This is an opinion post about ketosis. Is it good, bad or necessary?
Let's get the religion out of the way first. I follow an eating pattern loosely based around Dr Jan Kwasniewski's Optimal Diet. I vary from the OD in that I tend to vary my protein sources somewhat more than specified, I think a little omega 3 supplementation is worthwhile, that having a "normal" vitamin D level is probably worth while (though this is an interesting subject) and in that I specifically avoid gluten and most other grains. So I do my own thing somewhat, while still keeping a heavy emphasis on animal fat, egg yolks and trying to keep to real food as far as I practically can. When I say I avoid ketosis because Kwasniewski says avoid ketosis, that's religion.
My follow on problem from this that, when you can get hold of the data, Kwasniewski is usually correct. My even bigger problem is that, when you get beyond simple diet information, some of JKs ideas are very far off the wall. And some of the off the wall ones also seem to be correct to me, which is a little uncomfortable! So religion is a real non starter.
The first paper which had me thinking was this one:
"Both the pre-and post-exercise levels of adrenaline, noradrenaline, and cortisol were enhanced"
This is the sort of thing I file as interesting. That is, until the anecdotes trickle in about people who have gone to extreme ketogenic diets and have developed abnormal cardiac rhythms. You know the thought train that grabs you when you discover LC eating, that moment of realisation: Carbs are bad. Followed by: All carbs are bad. Most people can do zero carb with absolutely no problem. With reasonable protein intakes it is really very easy and doing a "Stefansson", using an all meat diet, is not difficult. But a few people will get in to problems. If you are wired for a heart problem along the lines of Wolff Parkinson White Syndrome, cranking up your adrenaline and noradrenaline levels might not be a good idea. If you have atrial fibrillation, ditto.
This is the effect of a water fast on sympathetic nervous tone:
"After 17 days of TF [total fasting] norepinephrine (NE) and epinephrine (EPI) urinary levels showed a two-fold and nine-fold increase respectively, but they became undetectable at the end of TF"
So increased sympathetic tone seems to be a feature of both fasting as well as ketogenic eating. It does look as if the effect is transient during fasting, so this may also be the case in ketogenic eating, but I have no data on that. The fact it may well be transient is no consolation if you have been admitted to a cardiology ward via A&E due to severe palpitations!
An aside: Hyperglycaemia is also a potent elevator of serum catecholamines and seems to be the routine trigger for atrial fibrillation.
The next issue has to be renal stones. Anyone who has looked at the RECHARGE trial enrollment criteria will immediately have noticed that kidney stones are an exclusion criterion. Now kidney stones are a complex issue. Anyone who has treated a cat or dog for struvite urinary stones will be well aware that they are exquisitely diet responsive. Shrinking a 1.5 cm asymptomatic renal stone to a 0.5cm stone which then wedges in your ureter will again have you in the A&E department pleading for morphine. But you don't want to live with the stone for ever and it might well dissolve in situ anyway, but maybe not! But the bottom line is that you might easily develop a symptomatic stone from an asymptomatic one.
This having been said there is undoubtedly a high incidence of very symptomatic renal stones using the Ketogenic Diet for epilepsy management, there are loads of papers covering this. It is difficult to say whether these are directly ketosis related, are due to some of the bizarre lipid choices made by cholesterophobe dietitians for the diet or are to do with the chronic dehydration which was part of the original Ketogenic Diet. There are a few other possible explanations, but I feel there is a source for concern here.
While we are talking about the epilepsy Ketogenic Diet, let's also cover pancreatitis. I've got the Freedman's third edition of their classic "The Ketogenic Diet". The index does not include pancreatitis and the recipes tend to use real foods. There have been a number of deaths from pancreatitis on the Ketogenic Diet. None of the case reports are available to me in full text, so I cannot see what sort of fats were given to these children. Certainly Vanitallie's pilot study of using the KD for Parkinsons management suggested using unsaturated fats as the lipid source (to lower cholesterol, dontchano). Do this and you deserve whatever is coming your way.
