Statin stupidity again

Read and cry.

Cure for C sections!

Perhaps a little less sugar might be a better approach!

I found this while searching for a snippet from Radio 4's Today Program announcing the recommendation from field leaders in the USA that children should start taking stains at 8 years of age, on the off chance it might eliminate all illness for ever. Happy happy happy I don't think. Couldn't find it on R4, but it'll surface soon in other places I guess.

Sigh.

Peter

Edit: You've all read Chris's post here? Never mind which end of life, you have a statin deficiency.

AGE, RAGE and ALE: The AGE of LDL

A glucose molecule can assume various shapes. If presented as a linear rather than a ring structure, one of the two end carbons will contain an aldehyde grouping. The C=O structure of the aldehyde can react chemically with an amino group on another organic molecule to give a Schiff base. This is a horribly complex structure where the carbon of the sugar is double bonded to the nitrogen of the amino group, which stays attached by its third bond to whatever structure it's part of. Classically this is a "free" amino group of lysine or arginine. Needless to say this structure is unstable and falls apart in various ways. The sugar can remain attached or break off taking the amino group with it. Either way there is damage to the protein and the potential for cross linkages to form. Lysine and arginine are, as I mentioned, the most susceptible amino acids. Glucose is one of the least problematic sugars, fructose is one of the worst.

The end result of this sugar driven reaction is the generation of Advanced Glycation Endproducts (AGEs). They're probably bad.

There is a section of the apolipoprotein B100 molecule (That's that sole protein on the surface of the LDL cholesterol particle) which is very prone to AGE formation. These people have looked at the process in detail. They have located, within the apoB100 protein, a distinct continuous sequence of 67 amino acids which are exquisitely prone to AGE formation. This section of apoB100 is probably not part of the binding domain for the LDL receptor, but formation of AGEs here does strongly influence the binding domain and effectively stops it working. So AGE formation in this area inhibits LDL particle attachment to its receptor, so reduces clearance from the plasma.

This is highly reminiscent of the situation in familial hypercholesterolaemia.

Why is apoB100 designed this way? Stuff doesn't just happen "accidentally" like this. Evolution has selected the sequence of apoB100 protein to provide a 67 animo acid section in which AGE formation inhibits uptake of the LDL particle in to cells which might want it.

Let's look at the logic.

During glycation conditions the LDL cholesterol particle stops sticking to its normal receptor. Why? My answer is that under these conditions it is more advantageous for the body to have the LDL cholesterol particle in the blood stream than it is to have it endocytosed by an endothelial cell.

Glycation is related to sugar concentration. Glucose is the sugar least prone to glycate anything to an AGE. Couple that with the tendency for humans, over an evolutionary time scale, to eat diets that rarely budge the blood glucose outside of a relatively narrow range, and I'm not sure hyperglycaemia is what the "switch" on LDL is evolved to look at.

No, my guess is that fructose was the original lever to develop a glycation based switch on the apoB100 molecule. Just about the only time a human ought to get a big enough load of sugar to risk any damage to themselves is during late summer or autumn in temperate regions, the source would be fruit. Possibly large amounts during a short period. If this happens in autumn it's a good source of calories to convert to fat and not to be wasted. But fructose is ten or seventeen times as good as glucose at AGE formation, depending on which AGE you look at and which model you use.

Fructose appears to be bad news, especially if any gets in to the systemic circulation. I can see some logic in taking the LDL particle away from arterial endothelial cells, which can make their own cholesterol anyway, and having it handy in the circulation for other purposes, like patching up fructose induced damage. Bear in mind that, while fructose is only present in the systemic circulation in trace amounts (which are probably bad for you) it will be present in copious amounts in the portal vein from gut to liver after each fruit meal. Lipoproteins are present throughout the circulation. Fructose will meet LDL particles with head on impact in the portal vein. AGEs on apoB100 suggest AGEs elsewhere, which mean repair is going to be needed. The LDL particle is diverted away from the endocytosis receptor. This is probably physiological.

But raising blood glucose from below 6mmol/l to above 30mmol/l would allow glucose to become the primary glycating agent. For a diabetic on the ADA diet the glycosylation of apoB100 is probably a fact of life. This is not our normal autumn carb loading pre winter. It's more of a pathological process.

