A brief discussion of ketosis

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

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

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

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

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

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

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

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

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.

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

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.

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

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!

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

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!

The thumb tack hypothesis

There are some interesting numbers in this paper from back in 2005. It's based around the well accepted fact that fat people move less than slim people. Apparently making heavy people move as much as thin people could easily result in 15kg of weight loss per year. That's pretty impressive for hiding the remote or putting drawing pins (thumbtacks?) on fat people's chairs.

The paper looked in great detail at the movement and energy expenditures of mildly obese people (BMI 33) or slim people (BMI 23). They found, as expected, that slim people move far more than fat people.

That's obvious from FIG 1. You really have to click to enlarge before it's readable:





From section A, top left chart, right hand pair of columns, you can see that thin people spent about 510 minutes up and walking.

Fat people were only up and moving for 370 minutes a day.

But now look at chart C, energy expended by activity, left hand pair of columns. The big red blocks on the tops of the columns are energy expended by being up and walking. Ignore the white extension, that's just the projection of what should (but won't) happen under the thumb tack hypothesis.


Thin people spent 800kcal per day on walking.



Fat people spent, guess what: 800kcal per day on walking.


Now, is that neat or is that neat? The lazy fatties were expending EXACTLY as many calories on being up and mobile as the slim people. This point seems to have escaped the authors' attention. Is this anti fat bias? Which group is laziest? Count those calories!

In fact, the only real difference between the groups is that obese people spent MORE calories overall per day and the excess is spent on basal metabolic rate. You cannot argue with a big body. It needs fuel. BMR is life. Obviously they have to eat more to do this.

The projection for 15 kg weight loss per year is based on making fat people mobile for as many minutes per day as thin people. But why should they do this? They are already spending as much energy as the thin person on spontaneous movement. They are spending MORE per day on BMR and an equal amount on odds and sods like the thermic effect of food. They eat more to make up for BMR and because their blood insulin levels steal a little food to store as fat.

Making them move more would simply need more calories. They would be hungrier.

The second phase of the experiment should have tested whether putting drawing pins on the chairs of fatties made them thin. The USA government is, after all, suggesting dance classes to replace TV viewing as the national pastime for its citizens. But I guess they really do know when they are on to a loser and decided not to test this.

Instead they looked at what happens when you make a fatty thin. Drop their weight down to BMI of 31 and look what happens. Well, nothing. A drop of 8kg from BMI 33 gets you down to BMI of 31, not 23. So we are not looking for a conversion from fat to thin, just a small increment, hopefully enough to show the trend. Here's FIG 2:





Weight loss means caloric deficit. BMR requires calories to sustain life so cannot be dropped much. The thermic effect of food etc expenditure makes little difference. If there are less calories spare during weight loss, what has to happen to movement? Look at chart A, right hand pair of columns. It drops from 390 minutes per day to 360 minutes per day, a drop of just under 10% in terms of time expended moving. Not statistically significant, but the trend is that weight loss by caloric restriction DECREASES spontaneous movement. This also was not noted by the authors, but would certainly have been predicted by Gary Taubes.

Get them down to BMI 23 and they would probably stay as still as practical for as long as practical. Then move to steal some food.


Over feeding makes you fat. It does it by increasing insulin levels. Do you then increase your spontaneous movement? The average extra free energy available during an increase of 4kg weight gain is small if insulin is packing most of those calories in to adipocytes, unless you are the outlier who upped their movement time by an hour a day (possibly the most insulin sensitive in the group?). The trend in spontaneous movement doesn't really show, but what hint there is is upward.

As Michael Eades has pointed out, he does see obese people who appear to be insulin sensitive, but they are uncommon. For most obese people the need is to lower insulin levels, then they won't need the thumb tacks on their chairs to either lose weight or become more mobile.

But thumb tacks on chairs is official policy. Without doing the trial.

Oh, I feel another paradox coming on!

Peter

Sucrose in pregnancy

While we're talking about suspected maternal/offspring sucrose based diets:

There are suggestions it is the same for humans. Just substitute "fatty liver" for the catalogue of abnormalities in the abstract (dysregulated glucose, insulin, leptin, the usual suspects) and you have the "high fat" (plus sucrose) fed rats in human incarnation from the last post. I don't suppose their offspring will have perfect liver function if weaned at day 1 on to a sucrose based formula.

