resistant so have to accept huge doses of glucose whenever hyperglycaemia occurs. Under these conditions the polyol pathway becomes active.

This pathway involves the conversion of glucose to sorbitol and then the rather slower conversion of sorbitol to fructose. The conversion of sorbitol to fructose unfortunately generates more NADH and so of course depletes NAD+ in the cytosol. Fructose then leaves the cell without forming pyruvate for conversion to lactate, so there is a net imbalance of excess NADH which must be converted back to NAD+ or glycolysis grinds to a halt.

This last conversion, NADH back to NAD+, is the one which generates the free radicals in the cytosol. There are other issues with NADP+, another product of the polyol pathway, but this post is way too complex already. So I'll leave the NADP+ aspect; it's also bad.



Hyperglycaemia increases the sorbitol level 9-18 fold in a rat's retina in vitro.

Hyperglycaemia increases the fructose level 55-74 fold.



These relative increases sound enormous until you realise there's not much sorbitol or fructose there to begin with! Still, this does look to be the main source of fructose in the cell and, en route to liver and muscles, of fructose in the blood.

So you could hypothesise that fructose in plasma represents activation of the polyol pathway (in the absence of liver failure which might allow dietary fructose to hit the systemic circulation). The more fructose, the more the polyol pathway is active.

It's interesting to note that blood fructose predicts, observationally, severity of diabetic retinopathy and that the retina is one of those tissues which cannot put up the protective shield of insulin resistance against the onslaught of hyperglycaemia. The retina accepts hyperglycaemic levels of glucose, shunts them down the polyol pathway, generating a bucketload of NADH and some fructose in the process.

Aberrant free radicals, generated in the cytosol from NADH reconversion to NAD+, have the option to be damaging under these fully pathological conditions. A blood glucose of 30mmol/l in a human is only acceptable to the ADA, and even they might consider it to be a little bit worrisome. So bad they might prescribe a statin.

Another aspect of hyperglycaemic metabolism touched on by the paper is the reliance of the retinal cells on the ATP derived from the excessive glycolysis driven by hyperglycaemia, particularly when the mitochandria are not working effectively. Classically this is triggered by hypoxia, but many type 2 diabetic people have poorly functional mitochondria associated with the illness. The sudden fall in glycolysis derived ATP is hypothesised to produce an acute metabolic failure and the exacerbation of diabetic retinopathy which can occasionally be seen following the sudden normalisation of blood glucose in unstable diabetic patients.

This is real and does happen, it's a well accepted standard complication. It's something which needs to be considered by anyone using any technique which suddenly normalises the blood glucose for a diabetic patient. Obviously there is minimal risk of this complication from mainstream diabetes management, but once you start sudden onset LC eating it becomes more possible. The ultimate verdict seems to be that this risk is low and that continued hyperglycaemia will progress the retinopathy relentlessly anyway. But just be aware...

Back to the pathological free radicals produced by the pathological hyperglycaemia: Is there a roll for pharmaceutical free radical scavengers here? Is this why exogenous antioxidants like n-acetylcarnosine are effective, certainly within the lens? There seems to be some logic to this in patients where normoglycaemia is not on the menu...

But to me it's pharmacology managing on going pathology. I can't see it as an evolutionary need to eat plants to mitigate this problem. Especially if those plants are full of sugar...

Peter

How does this fit in with naked mole rats and their tuber eating? That I would need to read more about these beasties for, so it's on the To Do list.