OK, fasting hyperglycaemia. I have this mildly on a low carbohydrate, high saturated fat diet. My FBG is about 5.5mmol/l, ie 100mg/dl. I've discussed it here.
But I do know at least one person who can achieve a FBG of 8.0mmol/l on a deeply ketogenic diet. This is 144mg/dl and not a number that I would personally wish to sustain for any period of time. This is not a standard response to marked ketosis, but unless you are checking you blood sugar levels, how would you know that it wasn't your response? A few carbs should reverse this.
Muscle cramps. Anyone who went from a normal carbohydrate based diet to Atkins induction knows all about these. You faff around with magnesium or potassium supplements and they seem to help a bit, sometimes, maybe. But upping your carbs works beautifully. You would almost certainly adapt out of this with time, but short term it can be a problem.
Finally, auto immunity. Hyperglycaemia is probably the immunosuppressive aspect of diabetes. There can be costs to pay when improving immune function if the trigger for an autoimmune problem is still present. This is close to religion as it is purely based around non scrutineered anecdote from Lutz' Life Without Bread. He is particularly talking about multiple sclerosis. His clinical experience (not always the best guide, but better safe than sorry) suggests a sudden drop to 72g/d is too fast and can promote a flare. Kwasniewski has nothing to say about this but always seems to use the OD as a sudden onset protocol. Lutz suggests staged drops of carbs over several weeks. He certainly would appear to caution against going ketogenic. I guess this would eventually be a non problem and ketosis is probably neuroprotective in its own right. In the short term, take care.
Of course the flip side is the use of water fasting in rheumatoid disease.... YMMV!
So...
I have to say that I am not anti ketosis. I drift in and out of ketosis as I'm quite active in a non-gym kind of a way. I suspect that by now I am VERY adapted to this. I'm a bit loathe to increase my carbs much above where they are now because I, in common with many other people, have better gut and joint function when I restrict starches. Adding a little glucose in the form of a chocolate truffle or two after my main meal is a pleasant way of augmenting the vegetables that were in the main meal but it's getting away from real food...
So I have some respect for the potential complications of ketosis, especially sudden onset. There are undoubtedly many plus sides, but nothing is ever completely problem free.
Peter
Friday, November 27, 2009
Sunday, November 22, 2009
Glucose, lactate and cancer
Here's an interesting paper, discussed in this editorial. Many cancer cells use glucose as their primary fuel. Under the hypoxic conditions, in the centre of a tumour mass, there is often a region where glycolysis is the only source of ATP with lactic acid as the main end product. This is quite old news, going back to Warburg and the concept of using low blood glucose to suppress tumour growth.
However, lactate is not a waste product. Lactate is an energy rich molecule which can be converted to pyruvate and so enter the mitochondria to generate a bucket load of ATP, given some oxygen. In fact there is a school of thought which suggests that brain neurons do not use glucose at all, glucose is converted to lactate by the astrocytes and it is lactate which feeds directly in to the neuronal mitochondria via pyruvate. It's controversial.
So lactate with oxygen is a potent combination for ATP generation. Oxygenated cancer cells burn lactate. They appear to love it. So the central anaerobic core generates lactate from glucose and the rest of the tumour feeds on lactate, so long as oxygen is present.
Lactate is taken up in to cells via the MCT1 transporter (mono carboxylate 1, it's a transporter for very small fatty acids, lactate being one of several). Inhibiting this transporter is bad news for lactate burning cancer cells and there are a number of drugs being developed along these lines.
What seems to happen when you block MCT1 is that the aerobic external layers of the tumour are suddenly deprived of lactate. They then turn to glucose for fermentation and in doing so deprive the anaerobic core of that particular source of usable energy. The cells in the anaerobic core die.
In the aerobic bulk of the tumour glucose can be burned via pyruvate in the mitochondria and there is no need for lactate production.
However lowering plasma glucose level when there is no longer any lactate available might provide a tool to use against this area of the tumour.
