Dr BG will have fun with this one when she gets the full text, but here's the sneak preview from the abstract she forwarded to me:
"In patients with IFG and hyperlipidaemia, rosuvastatin treatment was associated with a dose-dependent increase in insulin resistance."
That's an increase of 46% in the fasting insulin needed to maintain some semblance of no-worse-than-modest fasting hyperglycaemia. And probably wall to wall sdLDL in whatever cholesterol you have left.
IFG is just a random category on the road to diabetes. If you think rosuvastatin does any good to the insulin sensitivity of people with frank diabetes or of "normal" people who have yet to get themselves a label, I suspect you will be disappointed! But then what's a bit of extra insulin, sugar or both when you can have lipids to die for...
Peter
Sunday, November 08, 2009
Friday, November 06, 2009
Food: Lardo; the real thing
I don't do a lot of food picture or recipe posting, others do this well and our eating is quite simple really. But just occasionally some thing very special comes along, this time as part of a beautiful food gift from a friend in Italy to a beleaguered lipophile living in sucrose encrusted Glasgow... Many thanks!
This is Lardo. It's a bit like bacon, but not bacon as we know it... Possession is a criminal offence in both the USA and Finland but this appears to have been decriminalised in Sweden, which suggests that possession of small quantities, without intent to supply.....
The pig skin is there, as is a sliver of salted panniculus muscle. The two are separated by backfat. Lots of backfat. The meat end is encrusted in cracked black pepper and herbs.
I cut off about half a centimetre. Dry fried it to get the opaque fat transparent and that was breakfast.
Anyone in Italy will know how good it is. Now I do too.
Many many thanks (you know who!)
Peter
This is Lardo. It's a bit like bacon, but not bacon as we know it... Possession is a criminal offence in both the USA and Finland but this appears to have been decriminalised in Sweden, which suggests that possession of small quantities, without intent to supply.....
The pig skin is there, as is a sliver of salted panniculus muscle. The two are separated by backfat. Lots of backfat. The meat end is encrusted in cracked black pepper and herbs.
I cut off about half a centimetre. Dry fried it to get the opaque fat transparent and that was breakfast.
Anyone in Italy will know how good it is. Now I do too.
Many many thanks (you know who!)
Peter
Thursday, November 05, 2009
Dr Uffe Ravnskov MD PhD interview
Just a brief aside, here is part of an interview with Uffe Ravnskov MD PhD which neatly summarises the situation in Sweden at the moment. I'll link to the full text, which is much more wide ranging, when I've read through it all.
EDIT It's here.
Peter
Interviewer: Do you think mainstream medicine will ever relinquish its view that elevated cholesterol causes heart disease and that statins are the magic bullet?
Dr Ravnskov: I hope so. The failures of the most recent statin trials has been commented by several journalists in the major US newspapers. In Sweden a revolution is going on. Here, a general practitioner treated her own obesity successfully by eating a low-carbohydrate diet with a high content of animal fat. When she advised her obese and diabetic patients to do the same, she was reported to the National Board of Health and Welfare for malpractice. After a two-year-long investigation she was acquitted, as her treatment was considered to be in accord with scientific evidence. At the same time, the Board dismissed two experts, who had been appointed for updating the dietary recommendations for diabetics, because it came up that they were sponsored by the food industry. Instead the Board has asked independent researchers to review the scientific literature.
The subject has gained general attention due to a number of radio and television shows, where critical experts including myself have discussed the issue with representatives of the official view. Most important, thousands of patients have experienced themselves that by doing the opposite as recommended by the current guidelines they have regained their health. The effect has been that the sales of butter, cream and fat milk are increasing in Sweden after many years of decline, and a recent poll showed that a majority of Swedish people today think that the best way of losing weight is by a low-carbohydrate, fat-rich diet.