"Importantly, serum leptin concentration was affected by dietary sucrose intake both as quantitatively (r = 0.424, P = 0.009) and relative to energy intake (r = 0.408, P = 0.012) in overweight but not in normal-weight pregnant women."

"The novel finding that dietary sucrose intake is related to serum leptin concentration is in line with the current dietary recommendations to overweight pregnant women with impaired glucose metabolism advising the lower intake of sucrose during pregnancy."

What about the rest of the population?

Anyway, just observational, but the rats are an intervention study...

Peter

Once upon a time life was so simple. You just went to the AHA for diet advice, did the opposite and you were pretty well sure to do well. But now they're talking about sucrose limitation. For the health of the USA this is excellent. But it makes life so complicated! How could the AHA get anything right? Must be an accident!

More of the usual stuff

Brief discussion from off blog about this study:

Hi Jeniffer,

Finally got to download supplementary data, table 1. Unfortunately the authors lied about this giving the diet composition! While giving a detailed breakdown of the evil fat, no suggestion was made as to the composition of the carbohydrate. "Lab chow" (is almost always starch) is being compared to a "high fat" diet of unspecified carbohydrate composition which produces fatty liver. It probably tastes sweet too.

There was a time when this sort of research was published only in hard copy, which was useful as an emergency source of loo roll. Now it's all electronic and even the supplementary data are useless for that delicate purpose...

However, the supplementary data do tell us that the high fat mice were obese, hyperglycaemic and hyperinsulinaemic. So I guess they were eating their fat in the form of concentrated Fanta...

But no one is saying in the methods or supplementary data. This is not science!

Peter

Cancer and ketones

Just a brief post:

Dr Fine is looking at metabolic management of cancers. Cancers express uncoupling protein 2 (UCP2). UCP2 plugs in to the mitochondrial inner membrane, allows protons through, lowers the voltage across the membrane and so reduces both ATP and free radical production by the mitochondria. It might not be as physiological as UCP3, more of a survival tactic in hyper energetic states. UCP2 is not commonly present in normal tissues.

Lack of respiration drives the use of glucose-lactate fermentation, adapted to the the hypoxic environment which is a common location of cancer cells.

Ketone bodies are very special as regards mitochondria. I'll post on this eventually. But they switch on respiration (mitochondrial O2 based ATP production) and switch off glycolysis, ie they cause insulin resistance, but not at the GLUT4 level (post here). Dr Fine points out that cancer cells tend to use GLUT1, not GLUT4, so a non GLUT4 method of glucose deprivation might be a good idea. If a cancer cell's mitochondrial inner membranes are punched full of holes (UCP2s) then ketones cannot generate mitochondrial ATP effectively, but can still inhibit glycolysis. Result: decreased ATP and decreased cell growth. This is an aggressive cancer on a ketogenic diet.

There is no suggestion of apoptosis of the cancer cells, this requires increased free radical production. But slowed cell growth is a better option than runaway growth if you want your immune system to stand a chance of saving your life....

Dr Fine discusses the "model" like nature of his model, and it's flaws, nicely. Just tissue culture at the moment, but the project is aiming to go clinical at some stage soon.

OK, time for a nap before a night shift.

Peter

More from Japan

I was googling for an idea of what the current value is for LDL in the general population of the USA at the moment, when I accidentally hit on this paper. It's from the Japan cohort of the infamous Seven Countries Study, focusing on the farming town of Tanushimaru. Apart from the data presented, which are fascinating, there are the data not presented, which say a great deal more. What is also fascinating is the fossilised mindset of the investigators, inheriting from Ancel Keys the ability to look at, and in this case publish, data which destroy the lipid hypothesis as proposed by Keys so many years ago, but ignore what they have found. Lets look at some results tables.

The pdf is copy protected so if you would like the actual data just download the pdf and have a look-see.

I'll start with line one of Table 1, energy intake. This has fallen significantly between 1958 and 1999. Over that period BMI has risen from (Table 3) 21.7 to 23.7. The paper talks about less manual labour etc, suggesting BMI is some simplistic marker of calories in vs calories out. Duh. OK, people on the 1999 diet are storing more energy than they can access, compared to the massive caloric intake in 1958, which was being accessed at a rate which maintained a lower BMI. This to me suggests that the population in 1999 has a higher average insulin level despite lower carbohydrate intake. Think metabolic syndrome, not calories in vs calories out.