There is a very strong suggestion, certainly in rat brains, that ketone bodies inhibit the use of lactate. That's a physiological MCT1 inhibitor. Ketosis is usually (but not quite always) associated with low blood glucose levels. It is also associated with increased methylglyoxal production, an inhibitor of glycolysis.
So ketosis appears to provide the triple tools of MCT1 inhibition, glucose deprivation and glycolysis inhibition.
If it doesn't work against cancer, it should!
I hope Dr Fine has some success in his RECHARGE trial.
Peter
However, lactate is not a waste product. Lactate is an energy rich molecule which can be converted to pyruvate and so enter the mitochondria to generate a bucket load of ATP, given some oxygen. In fact there is a school of thought which suggests that brain neurons do not use glucose at all, glucose is converted to lactate by the astrocytes and it is lactate which feeds directly in to the neuronal mitochondria via pyruvate. It's controversial.
So lactate with oxygen is a potent combination for ATP generation. Oxygenated cancer cells burn lactate. They appear to love it. So the central anaerobic core generates lactate from glucose and the rest of the tumour feeds on lactate, so long as oxygen is present.
Lactate is taken up in to cells via the MCT1 transporter (mono carboxylate 1, it's a transporter for very small fatty acids, lactate being one of several). Inhibiting this transporter is bad news for lactate burning cancer cells and there are a number of drugs being developed along these lines.
What seems to happen when you block MCT1 is that the aerobic external layers of the tumour are suddenly deprived of lactate. They then turn to glucose for fermentation and in doing so deprive the anaerobic core of that particular source of usable energy. The cells in the anaerobic core die.
In the aerobic bulk of the tumour glucose can be burned via pyruvate in the mitochondria and there is no need for lactate production.
However lowering plasma glucose level when there is no longer any lactate available might provide a tool to use against this area of the tumour.
There is a very strong suggestion, certainly in rat brains, that ketone bodies inhibit the use of lactate. That's a physiological MCT1 inhibitor. Ketosis is usually (but not quite always) associated with low blood glucose levels. It is also associated with increased methylglyoxal production, an inhibitor of glycolysis.
So ketosis appears to provide the triple tools of MCT1 inhibition, glucose deprivation and glycolysis inhibition.
If it doesn't work against cancer, it should!
I hope Dr Fine has some success in his RECHARGE trial.
Peter
Monday, November 16, 2009
Glycaemic load and breast cancer
This struck me as fascinating when Dr Briffa posted it some time ago. I had this feeling that being skinny while eating as many sweets as you like might just be possible because you were running your metabolism in overdrive on glucose. That might just run the metabolism of a cancer cell in overdrive on glucose too. Being young and skinny does not appear to protect against breast cancer if you are sufficiently unlucky. No warnings necessarily given in terms of external markers of glucose dysregulation...
Of course the writing has been observable on this same epidemiological wall for some time.
Peter
Of course the writing has been observable on this same epidemiological wall for some time.
Peter
Fruit and vegetables (10) WHI and cancer
From Gary, just in case WHEL wasn't enough for you, a fruit and vegetables vs cancer study that I missed at the time. Moral: Don't bet your life on the gifts from plants. Look at the last line of the abstract for a some light entertainment:
"However, the nonsignificant trends observed suggesting reduced risk associated with a low-fat dietary pattern indicate that longer, planned, nonintervention follow-up may yield a more definitive comparison"
Invasive breast cancer at 0.42% in the eight years of fruit-n-veg vs 0.45% on the SAD. That's not much of a trend after you've employed 40 plus people for over eight years. As I see it all you can say, as per WHEL and PPT, is that they probably didn't kill anyone.
Peter
"However, the nonsignificant trends observed suggesting reduced risk associated with a low-fat dietary pattern indicate that longer, planned, nonintervention follow-up may yield a more definitive comparison"
Invasive breast cancer at 0.42% in the eight years of fruit-n-veg vs 0.45% on the SAD. That's not much of a trend after you've employed 40 plus people for over eight years. As I see it all you can say, as per WHEL and PPT, is that they probably didn't kill anyone.
Peter
Thursday, November 12, 2009
Liver and insulin (not a cooking recipe...)