Further progress was achieved this spring. Several times colleagues of mine and also myself have asked the Swedish Food Administration for the scientific basis of their warnings against saturated fat. We have been met with the argument that there are thousands of such studies, or by referrals to the WHO guidelines or the Nordic Nutrition Recommendations. As the main argument in the latter two is that saturated fat raises cholesterol we were not satisfied with their answer and finally the Food Administration published a list with 72 studies that they claimed were in support of their view on saturated fat and twelve that were not.
We scrutinized the lists and found that only two of the 72 studies supported their standpoint; eleven studies did not concern saturated fat at all, and the unsupportive list was incomplete, to put it mildly. We published a short report with our comments to these lists in the Swedish medical journal Dagens Medicin. A response from the Food Administration appeared seven weeks later in which they pointed out that their recommendations were directed to healthy people, not to patients. They maintained that they were based on solid scientific evidence without mentioning anything about saturated fat and without answering our critical comments.
But this is not all. Earlier this year Sachdeva et al reported that the mean cholesterol in 137,000 patients with acute myocardial infarction was lower than normal. As usual, the authors didn’t understand their own findings, but concluded that cholesterol should be lowered even more. A few months later Al-Mallah et al. came up with the same result and conclusion, although they also reported that three years later, mortality was twice as high among those who had been admitted with the lowest cholesterol.
These results created a fierce debate in one of the major Swedish newspapers. It was opened by ninety-one-year old Lars Werkö, the ‘Grand Old Man’ in Swedish medical science, retired professor in internal medicine and former head of The Swedish Council on Technology Assessment in Health Care, together with Tore Scherstén, retired professor in surgery and former secretary of the Swedish Medical Research Council. “Now it is time to sack the cholesterol hypothesis and to investigate the reason of this scientific breakdown” they wrote. They also criticized American researchers in AHA and NHLBI and their followers for sloppy and fraudulent science.
They were of course attacked by two professors and representatives of the current view, but none of them came up with any substantial evidence, only by personalities.
EDIT It's here.
Peter
Interviewer: Do you think mainstream medicine will ever relinquish its view that elevated cholesterol causes heart disease and that statins are the magic bullet?
Dr Ravnskov: I hope so. The failures of the most recent statin trials has been commented by several journalists in the major US newspapers. In Sweden a revolution is going on. Here, a general practitioner treated her own obesity successfully by eating a low-carbohydrate diet with a high content of animal fat. When she advised her obese and diabetic patients to do the same, she was reported to the National Board of Health and Welfare for malpractice. After a two-year-long investigation she was acquitted, as her treatment was considered to be in accord with scientific evidence. At the same time, the Board dismissed two experts, who had been appointed for updating the dietary recommendations for diabetics, because it came up that they were sponsored by the food industry. Instead the Board has asked independent researchers to review the scientific literature.
The subject has gained general attention due to a number of radio and television shows, where critical experts including myself have discussed the issue with representatives of the official view. Most important, thousands of patients have experienced themselves that by doing the opposite as recommended by the current guidelines they have regained their health. The effect has been that the sales of butter, cream and fat milk are increasing in Sweden after many years of decline, and a recent poll showed that a majority of Swedish people today think that the best way of losing weight is by a low-carbohydrate, fat-rich diet.
Further progress was achieved this spring. Several times colleagues of mine and also myself have asked the Swedish Food Administration for the scientific basis of their warnings against saturated fat. We have been met with the argument that there are thousands of such studies, or by referrals to the WHO guidelines or the Nordic Nutrition Recommendations. As the main argument in the latter two is that saturated fat raises cholesterol we were not satisfied with their answer and finally the Food Administration published a list with 72 studies that they claimed were in support of their view on saturated fat and twelve that were not.
We scrutinized the lists and found that only two of the 72 studies supported their standpoint; eleven studies did not concern saturated fat at all, and the unsupportive list was incomplete, to put it mildly. We published a short report with our comments to these lists in the Swedish medical journal Dagens Medicin. A response from the Food Administration appeared seven weeks later in which they pointed out that their recommendations were directed to healthy people, not to patients. They maintained that they were based on solid scientific evidence without mentioning anything about saturated fat and without answering our critical comments.