You would expect people with lower carbohydrate intake to have lower insulin levels, but anyone who follows Stephan's blog or any of the Kitava posts here will realise that very high carbohydrate diets per se are not the problem. The problem is failure to maintain efficient glucose usage at physiological concentrations of insulin. Something happened between 1959 and 1999 to increase insulin levels despite lowered carbohydrate intake. This means insulin resistance.

So the next thought is; what question do the investigators not ask, or at least not tell us so, if they did?

Table 1 tells us that in 1958 the farmers were eating 2837kcal/d, 84% of which was carbohydrate, ie 2383kcal of carbs. Flicking to table 2 we can see they were eating 593g/d of rice, ie 2668kcal of rice!!!!!!!!!!!!!!!! OK, they were eating more rice calories than carbohydrate calories! The numbers don't quite balance but this is not banking (jk) we're talking here. Assessing dietary intakes and the associated calories is not hard science and these researchers are not exactly famous for precision. Essentially all of this caloric intake was starch. I don't see a lot of scope for fructose intake when you are eating more rice calories than carbohydrate calories!

The same numbers in 1999 were 1365kcal as carbs and only 1062kcal of rice. There is now a deficit of 300kcal of carbs, ie people are now eating non-rice carbohydrate. The authors didn't comment on this. I don't suppose anyone who considers saturated fat to be the reason for elevated cholesterol would consider fructose, probably via sucrose, to have any relevance to cholesterol levels.

My guess is that 8 teaspoons a day of sugar is enough to both do some glycation of LDL and to put enough fat in to the liver to raise hepatic insulin resistance. Probably not enough to increase heart attack risk, just enough to raise LDL cholesterol. Not enough to cause hyperglycaemia. Just looking at the numbers needing hypertension meds (see below) I would expect HbA1c to have begun to rise after 1982. Of course sons of Keys would never think to look at HbA1c evels. Too suggestive of Prof Yudkin's ideas!

Is there any other support for the idea of progressively increasing insulin resistance? Back in table 3 we can see that BP is remarkably stable but there is a sudden increase in the percentage of the population needing hypertension medication to achieve this, from 7% in 1989 to 20% in 1999. The roll of elevated insulin in hypertension is not particularly contentious. If you had to say anything about overall health this line tells me that some sort of threshold was crossed in the 1990s. So where are the heart attacks?

Smoking started to fall around 1980, from around 70% of adults (Kitavan levels!) to 45% in 1999. There was zero drop in heart attack rate with this fall. Why not? Perhaps replacing nicotine with fructose is a balanced trade off!

Now, just to finish, TC levels skyrocketed from 152mg/dl in 1958 to 194mg/dl in 1999 and there was no effect on the incidence of coronary heart disease.

How do the jokers running this cohort view their data, which destroy the hypothesis on which their jobs depend?

"In conclusion, large changes in dietary patterns and remarkable changes in serum cholesterol levels among men aged 40-64 years in a Japanese farming area were demonstrated. Fortunately, incidence of coronary heart disease has not increased in our cohort for a couple of decades. The varied composition of the Japanese diet has probably prevented coronary heart disease. However, careful surveillance is needed in the future because of the increasing intake of fat, especially saturated fatty acids, with the potential of a modern epidemic of coronary heart disease in Japan."

The end.

Cholesterol skyrockets, CHD doesn't. A paradox. Unless Keys was wrong and his "offspring" are still wrong.

Oh, or the "varied composition" of the Japanese diet, of which 1000kcal/d is white rice, saves them (giggle, hysterical) from CHD!

Peter

SAD vs Traditional Japanese diet (2)

OK, many thanks to Lynne who managed to get the pdf. Extra Brownie Points for guessing that this was the paper I wanted, despite to my copy paste accident on the link!

It's talking about Japanese-Americans. You have to bear in mind that the information is limited by dietary preference questionnaires and the vagarities of deciding if someone has really had a heart attack. The group over 55 years is not shown as nothing much seems to make any difference in this group. Marmot discusses all of this in his paper. This is the relevant graph.



Now, you have to read this carefully. The pattern is the same, so I'll go through the top graph only. Looking at the left hand pair of vertical bars, the white one is the people who had a traditional Japanese up bringing and had a traditional Japanese diet preference. They had 2.5 heart attacks per hundred people.