I'm umm-ing and ah-ing about posting this at all. In the end I'm going to hit post. It's up for shredding! Peter
The function of insulin is the inhibition of lipolysis. I cannot argue with this.
There is a widely held belief that insulin is also necessary for the cellular uptake of glucose. This is incorrect.
I hit on this paper as an accidental result of the Atkins and methylglyoxal searching. It grabbed my attention because it reminded me of a paper I had read many years ago (on vacation, I used to take British Journal of Anaesthesia on vacation!) which was probably this one. And this is the one where they got type one diabetics to skip their insulin and be studied in the hyperglycaemic an-insulinaemic state (see below).
This is my summary of some of the main concepts carried in the papers.
I started off with simple analogies to baths, bathwater, flows etc. Unless you have a very, very strange plumbing system, this doesn't work. Back to metabolism.
Life is simpler if you are fasting.
If you have 5mmol/l of glucose in your blood, you cannot get more than 5mmol/l inside your cells. There are no pumps for glucose, it follows a concentration gradient. If your cells are using large amounts of glucose there will be a bigger concentration gradient and so more glucose will flow through the GLUTs, but perhaps not enough. You might need more "holes" to let glucose through. Enter insulin, more GLUT4s, more flow, sustained metabolism. Still no pumping and still blood glucose is 5mmol/l because whatever the cells take is being replaced. From the liver (we're fasting). Nowhere else for it to come from.
Let us say there is no insulin. There will be a basal number of GLUT4s and a few other GLUTs, which will allow glucose to flow. How much? Not enough. Not enough if the blood glucose is 5mmol/l. But what about with a blood glucose of 30mmol/l?
Would a blood glucose of 30mmol/l force enough blood glucose through the few GLUTs that are present without the help of insulin and its extra GLUT4s?
Well, apparently that's a pretty easy question to answer using tritiated glucose and the answer is yes. With a blood glucose high enough you do not need insulin to allow as much glucose to be used as would be used when blood glucose is 5mmol/l in the presence of insulin. This is fact.
You can read the paper about the type 1 diabetics who volunteered to withdraw their insulin and were studied in the hyperglycaemic an-insulinaemic state. They burn glucose.
So, if insulin is not essential for glucose based metabolism, what is its primary function?
Insulin allows the pancreas to talk to the liver. The liver controls, under the influence of insulin, how much glucose it adds to that teaspoonful of glucose which is normally present in the total blood volume.
This is core. As core as insulin's inhibition of lipolysis.
In a normal person 85% of the glucose from a carbohydrate meal never makes it past the liver. Under conditions where a bulk supply of rapid uptake glucose is unavailable, I doubt that any glucose gets past the liver. The pancreas knows about dietary glucose, the liver knows. It's their secret from the rest of the body. The liver rations out the glucose.
Diabetics, type 1 or 2, are not hyperglycaemic because they cannot use glucose. They are hyperglycaemic because their liver can no longer hang on to its glucose hoard. The liver's inability to be influenced by insulin is central to diabetes.
So the aim, in diabetes management, should be the control of leakage of glucose out of the liver. You can actually force a fructose damaged, insulin resistant liver to listen to insulin in exactly the same way as you can replace pancreatic insulin in type 1 diabetes. Use exogenous insulin. But it's hard.
Your liver does not listen to your subcutis, which is where injected insulin comes from. It listens to your pancreas. The pancreas secretes insulin in to the portal vein which has a blood flow of about a 1000ml a minute. A minute's worth of secreted insulin will be carried in 1000ml of blood. From the liver that minute's worth of insulin enters the systemic circulation and mixes with the cardiac output, which at rest is about 5000ml/min, so is clearly diluted. Peripherally measured insulin is always less than what the liver "hears" when it listens to the pancreas. What was in 1000ml/min of blood is now in 5000ml/min of blood. Of course insulin recirculates so systemic concentration won't be as low as one fifth of portal concentration.