But this is not all. Earlier this year Sachdeva et al reported that the mean cholesterol in 137,000 patients with acute myocardial infarction was lower than normal. As usual, the authors didn’t understand their own findings, but concluded that cholesterol should be lowered even more. A few months later Al-Mallah et al. came up with the same result and conclusion, although they also reported that three years later, mortality was twice as high among those who had been admitted with the lowest cholesterol.
These results created a fierce debate in one of the major Swedish newspapers. It was opened by ninety-one-year old Lars Werkö, the ‘Grand Old Man’ in Swedish medical science, retired professor in internal medicine and former head of The Swedish Council on Technology Assessment in Health Care, together with Tore Scherstén, retired professor in surgery and former secretary of the Swedish Medical Research Council. “Now it is time to sack the cholesterol hypothesis and to investigate the reason of this scientific breakdown” they wrote. They also criticized American researchers in AHA and NHLBI and their followers for sloppy and fraudulent science.
They were of course attacked by two professors and representatives of the current view, but none of them came up with any substantial evidence, only by personalities.
Naked mole-rats
OK, I hit the Naked mole-rats (NMRs). They're not pretty!
I would just like to point people towards Table 2, especially the lines Fasting glucose, GTT and insulin.
NMRs don't do insulin or, if they do, it is very different from ordinary rodent insulin. To the point where a normal rodent insulin assay simply can't find any insulin-like peptide in their blood.
Then there is Table 3 giving an HbA1c of 5.5%. Not suggestive of hypo or hyper glycaemia, with the normal caveats about HbA1c. BTW look at the HbA1c of normal lab mice. You too could be diabetic, just eat cr@pinabag.
NMRs also tend to fail GTTs:
"Surprisingly, NMRs even at a young age show impaired glucose tolerance (53), and insulin cannot be detected using rodent assays (Kang, Biney, and Buffenstein, unpublished data, 2004). We are currently assessing if this is because NMRs are naturally deficient in insulin or if their structure of insulin diverges to such an extent that it cannot be measured using common commercially available assays. Despite the apparent lack of insulin and abnormal glucose handling, glycated hemoglobin levels are low and similar in both 2- and 20-year-olds (Kang, Biney, and Buffenstein, unpublished data, 2004)."
Buffenstein has a bit to say on PUFA, DHA and D3 which are thought provoking.
I think it might be time to dig in to the pathological aspects of insulin sensitivity. We think of insulin sensitivity as a Good Thing. Well, maybe...
Peter
I would just like to point people towards Table 2, especially the lines Fasting glucose, GTT and insulin.
NMRs don't do insulin or, if they do, it is very different from ordinary rodent insulin. To the point where a normal rodent insulin assay simply can't find any insulin-like peptide in their blood.
Then there is Table 3 giving an HbA1c of 5.5%. Not suggestive of hypo or hyper glycaemia, with the normal caveats about HbA1c. BTW look at the HbA1c of normal lab mice. You too could be diabetic, just eat cr@pinabag.
NMRs also tend to fail GTTs:
"Surprisingly, NMRs even at a young age show impaired glucose tolerance (53), and insulin cannot be detected using rodent assays (Kang, Biney, and Buffenstein, unpublished data, 2004). We are currently assessing if this is because NMRs are naturally deficient in insulin or if their structure of insulin diverges to such an extent that it cannot be measured using common commercially available assays. Despite the apparent lack of insulin and abnormal glucose handling, glycated hemoglobin levels are low and similar in both 2- and 20-year-olds (Kang, Biney, and Buffenstein, unpublished data, 2004)."
Buffenstein has a bit to say on PUFA, DHA and D3 which are thought provoking.
I think it might be time to dig in to the pathological aspects of insulin sensitivity. We think of insulin sensitivity as a Good Thing. Well, maybe...
Peter
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 pharmacolgy 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.
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 pharmacolgy 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.
Sunday, November 01, 2009
Swedish children; dietary sins (2)
Just a quickie before getting round to comments if tonight's shift is quiet...