Move over to the right hand side of the chart. Again the white bar is those people with a traditional Japanese up bringing but these are the ones who are now eating to what was the SAD back in the 1950s and 1960s. They had 0.4 heart attacks per 100 people. That is a relative risk of about 0.20, ie an American diet preference, compared to a traditional diet preference, appears to be HUGELY protective against CHD. Both of these groups are of a traditional Japanese style up bringing.

An American up bringing essentially doubles your risk of CHD, irrespective of whether you have a traditional Japanese dietary preference or an American dietary preference. It's worth noting that the combination of an American diet preference with an American upbringing is pretty well indistinguishable (3.0 heart attacks per hundred) from a traditional Japanese diet with traditional Japanese upbringing (2.5 heart attacks per hundred).

The protective effect of a traditional Japanese upbringing allows you to question any "dietary" intervention if it also adds in stress management, relaxation and exercise while asking you to shovel 1500kcal of rice a day down your throat!


Here's what Marmot, who had the misfortune to base his PhD on these data, had to say:



As the shot messenger I'd like to limp away now.

Peter

SAD vs Traditional Japanese diet

Anyone reading DrBG will by now be aware that Loren Cordain might well be coming in from the cold on the saturated fat front, as a middle author of this nice perspective paper which I've yet to slog through in its entirety. This can only be good.

As always, occasional papers bring to mind studies that need discussing. The introduction to the above paper cites Marmot in this paper and this paper. I've been interested in these two papers ever since I read Dr Ravnskov's "The Cholesterol Myths" back when I found I had a TC of about 7.2mmol/l (gasp) in 2003. It's interesting for the aspects which don't get a mention, in particular the superior health benefits of the SAD compared to the traditional Japanese diet. That's right, the SAD wins.

So here's a paper request. Anyone have the two Marmot papers as pdfs?

The main conclusions are purported to be that Japanese in Japan have low levels of coronary disease. On emigration to Hawaii the incidence increases and in California it is higher still, especially in those who adopted an American lifestyle and values. However, in this later group, there is a subdivision who adopted everything American EXCEPT the diet.

On the traditional Japanese diet, with an American lifestyle, you are twice as likely to suffer heart disease than if you live the American way AND you eat at Burger King (OK, on the SAD of the 1970s).

Needless to say, I'd love to check this out, with the greatest of respect to Dr Ravnskov. Stuff this amusing just has to be seen in the bare pdf form. Copies of the two Marmot papers would be very much appreciated...

Peter

Dead people DO bleed...

This one cracked me up. Okay, so I have a warped sense of humour.

The crooked origin of the lipid hypothesis generates an almost infinite number of paradoxes, here's a nice abstract about (yet) another paradox, this time in survival after ACS.

"The association of hypercholesterolemia with better outcomes highlights a major challenge in observational analyses"

Which prompted this anecdote from an eminent THINCS member:

A schizophrenic patient believes he is dead.  The patient's psychiatrist, trying to cure the him of his delusion says, "Do dead people bleed?"  The patient says, "No, they don't bleed."  The Psychiatrist pricks the patient's finger and blood flows out.  The patient says, "Well, this shows that dead people DO bleed".

Peter

Excession

Iain Banks has written a mixed bag of science fiction but, in general, Excession is one that I like. Excession carries this paragraph (actually, it's all one sentence except that it has a ... stuck in the middle. I think it's intended to be a continuous stream of visual ideas, but maybe not). Anyway, this was one of the bits I liked from the novel. The "Outside Context Problem" is what the novel is all about. The paragraph explains:

"The usual example given to illustrate an Outside Context Problem was imagining you were a tribe on a largish, fertile island; you'd tamed the land, invented the wheel or writing or whatever, the neighbours were cooperative or enslaved but at any rate peaceful and you were busy raising temples to yourself with all the excess productive capacity you had, you were in a position of near-absolute power and control which your hallowed ancestors could hardly have dreamed of and the whole situation was just running along nicely like a canoe on wet grass... when suddenly this bristling lump of iron appears sailless and trailing steam in the bay and these guys carrying long funny-looking sticks come ashore and announce you've just been discovered, you're all subjects of the Emperor now, he's keen on presents called tax and these bright-eyed holy men would like a word with your priests."

There do seem to be some inconsistencies there, but you get the idea.

This abstract appears to describe an OCP from the 18th century in what was destined to become southeastern USA. It certainly brought Banks' novel to my mind. The final line caught my eye, as it was supposed to.