Finding high levels of LDL cholesterol is one of the more logical aspects of the hyperglycaemia of type 2 diabetes. Putting these patients on to LC diets usually drops their calculated LDL cholesterol levels along with their blood glucose levels. It probably markedly reduces AGE formation throughout their physiology. LDL can then get back to supplying normal lipid to normal cells through the LDL receptor.

Peter

Food, fremented cream and 85% chocolate

OK, another non technical post. I hit a patch of work so I'm just glad to have arrived home one day while Squiggs was still up and eating.

Voices are the neighbours... Except the lip smacking from Squiggs!




Peter

Opioid pictures

No, it's not Afghanistan, that's the A34 in the background. The NHS had (has?) a diamorphine supply problem since our foray in to the opium fields of Afghanistan. Now we're in to grow your own!




The surrounding fields are far less recreational but could be far more damaging!



No surprise people like bread, it's acting on the same receptors as the poppy juice....

Peter

Diabetes in Sweden update

Just an update from Nielson and Joensson, original comment here. Happened on it while chasing assorted lipoprotein numbers for another post.

HbA1c below 5% without meds is possible through diet. I wouldn't describe these people as cured, a pizza a week would have them in trouble, but with HbA1c this low I'd not be worrying about CVD too much.

"Of the total of 10 controls, who have switched diet, 2 persons after a weight reduction of 20 kg each are free of all signs of diabetes after 3 and 2 years respectively i.e. HbA1c below 5.0%, fasting blood glucose below 5.0 mmol/l and free of any blood glucose lowering medication"

Second comment is that, even with successful weight loss and diabetes imporvement, carb creep is real and hard to avoid.

"After 22 months 2 patients had resumed insulin treatment following an increase of carbohydrates."

I know that rye crisp bread was a feature of this diet. I wonder what would have happened in the complete absence of gluten? Or whether the problems of removing this potentially addictive carbohydrate source would just have sabotaged the initial compliance?

Peter

Gluten, thyroid and auto immunity

This an old press release, no longer available, sent to me by a friend from Dr Bernstein's forum. It appears to relate to this paper. Can't get the full text but the abstract and PR seems to sum up the results quite well.

There are three things of particular interest, one was the suggestion that coelaic disease patients develop other auto immune diseases. Second was that on withdrawl of gluten they not only loose both their anti endomysial antibody titers (traditional marker of coeliac disease) but they also loose their auto immune disease antibodies too. Third is that it's not overnight, 3-6 months is more like it.

From several people I get the impression that 2 weeks is often enough to see some change in an auto immune disease, a month is needed for convinving improvement and resolution needs about 6 months. There are good and bad patches in the process.

Nice to see a research group backing up the anecdote. Here's the press release:


"Dr. Tarcisio Not, of Clinica Pediatrica, I.R.C.C.S., Trieste, and colleagues, studied 172 patients with autoimmune thyroid disorders, and two control groups. The control groups comprised 498 patients with other diseases and 4,000 healthy blood donors. Screening was done with IgA-class endomysium antibody using immunofluorescence.

The findings, reported in the February issue of Digestive Diseases and Sciences, show that the prevalence of celiac disease was 3.4% in patients with autoimmune thyroiditis, and 0.6% and 0.25% among the two control groups.

Moreover, the study found an association between untreated celiac disease, gluten intake and autoimmune disorders. The researchers write, "We believe that undiagnosed celiac disease can cause other disorders by switching on some as yet unknown immunological mechanism. Untreated celiac patients produce organ-specific autoantibodies."

They add, "By following these subjects longitudinally, it has been seen that not only do the anti-gliadin antibodies and anti-endomysium antibodies disappear after 3 to 6 months of a gluten-free diet, but so do the organ-specific autoantibodies."

Given these results, Dr. Not and his team suggest that patients with autoimmune thyroiditis "may benefit from a screening for celiac disease so as to eliminate symptoms and limit the risk of developing other autoimmune disorders."

Dig Dis Sci 2000;45:403-406.(end)"


Peter

Gluten and gall bladders

Chris from Conditioning Research emailed this link to me, just before Troy asked about high fat eating after the surgical loss of your gall bladder. Many thanks Chris, immaculate timing. The main problem without a gall bladder is that there is no pulsatile release of bile acids to allow the formation of the lipid miceles needed for fat digestion and absorption. However, even without a gall bladder, there must be some on going bile secretion, even if there is no storage for a big release after a large meal. Is this enough? I commented that medium chain triglycerides might help, these are slowly absorbed without pancreatic lipase, but now I think about it, I'm not sure if this would work without bile acids to get the MCTs in to the enterocytes in the first place...