From Björn on the THINCS board. More observational stuff from Gothenburg University on what fat children don't drink and slim children do drink. Assuming any sort of causality, I'd just comment that the struggle to get full fat milk for my son in Glasgow coffee shops or restaurants doesn't bode too well for the populace. Luckily for us Cafe Nero usually has cream in stock for me and I can just add a little to the semi skimmed milk which is the only milk that's available for him... Other than fully skimmed tea whitener!
I think the whole of Dr Eriksson's thesis is here, an epic I've yet to try and read.
Peter
From Björn on the THINCS board. More observational stuff from Gothenburg University on what fat children don't drink and slim children do drink. Assuming any sort of causality, I'd just comment that the struggle to get full fat milk for my son in Glasgow coffee shops or restaurants doesn't bode too well for the populace. Luckily for us Cafe Nero usually has cream in stock for me and I can just add a little to the semi skimmed milk which is the only milk that's available for him... Other than fully skimmed tea whitener!
I think the whole of Dr Eriksson's thesis is here, an epic I've yet to try and read.
Peter
Friday, October 30, 2009
Honesty is for losers, of jobs that is! Jebb VS Nutt
Honesty is NOT the best, and certainly not the Government, policy. This is merely drugs. Imagine what would happen to Susan Jebb if she told the truth about current FSA advice on diet. She's possibly not as stupid as I thought, perhaps she shares intelligence with Professor David Nutt. He has the misfortune to be, in addition, honest and now unemployed. She has her job.
Peter
EDIT: What happens if you decriminalise ALL recreational drugs. This is not a hypothetical question. Portugal did it in 2001. It's now nearing the end of 2009. Had you heard about this happening or the outcome? Certainly makes Alan Johnson look like a monster to me, oh.... I forgot, he's a politician!
Peter
EDIT: What happens if you decriminalise ALL recreational drugs. This is not a hypothetical question. Portugal did it in 2001. It's now nearing the end of 2009. Had you heard about this happening or the outcome? Certainly makes Alan Johnson look like a monster to me, oh.... I forgot, he's a politician!
Worms and Stress: Live Long and Prosper
This is a very interesting paper about worms. The central thing to remember is that it is about WORMS. Most of us are not worms, but all of us do have mitochondria. Worm mitochondria are, I suspect, quite similar to human mitochondria, at least as far as basic signaling mechanisms are concerned.
Glucose, as a molecule, is full of oxygen. One oxygen atom per pair of hydrogen atoms. You just need to add an oxygen molecule for each carbon atom to get just over 40 molecules of ATP. Fats are different. There are only two oxygen atoms down at one end of that long string of carbon and hydrogen. To extract the stored energy requires much more molecular oxygen, so makes more use of mitochondrial respiration.
The electron transfer chain leaks free radicals. Running your metabolism on fat requires more use of the electron transfer chain. That means more free radicals.
Generally free radicals are considered to be a Bad Thing.
Actually, if you think about it, having your white blood cells throw free radicals at invading bacteria suggests that free radicals are one reason we are all still alive. Nothing is all bad.
So worms, under glucose restriction, generate far more free radicals than those able to access glucose.
Here's the best bit: The ones making all the free radicals also live longer. Don't forget, it's only a worm!
Why do they live longer? Because mitochondria can only work by using oxygen to run the respiratory chain. If using mitochondrial respiration was damaging, we wouldn't do it! It's POTENTIALLY damaging. Given the few billion years we've had, metabolism would have stopped this free radical production if it needed to. Evolution hasn't made the respiratory chain leak proof. Why? Free radical generation is the signal that mitochondrial respiration is happening and it's time to up regulate the cell's routine protection against free radical damage that has stood the test of time. This does not involve going off and eating some poor plant to steal its antioxidants.