"A reduced dietary breadth during the mission period may have contributed to the extinction of these populations in the eighteenth century"

Particularly the word extinction. So like excession.


John Hawkes has a post about the genetic changes in Europe between the origin of agriculture about 11,000 years ago in the Fertile Cresent and its arrival at the Western seaboard of Europe about 7,500 years ago.

In his classic essay "The Oil We Eat" Richard Manning cites archaeologists describing this rate of cultural spread as "blitzkrieg", specifically the leap across Western Europe in just 300 years.

This is the paper cited by Hawkes. The overwhelming impression I get is that mankind, the sort of mankind which had maintained a stable global population of around 10,000,000 for millenia, did NOT adopt agriculture. Agriculture was adopted by a subgroup of these humans. Agriculturalist genes then replaced those of hunter gatherers across Europe. I doubt the change was welcomed by the hunter gatherers.

Excession. Blitzkieg.

Oh, and if Manning is correct, famine. Gift of agriculture.

Peter

Chewing the FAT

CD36 is another of those cell surface proteins with an interesting use. It actually does quite a few things, but the one I'm thinking about is its role as Fatty Acid Translocase, hence its other name, FAT. The late 1990s seems to have been a fashionable time for CD36 research and this era has provided a number of interesting papers.

CD36 takes a molecule of free fatty acid, frequently palmitic acid, and transports it through the cell membrane to the cytoplasm, en route for beta oxidation to provide a bucket load of ATP. Of course, the palmitic acid will also signal the induction of insulin resistance. No point burning glucose if you have palmitic acid. Nowadays any competent lab can knock out a specific gene from a mouse and see if the gene loss does anything much. So in a CD36 knockout mouse we have the ability to make the cell membrane largely opaque to palmitic acid. What does this lack of intracellular fatty acids do to insulin sensitivity?

CD36 knockout mice have lower blood glucose than wild type mice.



Now this may be hunky dory for a mouse with ad lib access to mouse chow. You can have a nice low blood glucose and probably a nice low insulin level. But what if you were to glycogen deplete the mouse and then make it run to escape from a cat? Its glucose is already low. It can mobilise fatty acids perfectly well, but they can't enter the cells. So no insulin resistance forms and the mouse muscles continue to run on a progressively falling glucose concentration, in a sea of unusable fatty acids, until its brain stops working and the cat gets a mouse sized meal. This hypothesis is untested so far!

These mice also have lower blood insulin too (can't check this fully as it's a Nature pay-per-peep publication and insulin is not important enough to make it in to the abstract, so I'm taking Hajri's word on this). All of this is pretty much as you would expect. These mice are born and bred on glucose and virtually never use any palmitic acid unless they make it de-novo, intracellularly, from glucose. They are probably exquisitely insulin sensitive, for what good that might do them in the wild.




Over expressing CD36 gives the facility to get lots of fatty acids in to cells and this increases both blood glucose and blood insulin due to insulin resistance.


Again, a simple balance, put lots of fatty acids (probably as acyl-CoAs) in the cytoplasm and cells say no to glucose. Hence you need increased levels of insulin to keep blood glucose normal. So is there pathological insulin resistance here?



Apparently not.

It's worth noting that response to an IV glucose load was NOT damaged in these mice, though there is a "trend towards" higher glucose levels from 30-120 minutes after the bolus in mice over expressing CD36 (open circles).

I think it is a reasonable assumption in these CD36 over expressing mice that the insulin surge following the glucose bolus from the IVGTT can still reduce FFAs, and so increase insulin sensitivity, in exactly the way it should to normalise glucose.

It seems quite likely that the blood insulin will peak at a higher level in the CD36 over-expressing mice. In general, over secreting insulin is probably a Bad Thing. So should a low carbohydrate, high fat eating person be afraid of eating a portion of chips with their roast bellypork? Will it spike glucose and/or insulin to unreasonable levels?

Certainly not. You may have a slightly higher insulin level than a carb eater for an hour or two after 30 grams of potato derived glucose, of course. But a carb eater will not eat a small potato, they will eat ten times that weight of carbohydrate in 24 hours. At least. So a low carbohydrate eater's 24 hour exposure to insulin will be vanishingly small compared to someone nurturing chronic illness using the USA Food Pyramid and eating 300 grams of carbohydrate a day.

So OK, is it acceptable to have a portion of chips with your roast (after being marinaded in lemon juice and then rubbed with a Mexican spice mix) belly pork ? Well, that's a personal decision. Me, I'm fine with it.