But there is a separate problem anyway. If you have coeliac disease you don't seem to produce cholecystokinin (CCK) when fat hits your small intestine. So under these circumstances, you may as well not have a gall bladder anyway!

There is obviously a trade off between the severity of the coeliac disease and the degree of cholestasis. The link above mentions active disease... I get the impression that villous atrophy is needed to get the blunted CCK response.

But then it's worth remembering that 1mg, that's one milligram, no typo, of gluten per day will sustain villous atrophy in unlucky individuals. They will be clinically and serologically normal under these conditions. I bet they don't make a lot of CCK though! Or get picked up by the average gastroenterologist.

So is subclinical coeliac disease any worse than having no gall bladder? Many many many people have sub clinical coeliac disease. Perhaps this is the wrong question. Maybe it would be better to ask whether THE reason you have had your gall bladder removed is that sub clinical coeliac disease was the underlying cause of your gall stone anyway. No CCK means no gall bladder contraction, which means no bile acid deposition, which means cholestasis, which means gall stones. Also means blunted fat absorption. Which means no CCK release... It's a chicken and egg situation.

Apart from coeliac disease and CCK, the other aspect which fascinates me is the effect of opioids on the sphincter of Oddi, at the end of the bile duct (includes the pancreatic duct in some individuals). Opioids spasm this sphincter. I know, I precipitated pancreatitis in a dog with a (big) dose of morphine once. It recovered.

So what does a continuous flow of gluten derived opioids through the gut do to the sphincter of Oddi? There's nothing I can find on pubmed directly related to this, but anyone with cholestasis problems or recurrent "idiopathic" pancreatitis wants to dump gluten big time. As if there weren't enough reasons to do this already.

So is anyone who is missing their gall bladder any worse off than someone eating to the food pyramid? Probably not. But who would want to be as dyspepsic as a food pyramid eater anyway???????? I guess the answer is dump the gluten, start with medium fat carried in real Food, dump the gluten, work up to higher fat loads, dump the gluten and try for 70% fat calories if any Olestra like effect allows, dumping the gluten. Whatever the outcome, sticking to Food and dumping gluten is the best you can do. Did I mention gluten?

Peter

PS at my time of peak gluten eating I was ultra sound scanned for gall stones. Negative, but that's just how it felt. Reading the celiac.com comments, it turns out you get that particular ache from gluten even after your gall bladder is removed! Maybe it's spasm in the sphincter of Oddi!

PPS When spell checking "Oddi" in google I found a host of support sites for people with dysfunction of this particular organ. Looks like it is coeliac disease rearing its head again.

And again, note the stupidity of ONLY biopsy sampling people who are anti endomysial antibody positive. Under diagnosis rules. As does 1mg per day of gluten induced, sero negative coeliac disease. Causing gall bladder disease. Or pancreatitis. You do not want pancreatitis. Honestly.

Breast cancer BRCA1 and metabolic syndrome

There is a breast cancer gene, the BRCA1 gene. It controls certain aspects of metabolism, it's not just some random gene=cancer mystery mechanism. It's to do with energy metabolism. Just look at what delays the onset of breast cancer in BRCA1 genetically prone women:

"Interestingly, physical exercise and lack of obesity in adolescence have been associated with significantly delayed breast cancer onset for Ashkenazi Jewish women carrying BRCA1 gene mutations"


Now look at the potential therapies being considered:

"Further clinical work may explore a chemopreventative role of "low-energy-mimickers" deactivating the ACCA-driven "lipogenic phenotype" in women with inherited mutations in BRCA1. This goal might be obtained with current therapeutic approaches useful in treating the metabolic syndrome and associated disorders in humans (e.g., type 2 diabetes and obesity), including metformin, thiazolidinediones (TZDs), calorie deprivation, and exercise"

What is the glaring omission, the raging silence????

What is most effective management of metabolic syndrome, diabetes, hypertension, central obestity, dyslipidaemia, hyperglycaemia? Just pretend breast cancer is really diabetes. Never mind metformin (good) or TZDs (bad). Do I hear carbohydrate restriction anywhere?

No I don't.

I should.