So the normal liver should be seeing more insulin than is detected in peripheral blood. Adipocytes and muscle cells only see peripheral blood. When you inject insulin under your skin it is carried by the full cardiac output and will be delivered in dilute form to the liver compared to what should have happened if the same amount had come from the pancreas. Muscles will get the full hit.
A high carbohydrate diet, coupled with industrial doses of peripheral insulin, is doomed to fail. You cannot effectively inhibit glucose release from the liver without hitting the peripheral tissues with a relative overdose of insulin. This opens the GLUT4 floodgates in to the peripheral cells in the process of trying to stop glucose release from the liver. This sort of balancing act, high insulin, high glucose throughput, has to rely on hyperglycaemia to keep you safe from hypoglycaemia. Hello ADA.
EDIT: The papers discuss ketones as producing blockade of peripheral glucose metabolism, as we know they do. Palmitic acid is my idea.
The only sensible solution is to make the peripheral tissues as resistant to insulin as possible (so minimal extra GLUT4s pop up as a result of exogenous insulin) and then supply enough exogenous insulin to inhibit hepatic glucose release, delivering it through the hepatic artery as well as the portal vein. Two things allow this to work. Palmitic acid and ketones. Palmitic acid can be delivered through chylomicrons or VLDLs, it causes insulin resistance, thank goodness, so makes exogenous insulin less effective on muscles (where most of the GLUT4s are). It's worth noting that MCTs (I would guess through ketones) raise peripheral insulin resistance but still dip blood glucose (ie they allow the liver to listen to insulin). Ketones are made by the liver. I can't see ketones making the liver insulin resistant. They will inhibit peripheral glycolysis independent of glucose uptake. They effectively replace the insulin/glucose combination in metabolism. Insulin can then be given to the liver to inhibit glucose release without turning the muscles in to a glucose sump. Most tissues outside of the brain and a few other places can run perfectly well on the palmitic acid.
Low carbing is the solution, aiming for mild ketosis, intense physiological insulin resistance and minimal insulin doses (aimed at the liver). Bernstein is the guru, Kwasniewski has a slightly more relaxed approach. Both seem correct to me. Neither shuns saturated fat. But it doesn't seem as simple as balancing insulin against carb intake (though this is an excellent, and probably the only practical, rule of thumb). I would expect it to work better on a palmitic acid based diet than one using any unsaturated fatty acid for bulk calories. Using PUFA and oleic acid (to keep LDL down, dontcha-no) won't hack it in providing the physiological insulin resistance that should be helpful for tight glucose control.
As an afterthought; it is under low insulin levels that the liver ships out VLDLs too. More palmitic acid to the periphery.
We're back very close to low carbohydrate eating mimicking starvation, without the weight loss.
Peter
The function of insulin is the inhibition of lipolysis. I cannot argue with this.
There is a widely held belief that insulin is also necessary for the cellular uptake of glucose. This is incorrect.
I hit on this paper as an accidental result of the Atkins and methylglyoxal searching. It grabbed my attention because it reminded me of a paper I had read many years ago (on vacation, I used to take British Journal of Anaesthesia on vacation!) which was probably this one. And this is the one where they got type one diabetics to skip their insulin and be studied in the hyperglycaemic an-insulinaemic state (see below).
This is my summary of some of the main concepts carried in the papers.
I started off with simple analogies to baths, bathwater, flows etc. Unless you have a very, very strange plumbing system, this doesn't work. Back to metabolism.
Life is simpler if you are fasting.
If you have 5mmol/l of glucose in your blood, you cannot get more than 5mmol/l inside your cells. There are no pumps for glucose, it follows a concentration gradient. If your cells are using large amounts of glucose there will be a bigger concentration gradient and so more glucose will flow through the GLUTs, but perhaps not enough. You might need more "holes" to let glucose through. Enter insulin, more GLUT4s, more flow, sustained metabolism. Still no pumping and still blood glucose is 5mmol/l because whatever the cells take is being replaced. From the liver (we're fasting). Nowhere else for it to come from.