Actually, last night the pork was chip-less but followed by two gluten free muffins for dessert (mostly almonds and millet flour, living dangerously with the millet perhaps).

Peter

Overfeeding humans: Jebb

"Obesity implies a failure of autoregulatory homeostatic responses to caloric excess"

The quote comes from this paper first authored by Mario Siervo but with Susan Jebb as the group leader. I'll discuss the paper in a moment.

Who is Susan Jebb?

From the Medical Research Council website:

Cross-government 2007- Chair, Expert Advisory Group on Obesity - Susan Jebb

Department of Health 2006 - Chair, Expert Group developing the Healthy Living Social Marketing Programme - Susan Jebb

Department of Health/Food Standards Agency 2004-2005 Expert Working Group on Nutrient Profiling - Susan Jebb

Government Office for Science 2006-2007 Science Advisor, Foresight Project 'Tackling Obesities: Future Choices' - Susan Jebb

You get the idea. An obesity politico. This sort of politico. Also check the date on that link. 2003. I was just starting on low carbohydrate eating at the time. Jebb was all over the papers. One very obvious thing, to someone who had just read Atkins' "New Diet Revolution" from cover to cover, was that none of the experts being quoted had read the book!

So that puts Jebb in context. Here's the interesting study on overfeeding humans rather than dogs. This is the feeding protocol:

3 weeks run in feeding
3 weeks 20% extra calories
1 week rest, eat as much of a Jebb diet as you feel like
3 weeks 40% extra calories
1 week rest
3 weeks 60% extra calories
3 weeks rest

This is the table detailing exactly what was eaten.

These are the weight changes, also subdivided in to tissue composition.


This is the executive summary: People got fat on the excess calories and couldn't loose the weight within 3 weeks. Some people couldn't loose any of the weight at all.

Jebb's conclusion. People pig out at Christmas and fail in their New Year diets. Greed and sloth, greed and sloth. Once you've pigged out, if you're greedy, you'll keep troughing.


Now, let's ignore Jebb and look what happened.

Protein was increased from 85g/d through 101g/d, 112g/d to 126g/d from baseline through over feeding protocol. Some increase, but not unreasonable.

Fat was used to increase the "energy density" of the diet and so was increased from 120g/d through 158g/d, 196g/d to 231g/d. The later being Kwasniewski levels for optimal health (but without the carbs!).

Carbs started at 322g/d and ramped up through 375g/d, 409g/d to 446g/d. Okayyyyy. Interestingly, just reducing these carbs to a tenth of this overfeeding level would have given quite easy weight loss for most people, with the fat left alone!

There were snacks too but they don't affect the basic argument.

Jebb is a calories in calories out sort of a person, so fructose is the same as glucose to her. We'll never know how much fructose was fed.

Now let's look at substrate oxidation. With all that increased fat intake what happened to fat oxidation? (All of the values are approx and from the figure)


With a fat intake of 4.5MJ/d fat oxidation was 4.5MJ/d. Neat that!

On 20% overfeeding fat intake went up to 6MJ/d and fat oxidation DROPPED to 3.8MJ/d.

On 40% overfeeding fat intake increased to about 7.7MJ/d and oxidation DROPPED FURTHER to 3.5MJ/d.

On 60% overfeeding fat intake was 8.5MJ/d and fat oxidation seems to have bottomed out at 3.5MJ/d, no further drop.

Three points,

Carbohydrate oxidation went up as carbohydrate intake increased. This cannot happen without insulin. Increased carbohydrate oxidation means increased insulin, certainly at this level of increase of glucose oxidation. Jebb either doesn't know this, and is an idiot, or does know this and didn't measure insulin for a personal agenda. I favour the idiot theory with Jebb. I guess you could argue insulin sensitivity increased but this is a study of gross overfeeding, so that's unlikely.

Fat oxidation decreased with increased calories. What controls lipolysis? Insulin. More insulin, less lipolysis. Less lipolysis means less fat oxidation. Fat is stored more effectively and is locked in to storage. You can't oxidise stored fat.

Body water went up. Water retention means sodium retention (water retention without sodium retention = hyponatraemia = death). Sodium retention is a hallmark of elevated insulin acting on the kidneys.