Catalase, superoxide dismutase and glutathione peroxidase will do for a start. These are local antioxidant enzymes produced where they are needed, when they are needed by a cell which needs them to run its power plants safely. The fact that they seem to have overall benefits, apart from the smooth running of the mitochondria, is a useful spin off. And they don't involve eating anything green.
There are a few summary points to the study:
Glucose restriction by any technique extends lifespan in worms.
Glucose supplementation produces a dose related shortening of life span in worms.
Glucose supplemented worms store FAT!
N-acetylcysteine, ascorbate or a vitamin E derivative (Trolox) each eliminates the life extension provided by glucose restriction in worms.
Here's the consolation for people knocking back the antioxidants: They probably do no harm directly, just eliminates any benefit from glucose restriction. If you live on glucose, well shrug...
This is how this research group view the impact of their work on diabetes management:
"In light of our findings, the current body of evidence tentatively calls into question the efficacy of increasing cellular glucose uptake in diabetics and suggests that other methods of lowering blood glucose (Isaji, 2007; Wright et al., 2007) may be preferable to achieve normal life expectancy in human type 2 diabetes patients."
The two refs cited refer to techniques for extracting glucose through the kidneys or possibly reducing its uptake through the gut. No consideration seems to be given to not actually putting quite so much glucose in to the system in the first place!
If anyone finds this remotely interesting, while not feeling particularly worm-like, you can go and look at the evidence in Jenny Ruhl's post on antioxidants in humans.
I'd just like to point you towards this particular one. I was surprised that as little as 1000mg of ascorbate per day with 400iu of vitamin E had a measurable effect. But, if the study is replicable, it might well fit in with the observational evidence.
Really must give up the chocolate (only kidding, my liver will save me!).
Peter
Glucose, as a molecule, is full of oxygen. One oxygen atom per pair of hydrogen atoms. You just need to add an oxygen molecule for each carbon atom to get just over 40 molecules of ATP. Fats are different. There are only two oxygen atoms down at one end of that long string of carbon and hydrogen. To extract the stored energy requires much more molecular oxygen, so makes more use of mitochondrial respiration.
The electron transfer chain leaks free radicals. Running your metabolism on fat requires more use of the electron transfer chain. That means more free radicals.
Generally free radicals are considered to be a Bad Thing.
Actually, if you think about it, having your white blood cells throw free radicals at invading bacteria suggests that free radicals are one reason we are all still alive. Nothing is all bad.
So worms, under glucose restriction, generate far more free radicals than those able to access glucose.
Here's the best bit: The ones making all the free radicals also live longer. Don't forget, it's only a worm!
Why do they live longer? Because mitochondria can only work by using oxygen to run the respiratory chain. If using mitochondrial respiration was damaging, we wouldn't do it! It's POTENTIALLY damaging. Given the few billion years we've had, metabolism would have stopped this free radical production if it needed to. Evolution hasn't made the respiratory chain leak proof. Why? Free radical generation is the signal that mitochondrial respiration is happening and it's time to up regulate the cell's routine protection against free radical damage that has stood the test of time. This does not involve going off and eating some poor plant to steal its antioxidants.
Catalase, superoxide dismutase and glutathione peroxidase will do for a start. These are local antioxidant enzymes produced where they are needed, when they are needed by a cell which needs them to run its power plants safely. The fact that they seem to have overall benefits, apart from the smooth running of the mitochondria, is a useful spin off. And they don't involve eating anything green.
There are a few summary points to the study:
Glucose restriction by any technique extends lifespan in worms.
Glucose supplementation produces a dose related shortening of life span in worms.
Glucose supplemented worms store FAT!
N-acetylcysteine, ascorbate or a vitamin E derivative (Trolox) each eliminates the life extension provided by glucose restriction in worms.
Here's the consolation for people knocking back the antioxidants: They probably do no harm directly, just eliminates any benefit from glucose restriction. If you live on glucose, well shrug...
This is how this research group view the impact of their work on diabetes management:
"In light of our findings, the current body of evidence tentatively calls into question the efficacy of increasing cellular glucose uptake in diabetics and suggests that other methods of lowering blood glucose (Isaji, 2007; Wright et al., 2007) may be preferable to achieve normal life expectancy in human type 2 diabetes patients."