Let us say there is no insulin. There will be a basal number of GLUT4s and a few other GLUTs, which will allow glucose to flow. How much? Not enough. Not enough if the blood glucose is 5mmol/l. But what about with a blood glucose of 30mmol/l?
Would a blood glucose of 30mmol/l force enough blood glucose through the few GLUTs that are present without the help of insulin and its extra GLUT4s?
Well, apparently that's a pretty easy question to answer using tritiated glucose and the answer is yes. With a blood glucose high enough you do not need insulin to allow as much glucose to be used as would be used when blood glucose is 5mmol/l in the presence of insulin. This is fact.
You can read the paper about the type 1 diabetics who volunteered to withdraw their insulin and were studied in the hyperglycaemic an-insulinaemic state. They burn glucose.
So, if insulin is not essential for glucose based metabolism, what is its primary function?
Insulin allows the pancreas to talk to the liver. The liver controls, under the influence of insulin, how much glucose it adds to that teaspoonful of glucose which is normally present in the total blood volume.
This is core. As core as insulin's inhibition of lipolysis.
In a normal person 85% of the glucose from a carbohydrate meal never makes it past the liver. Under conditions where a bulk supply of rapid uptake glucose is unavailable, I doubt that any glucose gets past the liver. The pancreas knows about dietary glucose, the liver knows. It's their secret from the rest of the body. The liver rations out the glucose.
Diabetics, type 1 or 2, are not hyperglycaemic because they cannot use glucose. They are hyperglycaemic because their liver can no longer hang on to its glucose hoard. The liver's inability to be influenced by insulin is central to diabetes.
So the aim, in diabetes management, should be the control of leakage of glucose out of the liver. You can actually force a fructose damaged, insulin resistant liver to listen to insulin in exactly the same way as you can replace pancreatic insulin in type 1 diabetes. Use exogenous insulin. But it's hard.
Your liver does not listen to your subcutis, which is where injected insulin comes from. It listens to your pancreas. The pancreas secretes insulin in to the portal vein which has a blood flow of about a 1000ml a minute. A minute's worth of secreted insulin will be carried in 1000ml of blood. From the liver that minute's worth of insulin enters the systemic circulation and mixes with the cardiac output, which at rest is about 5000ml/min, so is clearly diluted. Peripherally measured insulin is always less than what the liver "hears" when it listens to the pancreas. What was in 1000ml/min of blood is now in 5000ml/min of blood. Of course insulin recirculates so systemic concentration won't be as low as one fifth of portal concentration.
So the normal liver should be seeing more insulin than is detected in peripheral blood. Adipocytes and muscle cells only see peripheral blood. When you inject insulin under your skin it is carried by the full cardiac output and will be delivered in dilute form to the liver compared to what should have happened if the same amount had come from the pancreas. Muscles will get the full hit.
A high carbohydrate diet, coupled with industrial doses of peripheral insulin, is doomed to fail. You cannot effectively inhibit glucose release from the liver without hitting the peripheral tissues with a relative overdose of insulin. This opens the GLUT4 floodgates in to the peripheral cells in the process of trying to stop glucose release from the liver. This sort of balancing act, high insulin, high glucose throughput, has to rely on hyperglycaemia to keep you safe from hypoglycaemia. Hello ADA.
EDIT: The papers discuss ketones as producing blockade of peripheral glucose metabolism, as we know they do. Palmitic acid is my idea.
The only sensible solution is to make the peripheral tissues as resistant to insulin as possible (so minimal extra GLUT4s pop up as a result of exogenous insulin) and then supply enough exogenous insulin to inhibit hepatic glucose release, delivering it through the hepatic artery as well as the portal vein. Two things allow this to work. Palmitic acid and ketones. Palmitic acid can be delivered through chylomicrons or VLDLs, it causes insulin resistance, thank goodness, so makes exogenous insulin less effective on muscles (where most of the GLUT4s are). It's worth noting that MCTs (I would guess through ketones) raise peripheral insulin resistance but still dip blood glucose (ie they allow the liver to listen to insulin). Ketones are made by the liver. I can't see ketones making the liver insulin resistant. They will inhibit peripheral glycolysis independent of glucose uptake. They effectively replace the insulin/glucose combination in metabolism. Insulin can then be given to the liver to inhibit glucose release without turning the muscles in to a glucose sump. Most tissues outside of the brain and a few other places can run perfectly well on the palmitic acid.