In a short communication the same group measured leptin and ghrelin levels, which indictaed everything should be hunky dory for return to normal body weight, but clearly things weren't. That's assuming leptin satiates and ghrelin makes you hungry. In a simple balance of energy in vs energy out, weight is controlled by appetite. This being a Jebbish paper, they didn't measure insulin. They didn't measure the primary fat storage hormone. Oh, Susan, how could you not do this?

So what really happened in this study?

Weight gain, to anyone with half a brain, is a phenomenon of the diversion of ingested calories to storage as adipose tissue. Metabolic fuel requirement must be met at the cellular level, above that calories can go to storage as fat. Weight loss means the body gaining access to stored fat calories. Hunger controls eating behaviour when there is no artificial requirement to over eat by 60%. Hunger will adjust food intake until there is an adequate supply of metabolic fuel for the whole body.

If a large chunk of those calories consumed go in to storage, even without overeating, you will maintain hunger until you achieve enough AVAILABLE calories which are needed to run your metabolism. Whether these come from food or bodyfat depend on blood insulin level. High insulin levels lock energy in to fat, so you must eat more food to obtain metabolic fuel. Hence you don't lose weight because energy locked in to bodyfat isn't being used.

You don't need to measure insulin to know it goes through the roof when you eat nearly half a kilo of carbohydrate in a day. You don't need to measure insulin to know it is elevated when you see fatty acid oxidation plummet. You don't need to measure insulin to know it is elevated when you see glucose oxidation rise.

You MUST measure insulin if you want the readers of your scientific publications to think you remotely know anything about weight control and are in a position to advise the nation.

Ultimately, the verdict on Susan A Jebb will be that she she did not measure insulin.

Peter

Oh, and weight loss was impossible for some people, they were the ones who got most fatty liver infiltration per unit fructose ingestion. As a guess.

Thanks to Robert for the link to the papers in this post.

Physiological insulin restisance: Guess what?

There are a series if papers from back in the 1950s by Drury and Wick plus occasional others. I had the misfortune to read the methods of a couple in some detail and, unless you have a strong stomach or are intrinsically sadistic, I suggest you don't. Physiologists in the 1950s had a different view of animal welfare to that now prevalent. The studies would not be allowed in any civilised country today or published in any reputable journal if carried out. I'm not going to link to them.

The main finding is that the oxidation of glucose can blocked, even in the presence of large amounts of injected insulin, by a modest quantity of a particular small molecule. This form of insulin resistance, if you want to call it that, does not seem to occur at the cell surface, so it's probably not mediated through the failure of insulin to mobilise GLUT4s. And, as glucose seems to enter the cells and disappear, the presumption has to be that it is "non oxidatively disposed" as the modern parlance has it. Probably to glycogen, there's not really anywhere else for it to go.

So what is this evil chemical which blocks glucose oxidation even in the face of hyperinsulinaemia?

Beta hydroxy butyrate. That's it. Ketone bodies (acetoacetate seems to work as well) are triggers for insulin resistance. Hence the appalling problems of type two diabetics on the Atkins induction diet. What problems? Oh, normoglycaemia and weight loss! Well, maybe there are problems long term or or or...

Again ketone bodies, one of the hall marks of carbohydrate or total calorie restriction, channel glucose away from muscles, toward brain and add a modest supplementary energy supply to brain tissue too.

It's exactly what you expect on an adaptive basis, exactly the same function as palmitic acid performs and clearly the two metabolic pathways are closely linked, though ketones seem to work downstream of the action of palmitic acid.

The fact that ketones do still allow insulin to move plasma glucose in to cells, and probably store it as glycogen, might be of interest to those who's blood glucose seems to do strange things after they eat medium chain triglycerides. MCTs (in rats anyway) undoubtedly spike both insulin and ketones, but usually result in normoglycaemia (insulin resistance?). But this is in a carbohydrate fed, glycogen replete rat. If you are initially glycogen depleted the shift to replete glycogen under ketones from MCTs might just leave you hypoing. No one has looked at this as far as I'm aware but ItsTheWoos' experience is interesting on this front...



Actually, looking carefully at the graph from Yeh and Zee, glucose does dip through an amount which might be clinically noticeable...

Anyway, there you have it. Metabolic poison number three, beta hydroxy butyrate. Evolution sure made a lot of b@lls-ups on the way to where we are today. I'm doomed, as always.

Peter

Mortality and cholesterol

People might enjoy O Primitivo's latest excel plot here. I did. I also suspect the effort involved in this is stupendous. Thanks!

