Wednesday, November 04, 2009

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...


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.


Jenny said...

The worsening of retinopathy when blood sugars are normalized occurs no matter HOW they are normalized or how fast or slowly.

The long term DCCT results found that the small proportion of people with Type 1 who suffered the worsening after lowering their blood sugars still had better vision ten years later than those who did not lower their blood sugar.

Unfortunately, it looks like this possible worsening is the price people pay for having had the very high blood sugars. If they leave them high because they already have retinopathy, blindness is almost assured. If they lower the blood sugar, temporary worsening of the retinopathy may occur but long term they will be in better shape.

I have seen people cite this temporary worsening to frighten people away from lowering blood sugar, but that is a huge mistake. And after searching the literature I found the experts agreeing that speed of lowering did not appear to be a factor.

Senta said...

Very interesting Peter! Since you mentioned that the kidneys, like the retina, are unable to protect themselves with insulin resistance, do you think there is something similar happening with regard to kidney stones? Possibly people who have asymptomatic stones when they are hyperglycemic experience a temporary flare of symptoms when they lower their blood sugar?

Ken said...

'Effect of oral cholecalciferol supplementation at physiological and supraphysiological doses in naturally vitamin D3-deficient subterranean damara mole rats'
It appears, therefore, that these animals function optimally at the low concentrations of D3 metabolites found naturally. Supplementation at both physiological and supraphysiological doses of D3 may disadvantage the damara mole rat.

'Prolonged longevity in naked mole-rats: age-related changes in metabolism, body composition and gastrointestinal function'

Maximum lifespan of these 40 g rodents (>27 year) is 9 times greater than predicted allometrically. [...]The observed absence of age-related bone loss in naked mole-rats may be explained by their employment of vitamin D-independent mineral metabolism

Peter said...

Hi Senta,

That's an interesting hypothesis!


Gregory said...

Has anyone seen this?:

Scroll down to: "In with the new, out with the old (fat)"

It would seem to be relevant: got to up the fat, to keep the liver in shapre, if you cut carbs.

Peter said...

Hi Gregory,

That's very interesting. The implication seems to be that FFAs from lipolysis are treated differently to those from either in situ lipogeneis or delivered by chylomicrons (or VLDLs?). That has all sorts of possible knock on effects... Also, what do they mean by dietary fat... Of course not many of us are FAS deficient, but interesting to think about mechanisms