Peter (grinding teeth)

PS Never mind <10% of calories from fat and all of those fat calories to be from fish oil. What would that do for diabetes? (not a dig at you Gyan, the low fat mantra is ubiquitous and wrong).

Fruit and vegetables, WHEL study and McDougall

This was mentioned in the comments section of another thread. Needs its own post!

Because Stan (Heretic) visits some pretty weird places on the net, he led me astray to this bizarre commentary from some vegan low fat nut on the WHEL study. McDougall is a Dr no less. Here are some of the things he has to say:

"Breast cancer is a fatal disease and women will do almost anything to live. They will endure poisoning by toxic chemotherapy, burning with radiation, and mutilation from breast-amputating mastectomy; in the hopes of living a few more days. Obviously, if asked to do so, and given proper support from their doctors and dietitians, they would do something as simple, safe, costeffective, and enjoyable as eating oatmeal and bean burritos while avoiding beefsteaks and cheese omelets"

This initial quote from McDougall sums up what I imagine is the mental outlook of the WHEL study intervention group nicely. Women in the aftermath of breast cancer surgery DO want to live. As the dietary intervention tested in the WHEL study failed utterly to make an iota of difference to breast cancer recurrence, what is the explanation for its failure? This is how McDougall sees it:

"Data collected by asking the study participants about what they ate suggested they were eating more fruits and vegetables and less fat after being given instructions dictated by the study guidelines. But people don’t always tell the truth—they often want to please the investigators, so they tell them what they think they want to hear, which in this case was clearly inaccurate"

I'd summarise this as "the patients lied and the patients cheated". Now just try and reconcile statement one with statement two. Women will do anything to survive, statement one. Women will cheat and lie in a study which is trying to save their lives with vegetables, statement two. McDougall's answer as to what actually happened?

Statement one is correct, they cheated and lied. How can he tell?

Easy, next quote:

"Proof that the data collected from asking the women what they ate was inaccurate is shown in table 2. The women eating “a dietary pattern very high in vegetables, fruit, and fiber and low in fat” were reported to have decreased their daily calorie intake by an average of 181 calories (1719 initially, and 1538 six years later), yet they gained weight"

I hate to mention insulin, but ALL fruit and vegetables raise insulin levels. No one looses weight while insulin levels are high. Fruit and vegetables raise insulin. The only way that you can loose weight on a carbohydrate based diet is by caloric restriction to the extent that insulin levels fall between meals. The WHEL study was not a weight loss project, it was a "fruit and vegetables to save your life" project. Lack of weight loss can be taken as the removal of a variable extraneous to the study. It's a marked plus point about this particular study.

The increased weight in the intervention group, to my mind, is the clincher that the patients DID comply. They ate fruit and veggies, raised their insulin and kept any fat they stored post prandially.

I'd just like to point out that anyone on a vegan low fat diet who IS loosing weight is sourcing their calories from the ANIMAL fat on their own butt (this was a USA study, pardon the phraseology). Any health benefits claimed for veganism WITH weight loss has to accept this undeniable fact. Humans carry animal fat on their butt. Wasting muscles will provide animal protein.

I do have to thank Dr McDougall for one pointer.

Long term readers will know that I tend to believe people unless it's patently obvious that they're lying. The WHEL intervention group FAILED to maintain their fat intake reduction, and reported this truthfully. It was always below the non intervention group's fat intake, but it drifted up to 28.9% of 1538kcal, ie about 40g/d. The non intervention group ended up on 32.4% of 1159kcal (50g/d) of fat.

Why is this good? I was worried, at the back of my mind, that there had to be a reason why the death rate was identical in both groups. Given the background of the SAD, any increase of carbohydrate on top of the saturation levels of PUFA and sugar likely to be eaten routinely should have increased the death rate. The answer seems to be that the fat intake drop never really happened, so carbs never really increased and so luckily no one extra died in the intervention group.

This lack of compliance in dietary fat reduction occurred because the elevated insulin was locking energy in to adipose tissue and so energy had be sourced from the diet. That's called hunger. The effect on weight gain was small, in proportion to the small decrease in dietary fat.

The kindest thing I can say about McDougall is that he is a ranting extremist. He is stuck in his vegan rut and doesn't seem to understand how metabolism works.

The weird thing is that I believe he gets results! How come?