Low carbing is the solution, aiming for mild ketosis, intense physiological insulin resistance and minimal insulin doses (aimed at the liver). Bernstein is the guru, Kwasniewski has a slightly more relaxed approach. Both seem correct to me. Neither shuns saturated fat. But it doesn't seem as simple as balancing insulin against carb intake (though this is an excellent, and probably the only practical, rule of thumb). I would expect it to work better on a palmitic acid based diet than one using any unsaturated fatty acid for bulk calories. Using PUFA and oleic acid (to keep LDL down, dontcha-no) won't hack it in providing the physiological insulin resistance that should be helpful for tight glucose control.
As an afterthought; it is under low insulin levels that the liver ships out VLDLs too. More palmitic acid to the periphery.
We're back very close to low carbohydrate eating mimicking starvation, without the weight loss.
Peter
Methylglyoxal on Atkins... Uh oh!
OK, time for a post. Shawn forwarded this this report which is interesting on several fronts.
It includes a specific named weight loss diet in the title of the paper. They omitted the "TM" after "Atkins" but I'm sure that won't offend anyone too much. This is science after all. This is not about ketogenic diets in general, it's got a commercial title. Smells bad to me.
What did they find? Well, ketosis produces ketones and these include acetol and acetone. Acetol is a scary chemical that I know nothing about, except I probably make a bit more now than I did 10 years ago.
Acetone is just acetone and, as these clowns undoubtedly know, acetone is a prime suspect as the candidate molecule which deprives intractable epileptics of their refractory seizures. Obviously something to avoid at all costs. Buy the phenobarbitone instead, even if it doesn't work for you.
But methylglyoxal, now there's a scary chemical. Apparently:
"...beta-hydroxybutyrate, acetoacetate and its by-products acetone and acetol... are potential precursors of the glycotoxin methylglyoxal."
A glycotoxin (gasp) from ketones (extra gasp)! Skip your pasta and you will die, from a glycotoxin. Hmmmmm.
No one (with a few exceptions) doubts that methylglyoxal is Bad Stuff. It does make me wonder why our poor body manufactures it in the first place. Blood concentration certainly increases in pathological ketoacidosis, so it may not have come as a complete surprise to these seekers-after-truth that methylglyoxal is also modestly elevated in benign ketosis.
Methylglyoxal is elevated in ketosis, but the bulk is produced by glycolysis. Why should this be so?
I would just like to speculate that it might actually be related to glycerol metabolism. The glycerol produced by the breakdown of triglycerides in adipocytes is exported to be used for gluconeogenesis or burned for energy production. Glycerol is phosphorylated then dehydrogenated to give DHAP. DHAP can break down spontaneously to give methylglyoxal but, when this method of production is inadequate, metabolism simply uses the enzyme methylglyoxal synthetase to do a better job.
Apart form diet assisted suicide and any career ehancing denigration of the Atkins TM diet, is there any use for methylglyoxal in the body? Methylglyoxal is an inhibitor of glycolysis. Well, it might just be useful to inhibit glycolysis under conditions when glycerol is more freely available than usual. As in lipolysis. It looks very neat to me that a product of lipid breakdown should inhibit the process of glycolysis. I'll bet that the gene for methylglyoxal synthetase is not expressed in neurons, certainly not during ketosis.
An aside. Let's just imagine this group had found that glucose restriction in C elegans worms produced a marked increase in respiration due to the use of fat and a significant increase in the production of free radicals as a result of this. As it does. I can just see the headline:
"Increased fat metabolism might generate excess free radicals. The increase in free radicals implies that potential tissue and vascular damage can occur on the Atkins diet and should be considered when choosing a weight-loss program"
I guess they either would forget to mention the increased longevity in their worms or have been damned sure to have thrown out their worm colonies at two weeks of age!