The two refs cited refer to techniques for extracting glucose through the kidneys or possibly reducing its uptake through the gut. No consideration seems to be given to not actually putting quite so much glucose in to the system in the first place!
If anyone finds this remotely interesting, while not feeling particularly worm-like, you can go and look at the evidence in Jenny Ruhl's post on antioxidants in humans.
I'd just like to point you towards this particular one. I was surprised that as little as 1000mg of ascorbate per day with 400iu of vitamin E had a measurable effect. But, if the study is replicable, it might well fit in with the observational evidence.
Really must give up the chocolate (only kidding, my liver will save me!).
Peter
Monday, October 26, 2009
Renal stones and the OD
There have been comments from two people on the blog recently who have developed symptomatic kidney stones. Very symptomatic in one case.
I did a quick Google for kidneys stones and found that they can occur in up to 10% of the population, peak incidence between 30 and 50 years of age. A "significant" portion are asymptomatic.
So why should two people on a high fat, lowish protein and low carbohydrate diet develop symptomatic kidney stones?
That depends on what you think is happening and what actually causes kidney stones. There is quite a lot of information on PubMed about the physiology involved. One of the core findings is that magnesium is lost in to the urine under conditions of hyper insulinaemia and/or hyperglycaemia, most especially under hyperglycaemia.
Some of the core observations were made by Djurhuus, predominantly looking at type one diabetics. While he accepts that elevated insulin causes Mg loss in the urine, hyperglycaemia appears to be the main drive. This gets to the point where you can correlate magnesium deficiency with HbA1c in type one diabetics. As an elevated HbA1c suggest relative insulin deficiency in this group, then hyperglycaemia appears to be the problem.
It's open to speculation whether Mg deficiency is a specific cause of metabolic syndrome or a result of the hyperglycaemia associated with it, but there is undoubtedly a clear association between the two.
Once you have mangled your magnesium status you appear to be wide open to calcium based stones.
In fact metabolic syndrome might be enough to trigger calcium stone formation on its own, especially if you are not thinking about magnesium status...
But the message I get is that Mg, Ca and PO4 are lost through the kidneys under glucose/insulin dysregulation. These strike me as the reason for the massive requirement of both calcium and magnesium in diets which promote hyperglycaemia. Calcium and magnesium are elements. You don't "break them down", they're there to stay unless you put them down the loo. If they are so essential (which they are) I doubt your body would do this if it was working correctly.
So we have hyperglycaemia and/or hyperinsulinaemia as the most likely cause of urinary calcium, magnesium and phosphate loss.
Once these ions are in to the urine subsequent stone formation depends on urine concentration and pH. In alkaline urine you get magnesium based struvite, in acid urine you get assorted calcium derived stones.
Ultimately urinary stones appear to be a common feature of metabolic syndrome. They may well be present in much more than 10% of this population. What happens when you have metabolic syndrome and suddenly start living within the carbohydrate limits imposed on you by that syndrome? When you suddenly become normoglycaemic and norm-insulinaemic?
I doubt any of us starting out on low carbohydrate diets gets an MRI done to check if we have renal stones before we begin, just on the off chance. A sizeable number of the population drawn to low carbohydrate eating might well carry asymptomatic renal stones. The stones then begin to dissolve once people stop peeing their bones down the loo. How many will convert a large asymptomatic renal pelvic stone to a smaller stone which can enter the ureter to begin its agonising journey to the bladder?
Some, it seems!
I have vague memories of Kwasniewski and Lutz both warning about this feature of stone dissolution, and a similar scenario with gall stones dissolving and entering the bile duct too.
Of course all of this may be total BS and the case might be that saturated fat causes renal stones. You could always just ask any cardiologist.
The flip side to all of this is that the management for osteoporosis might just be normoglycaemia...