A real low fat diet will dump almost all PUFA. A real Food diet will eliminate all sugar. A hypocaloric weight reduction diet will both reduce insulin levels (a growth promoter for breast cancer) and switch metabolism to animal sourced saturated fat, the best source of calories available. Of course ketosis is out of the question, low fat veganism is a very limited approach.

Does McDougall know what he's doing, to get whatever results he does get?

No way.

Peter

Junk Food binge

My greenhouse is full of junk food, sugar ladened and delicious. Pretty hot on fructose too. These are gustatory recreation, not food. Going to live dangerously for a few weeks!





The weeds below are growing in an untended border outside my son's nursery. The unripe fruits are as big as they are going to get, though they too will go red and delicous in a week or so. They appear to be food, certainly better than starvation if hunting is bad. How long would it take to gather enough to keep yourself out of ketosis for a day?




I don't think many hunter gatherers had greenhouses or ate strawberries!

Peter

Gluten Dr Briffa link

Not sure if this sort of thing has ever happened in the UK before, perhaps the parents and child discussed by Dr Briffa live in Nottingham. The case is highly complex, but here's the summary:

Wheat=diarrhoea

No wheat=no diarrhoea

Now, to assemble this Apollo 13 rocket, first remove all contents from packaging and make sure all pieces are present, locate an appropriately sized launch pad, take the first nut and an appropriately sized spanner (not supplied)...

The question is whether the dietitian and gastroenterologist can hide behind a negative coeliac antibody test (in a wheat avoiding, currently digestively normal coeliac) to justify their execrable behaviour.

I'm not much of a clinician nowadays, I'm pretty well ruined as far as belief structure in the marvels of the latest anti inflammatory drug or chemo protocol goes, but the one thing that I do still try very hard to do is to listen to my patient's owners. In their own way, from articulate to incoherent, these people are trying to tell you what the problem is. Relying on a set of bloods (normal) and an abdominal ultrasound (inconclusive) will miss you the opportunity to sort out an awful lot of problems.

Luckily the child's problems were limited to the superficial and highly responsive problem of diarrhoea in response to gluten. What if the presenting symptom had been gluten ataxia, hypothyroidism or systemic lupus. Scary.

Anyway, skip's arrived, time to shift some rubble!

Peter

IHD and ghee

Just while ghee is in focus, there's this abstract from Jaipur. There's a typo three lines from the end where the 1 is missing from the "greater than 1 kg". I've re checked the "greater than" sign in IBIDS and it is correct, the one is still missing.

So the ghee eaters were fatter, ate more calories, more sat fat and more monounsaturated fat. Same total PUFA as the low ghee eaters. Oh, they had less coronary heart disease too. The only serious potential confounder is that the ghee eaters were younger. With multivariate analysis to account for this, p was still less than 0.001. The odds ratio was 0.23. I think this means that they were less than a quarter as likely to have a heart attack. Eat your heart out statinators! Oh!!! That pun was NOT intentional. If only ghee were patentable!

Of course the dietitians probably forgot to ask about sugar consumption. If they did check, they're not saying. Certainly not in the abstract. This gets a bit tedious sometimes!

Fatty acid intake summary from the abstract:

"This group [ghee eaters] consumed significantly more calories, saturated and mono-unsaturated fats while the consumption of polyunsaturated fats was similar in the two groups"

"Fatty acid intake analysis showed that group 1 males consumed more mono-unsaturated (n-9) fatty acids than group 2. Intake of polyunsaturated n-3 and n-6 fatty acids was similar"

I take it from the second quote that the cardiologists are falling back on monounsaturates to save the lipid hypothesis. In their repetition, they forgot to repeat the higher saturated fat intake. Some people are just so forgetful!

But it looks to me to be more likely that you can eat extra calories and be fatter while being less likely to have heart disease, provided your excess calories come from non PUFA fat sources. The sugar intake? If anyone has the full text, and if it was even remotely enquired about, I'll bet it was lower in the healthier, heavier ghee eaters.

Peter

EFA deficiencies?

Arachidonic acid is essential. Apart from the fact that your brain is largely made out of it (I exaggerate here slightly) and it has a roll as a precursor to a myriad signaling molecules, there is a definite deficiency syndrome in the skin. The deficiency syndrome is a bit dubious in humans, especially adults, but pretty clear cut in lab animals, especially during growth. Chris Masterjohn covers this pretty thoroughly and it seems quite plausible.