Another aside. How toxic is methylglyoxal? Compared to what? How about carbon monoxide, nitric oxide or hydrogen sulphide, all essential mammalian signaling molecules that you don't want to inhale in bulk. Well you can drink methylglyoxal. What happens?
It looks like you don't die immediately. Lots of your cancer cells, many of which are glycolysis dependent, might not fare quite so well under inhibited glycolysis.
So I would concur with Beisswenger et al in their Atkins bashing paper. Choose your diet for weight loss with care. Great care.
Peter
It includes a specific named weight loss diet in the title of the paper. They omitted the "TM" after "Atkins" but I'm sure that won't offend anyone too much. This is science after all. This is not about ketogenic diets in general, it's got a commercial title. Smells bad to me.
What did they find? Well, ketosis produces ketones and these include acetol and acetone. Acetol is a scary chemical that I know nothing about, except I probably make a bit more now than I did 10 years ago.
Acetone is just acetone and, as these clowns undoubtedly know, acetone is a prime suspect as the candidate molecule which deprives intractable epileptics of their refractory seizures. Obviously something to avoid at all costs. Buy the phenobarbitone instead, even if it doesn't work for you.
But methylglyoxal, now there's a scary chemical. Apparently:
"...beta-hydroxybutyrate, acetoacetate and its by-products acetone and acetol... are potential precursors of the glycotoxin methylglyoxal."
A glycotoxin (gasp) from ketones (extra gasp)! Skip your pasta and you will die, from a glycotoxin. Hmmmmm.
No one (with a few exceptions) doubts that methylglyoxal is Bad Stuff. It does make me wonder why our poor body manufactures it in the first place. Blood concentration certainly increases in pathological ketoacidosis, so it may not have come as a complete surprise to these seekers-after-truth that methylglyoxal is also modestly elevated in benign ketosis.
Methylglyoxal is elevated in ketosis, but the bulk is produced by glycolysis. Why should this be so?
I would just like to speculate that it might actually be related to glycerol metabolism. The glycerol produced by the breakdown of triglycerides in adipocytes is exported to be used for gluconeogenesis or burned for energy production. Glycerol is phosphorylated then dehydrogenated to give DHAP. DHAP can break down spontaneously to give methylglyoxal but, when this method of production is inadequate, metabolism simply uses the enzyme methylglyoxal synthetase to do a better job.
Apart form diet assisted suicide and any career ehancing denigration of the Atkins TM diet, is there any use for methylglyoxal in the body? Methylglyoxal is an inhibitor of glycolysis. Well, it might just be useful to inhibit glycolysis under conditions when glycerol is more freely available than usual. As in lipolysis. It looks very neat to me that a product of lipid breakdown should inhibit the process of glycolysis. I'll bet that the gene for methylglyoxal synthetase is not expressed in neurons, certainly not during ketosis.
An aside. Let's just imagine this group had found that glucose restriction in C elegans worms produced a marked increase in respiration due to the use of fat and a significant increase in the production of free radicals as a result of this. As it does. I can just see the headline:
"Increased fat metabolism might generate excess free radicals. The increase in free radicals implies that potential tissue and vascular damage can occur on the Atkins diet and should be considered when choosing a weight-loss program"
I guess they either would forget to mention the increased longevity in their worms or have been damned sure to have thrown out their worm colonies at two weeks of age!
Another aside. How toxic is methylglyoxal? Compared to what? How about carbon monoxide, nitric oxide or hydrogen sulphide, all essential mammalian signaling molecules that you don't want to inhale in bulk. Well you can drink methylglyoxal. What happens?
It looks like you don't die immediately. Lots of your cancer cells, many of which are glycolysis dependent, might not fare quite so well under inhibited glycolysis.
So I would concur with Beisswenger et al in their Atkins bashing paper. Choose your diet for weight loss with care. Great care.
Peter
Sunday, November 08, 2009
Rosuvastatin and insulin sensitivity
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
"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
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 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.
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.
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
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