Peter
BTW Djurhuus did an intervention study supplementing Mg in type 1 diabeteics. It REDUCES insulin stimulated glucose uptake! It's hard to see what is happening here. Usually type 1 diabetics are exquisitely insulin sensitive until some joker pumps then full of insulin then says "there's the bread, eat it to stay alive". Then it's not so clear what might happen to insulin sensitivity in the medium to long term. Anyway, Djurhuus didn't seem to find Mg to be a panacea of any sort. Dropped the LDL particle count thought FWIW!
I did a quick Google for kidneys stones and found that they can occur in up to 10% of the population, peak incidence between 30 and 50 years of age. A "significant" portion are asymptomatic.
So why should two people on a high fat, lowish protein and low carbohydrate diet develop symptomatic kidney stones?
That depends on what you think is happening and what actually causes kidney stones. There is quite a lot of information on PubMed about the physiology involved. One of the core findings is that magnesium is lost in to the urine under conditions of hyper insulinaemia and/or hyperglycaemia, most especially under hyperglycaemia.
Some of the core observations were made by Djurhuus, predominantly looking at type one diabetics. While he accepts that elevated insulin causes Mg loss in the urine, hyperglycaemia appears to be the main drive. This gets to the point where you can correlate magnesium deficiency with HbA1c in type one diabetics. As an elevated HbA1c suggest relative insulin deficiency in this group, then hyperglycaemia appears to be the problem.
It's open to speculation whether Mg deficiency is a specific cause of metabolic syndrome or a result of the hyperglycaemia associated with it, but there is undoubtedly a clear association between the two.
Once you have mangled your magnesium status you appear to be wide open to calcium based stones.
In fact metabolic syndrome might be enough to trigger calcium stone formation on its own, especially if you are not thinking about magnesium status...
But the message I get is that Mg, Ca and PO4 are lost through the kidneys under glucose/insulin dysregulation. These strike me as the reason for the massive requirement of both calcium and magnesium in diets which promote hyperglycaemia. Calcium and magnesium are elements. You don't "break them down", they're there to stay unless you put them down the loo. If they are so essential (which they are) I doubt your body would do this if it was working correctly.
So we have hyperglycaemia and/or hyperinsulinaemia as the most likely cause of urinary calcium, magnesium and phosphate loss.
Once these ions are in to the urine subsequent stone formation depends on urine concentration and pH. In alkaline urine you get magnesium based struvite, in acid urine you get assorted calcium derived stones.
Ultimately urinary stones appear to be a common feature of metabolic syndrome. They may well be present in much more than 10% of this population. What happens when you have metabolic syndrome and suddenly start living within the carbohydrate limits imposed on you by that syndrome? When you suddenly become normoglycaemic and norm-insulinaemic?
I doubt any of us starting out on low carbohydrate diets gets an MRI done to check if we have renal stones before we begin, just on the off chance. A sizeable number of the population drawn to low carbohydrate eating might well carry asymptomatic renal stones. The stones then begin to dissolve once people stop peeing their bones down the loo. How many will convert a large asymptomatic renal pelvic stone to a smaller stone which can enter the ureter to begin its agonising journey to the bladder?
Some, it seems!
I have vague memories of Kwasniewski and Lutz both warning about this feature of stone dissolution, and a similar scenario with gall stones dissolving and entering the bile duct too.
Of course all of this may be total BS and the case might be that saturated fat causes renal stones. You could always just ask any cardiologist.
The flip side to all of this is that the management for osteoporosis might just be normoglycaemia...
Peter
BTW Djurhuus did an intervention study supplementing Mg in type 1 diabeteics. It REDUCES insulin stimulated glucose uptake! It's hard to see what is happening here. Usually type 1 diabetics are exquisitely insulin sensitive until some joker pumps then full of insulin then says "there's the bread, eat it to stay alive". Then it's not so clear what might happen to insulin sensitivity in the medium to long term. Anyway, Djurhuus didn't seem to find Mg to be a panacea of any sort. Dropped the LDL particle count thought FWIW!
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