In most adult humans there is enough linoleic acid stored in fatty tissue to act as a reservoir for the synthesis of arachidonic acid for a long time. Even after years on a PUFA free diet it is unlikely you could precipitate an arachidonic acid deficiency. Bear in mind that a completely PUFA free diet must be synthetic or largely so. No food, just a fat free protein source, sucrose, glucose and some multivits should cover it! Otherwise enough arachidonic acid would sneak in from meat and eggs to supply an adult's needs. Or maybe some linoleic acid from lettuce!

I suppose the flip side of this is that if you drop your PUFA intake deliberately it may well be quite a long time before you lower your blood linoleate levels. Obviously this depends on how much vegetable oil you've squirreled away in your fatty tissue, how much fat you (and your gut microbiota) actually own and if your hormone sensitive lipase ever actually gets working... And of course how low you think you need to get your linoleate level before a deficiency syndrome appears. No healthy adult has managed so far in the literature.

So arachidonic acid deficiency in an adult human seems to be very, very unlikely. Especially if they occasionally eat items of food.


What about DHA? Amongst the many things which control elongation and desaturation of fatty acids I posted about recently, the parent molecules, linoleic acid and alpha linolenic acids, are effective depressors of the system. That is, if you eat a diet absolutely loaded with linoleic acid there is a down regulation of its conversion to arachidonic acid. That's logical. No one would want an unlimited supply of arachidonic acid. It does a lot of things to you, all of which would want to be done under careful control. It doesn't seem to be possible to down regulate to the point of arachidonic acid deficiency though, some will get through even under very high linoleate intake. Not so DHA.

Exactly the same elongase desaturase system used to manufacture arachidonic acid converts alpha linolenic acid to EPA, heading for DHA. Down regulating the system with linoleic acid, as above, will down regulate DHA production too.


Anyone on a "healthy" oils diet may well need to be getting preformed DHA. As DHA is only available from animal (or algal) sources, the problem person here looks to be the high PUFA eating vegan. That's fair enough, that particular diet choice comes with its own special consequences!

The quote below, which comes from this paper, seems to sum up the current state of unknowledge as to whether this problem is real:

"individuals who adhere to vegetarian and vegan diets do synthesize small amounts of DHA, and evidence to indicate deficits in brain development among vegetarians has not been published"

Of course there is plenty of evidence that being on total intravenous nutrition (TPN), based on linoleic acid as your sole source of lipid, means that you will require more than an absolute minimum of alpha linolenic acid before you actually get any DHA produced at all.

Under these conditions there could easily be an absolute DHA deficiency. There often is.

I think a strong admonition to avoid abdominal gunshot wounds, or anything else requiring years on intravenous feeding, would (if heeded) improve your DHA status. If you must do the iv feeding thing, adding some ALA to the lipid emulsion might be a good idea. Getting pregnant under these conditions might not be the best idea either, even if you felt that way inclined and were adult...

If you are a pregnant mother who avoids fish because of the mercury concern, avoids liver due to the vitamin A concern, avoids animal fats due to the cholesterol concern then your child's eyes and brain might be marginal on the DHA front. Pregnancy and growth seems to be when the body needs bulk DHA. Again, working through this review will fill in the background. Being DHA deficient in utero and during early post natal development seems to be bad news, not fully correctable by later DHA supplementation.

Of course, once you have started eating food as opposed to junk, dumped your heart healthy oils and are eating a little liver occasionally, the chance of developing any sort of PUFA deficiency seems rather small. Occasional fish or a decent amount of ruminant meat would eliminate the risk.

The problem is, how many people eat food and how many live on junk? If everyone were to switch to eating food, would DHA supplements be needed? If the intake of linoleic acid is low enough no doubt even the alpha linolenic acid from green leaf vegetables might end up as DHA.

So it looks as if there are certain circumstances, especially with those junk food based vegetarian diets easily achieved today, when DHA may not be available to meet foetal and neonatal needs. Taking a little DHA supplement may well be needed at this time or, better still, eat some food. Food's a good idea.

That seems to sum up the risk of deficiency to me, as far as I can see. We need some EFAs, more during pregnancy and nursing. Arachidonic acid is not a problem, DHA looks to be the weakest link. TPN is bad news (in case you want more bad news than whatever the reason is for your being on intravenous feeding).

So should we all be taking fish oil supplements, all of the time? Do we need to do anything except to avoid frank DHA deficiency as a foetus or newborn baby?