Peter

Physiological insulin resistance and palmitic acid again

I like palmitic acid. It causes insulin resistance. Thank goodness.

Ted sent me this link. It's depressing.


I'm going to discuss a thought drug. I'm going to call it Palmitofake, and it can be developed by Pfizer, no, Fort Dodge. I particularly dislike FD for anaesthesia related reasons.

So what does Palmitofake do? BTW, if you didn't need any other hint you can tell this drug is going to bomb as there is neither an x, y or z in its name. Trust FD to screw up (in my mind).

Palmitofake is a fluoride substituted analogue of palmitic acid which irreversibly binds to the acyl-CoA interaction site of JNK1 and so inhibits the pathway by which palmitic acid keeps GLUT4 transporters off of the cell surface membrane, whole body-wide.

The logic to this is that the lipotoxin, palmitic acid (nature's second biggest mistake, the biggest was obviously cholesterol) can no longer keep glucose out of cells and metabolism can run, unimpaired by fat, for ever on glucose. Woo hoo bring on the glucose.

This concept is so obviously safe and utterly in keeping with modern thoughts on type 2 diabetes that no safety testing is deemed necessary and it can be sold direct to the public via placement in the drinking water. OK, maybe as an over the counter pill. Let's look at a case study:

Jim has just done a heavy workout at the gym. Like really heavy and, catastrophe of all time, he forgot his Sportzaide. Sportzaide is a glucose drink used to maintain blood glucose levels during workouts, it promotes sufficient insulin secretion that no fat is ever burned and no glycogen ever depleted. We wouldn't want him to lose weight from exercise would we?

So Jim is modestly glycogen depleted for the first time in his life. It's an odd situation but, in the last few million years, it has been known to happen occasionally to the hominids who eventually became us. It's called not having anything to eat for a week before having to chase your diner.

If Jim is in government you might argue that brain function is unimportant, but you would be wrong. Jim needs a functional brain, just to stay alive. Whatever else happens, he needs some glucose for his brain. There is no active transport of glucose, it runs down a concentration gradient in to brain cells using GLUT1 and GLUT3. However many transporters are present, if blood glucose drops below 2.0mmol/l Jim is going to be unwell and if it goes below 1.0mmol/l he's going to be very dead.

Jim's blood glucose drops. His liver would happily pump out lots more, but it's got none left. His pancreas has stopped producing insulin above basal rates some time ago and is now powerless to mobilise glucose in any way that doesn't need protein catabolism, and this is not exactly a supply on demand source.

In the natural order of things Jim will, by now, be mobilising enormous amounts of free fatty acids from his 40kg of beer gut. These free fatty acids rush to his muscles and provide an almost inexhaustible supply of energy. They don't rush to his brain. His brain wants glucose. His brain needs glucose. His brain will have a temper tantrum for glucose. Ultimately it will kill Jim if it doesn't get it.

Jim's body, metabolically, is in starvation mode. It needs to stop wasting glucose on his biceps and give it to his brain. The biceps do fine on free fatty acids, the brain dies in a sea of energy without glucose. The trick to staying alive when glycogen depleted is to keep glucose out of any tissue that can cope without it and save almost all of it for brain use.

So the rule is, when the body is flooded with free fatty acids, all fat using tissues should stop using glucose. They should see those free fatty acids and internalise their GLUT4 transporters so they don't waste brain glucose on dumb muscle.

The message to put this change in place is palmitic acid.

Jim has a very specific and very serious problem. He just started on Palmitofake yesterday as part of the initial clinical trials. As soon as he floods his muscles with palmitic acid he should have internalised his GLUT4 glucose transporters. Palmitofake stops this. He got in to the lift as an irritable exec with a blood glucose of 2.0mmol/l, got out of the lift on a stretcher with a blood glucose of 1.0mmol/l and died before the paramedics could get a glucose infusion up on him, with a blood glucose of 0.1mmol/l

PALMITIC ACID CAUSES INSULIN RESISTANCE. YOU WOULD BE DEAD WITHOUT IT. IT'S ADAPTIVE.

We should be looking at what gets broken in metabolic syndrome at the cellular energy processing level, not shooting the messenger. And we all know that low fat diets reduce mitochondrial number and high fat diets, especially if ketogenic, increase mitochondrial numbers. I really must get back to those high fat fed mice from 10 posts ago!

It's Saturday night. I need a glass of wine and bed!

Peter