Maybe, maybe not. That's another post.

Peter

Casein, gluten and gastric pH

In a very interesting paper from Bloggeier on rheumatoid disease and multiple food allergies (worth a post on its own) there was this snippet:

"Thus infants are prone to develop cow’s milk allergy while their gastric acidity is pH 3–4 (compared with pH 2 in adults); at pH 4 the degradation of a-lactalbumin, BSA, and bovine IgG is markedly reduced in contrast to b lactoglobulin".

Following the ref gave this abstract. Just a pity that they didn't look at casein too. It brought to mind the idea that taking gastric acidity suppressing drugs is possibly the best technique we've developed to get ourselves a food allergy, obviously excluding wheat consumption. Of course the combination is probably a cracker.

Now, what does the cow's milk get poured over when weaning a child, who's gastric pH is 3-4?

Well, in this house the wheat is notably absent! Actually so is the cow's milk pretty well and weaning, what there is of it, seems to be going fine on beef and pork purees with some root veggies (plus a little vitamin C to be on the safe side) thrown in.

Peter

Dr Davis links

I browse Dr Davis' blog occasionally. Although Dr D seems to be a total cholesterol believer and has his sights set on 60:60:60 for HDL, LDL and Trigs (and goes with the drug therapy needed to get there) he does have very extensive experience of getting people to change their eating habits. His dislike of wheat seems to come more from using it as a metaphor for junk food, but the addiction aspect is clearly up there too. This post and this one drop in to that last category.

I really like this one too. Been reading Sholokhov's "Virgin Soil Upturned". I'm thankful to be able to make food choices. I'm never hungry. I am grateful.

And then we have this one too. The beginnings of saturated fat acceptance!!!! Woo hoo. Here's the bit I like:

"Adding back saturated fat. I say "adding back" since most of us (including myself) went too far down the "saturated fat is bad" path over the past few years. While I do not advocate a carte blanche approach to saturated fat, I believe that adding back eggs (preferably free-range and/or omega-3 rich), lean meats, and hard cheeses is a good idea"

Okay, it's cautious, but its a shift in the right direction. Bring on the carte blanche and let the chickens choose their own weeds. Of course there's not a lot of saturated fat in eggs, so here we have cholesterol acceptance too, if only dietary... That's nice to read.

Peter

Metabolism nuts and bolts PUFA

This post is basic biochemistry that we probably all know. I've just stuck it down as I've slogged through it while I've been working through Chris Masterjohn's treatise on PUFA, it seems a waste not to use it. Ignore if you're happy with elongase and desaturase enzymes.

Omega counted double bonds are very straight forward, they are counted from the methyl end of a long chain fatty acid. Because mammals can't add extra chain length or desaturate at the methyl end, these bonds are "fixed" in their identity. So mammals can pop a double bond in to stearic acid in the omega 9 position to give oleic acid and that's it as far as the methyl end is concerned. Double bonds at the omega 3 and 6 positions are also fixed and come from the diet (mostly, there may be an exception). No chance of elongating at the methyl end, so the 9th/6th/3rd will always be the ninth (or 6th or 3rd) bond down from the omega end of the chain. So oleic acid is an omega 9 fat and all of its derivatives are too. Whatever elongation/desaturation happens, it happens at the carboxyl end. Ditto omega 3s and 6s.

Delta refers to desaturase enzyme's ability to change a single bond to a double bond, extracting two hydrogen atoms in the process. So delta 6 desaturase pops a double bond in to the place of the 6th carbon-carbon bond, counting from the carboxyl group end of a fatty acid. This number is the alpha number, as it's counted from the opposite end to omega number. The desaturases mostly don't care how long the fatty acid is, they just grab the acid end, count six (or seven or nine or five etc) and stick in a double bond.

We definitely have a delta 5 and a delta 6 desaturase. Oddly enough we never put double bonds in to adjacent locations in our fatty acid carbon chains, there is always a gap. The pattern goes double bond, two singles, double, two singles etc, as far as I can see. That is if you want extra double bonds at all.

Fatty acids get elongated. This always happens from the carboxyl end, and always involves adding two extra carbon atoms, using single bonds only. In mammals anyway.

So when the fatty acid with a recently added double bond placed in the alpha 6 position by our delta 6 desaturase gets elongated, that new double bond gets promoted from the alpha 6 position to the alpha 8 position.

To keep the pattern we want two single C-C bonds then the new double. That mean going for the 5th C-C bond using delta 5 desaturase.

This neatly gives us the end product of arachidonic acid from linoleic acid.

We also get to eicosapentaenoic acid (EPA) by the same pathway if we start from the alpha linolenic acid parent. Then a simple elongation and a delta 4 desaturation gives docosahexanoic acid (DHA). If your delta 4 desaturase doesn't work you can try this:

Double elongation w/o desaturation to 24 C chain with first double bond now pushed to the 9 position from the carboxyl end. Delta 6 desaturase places an appropriate double bond at the 6 position, as it always does. This weird fatty acid is then shortened by two c atoms (off of the COOH end of course) to give DHA, the new double bond thus ending up, as it should for DHA, at the 4 position (from the 6 position where it was placed by delta six desaturase).

That last paragraph is from Mary Enig's book "Know Your Fats". The rest is general biochemistry.

There is no arguing with the essentiality of arachidonic acid and probably the same goes for DHA. If we don't get them pre formed in our diet, this is how we make them.

Peter

Gluten links from Bloggeier

My thanks to Bloggeier for these links, especially for the full text of the letter to GUT from the Spanish group.

These are various groups who are interested in innate gluten toxicity (GUT letter), non antibody investigation of food sensitivity and combined reactivity to gluten and casein in some coeliacs.

Quotes from the letter to GUT, which has restricted access:

"Nowadays it is assumed that an innate immunity to gluten plays a key role in the development of coeliac disease (CD). This innate response, mediated by interleukin (IL) 15 and elicited by "toxic peptides", like the 19-mer, through a DQ2-independent mechanism, induces epithelial stress and reprogrammes intraepithelial lymphocytes into natural killer (NK)-like cells leading to enterocyte apoptosis and an increase in epithelium permeability"

Try telling that to a Nottingham gastroenterologist!

"We consider that, to our knowledge, this is the first time that an IL15-mediated innate response to gliadin and gliadin peptides is described in individuals without CD, as well as an IL15-mediated innate response to the "non-toxic" deaminated immunodominant 33-mer peptide"

The 33 amino acid section is supposed to be non toxic itself (which turns out to be incorrect, it is toxic) but provides a focus for antibody production, which leads to severe secondary damage by the antibody. This still happens.

"Moreover, the IL15-mediated response in patients without CD was also triggered by the toxic 19-mer gliadin peptide (three of six) and, especially, by the 33-mer gliadin peptide (five of six). Importantly, none of the basal cultures produced this cytokine and, although not expected, the "non-toxic" immunodominant 33-mer was also able to induce an innate response"

Of their biopsy samples from NON COELIAC DISEASE people, one out of six did NOT respond to the 33-mer with interleukin 15. Five out of six did. I fully accept that there may be things going on with our immune systems to increase the frequency of allergies (grass pollen has always been around, hay fever was first reported just over 100 years ago as a case report in the Lancet...) but gliadin is directly toxic. It looks like allergy comes later, facilitated by toxicity causing intestinal leakage.

So it is just possible that maybe 1 person in six might NOT respond adversely to gluten. Notice that the researchers put "non toxic" in quotation marks, at least twice. These people know what they're talking about. I wonder if any of the group eat digestive biscuits with their coffee at lab meetings?



I'm not sure if I got the full text of the multimodal imaging paper through my athens account or if it's free access, but the interest this group has in getting away from crude antibody tests for food intolerance is impressive. Using some of their techniques would allow you to look at things like salicylate and amine toxicity, which probably have nothing to do with antibody production and very little to do with the immune system at all. The sort of sensitivity that gets you labeled as a malingerer in Nottingham...

Peter

Congratulations: You have coeliac disease!

It may come as a surprise to find that not all people with coeliac disease sit on the loo for all of their lives until the time they get a diagnosis. In fact they perceive themselves as healthy, if it's occult enough.

I posted on what I though of the neurology department at the Queen's Medical Centre in Nottingham when it comes to gluten ataxia: 

Go to Sheffield!!!!!

Now I've stumbled across this glowing account of the benefits of occult coeliac disease, again from the Queen's Medical Centre, Nottingham. Here are a few snippets from the main text:

"EMA positive participants (n=87) were on average slightly lighter by 2.2 kg (p=0.08), were more likely to have reported their general health as being good or excellent"

"EMA positivity was associated with an 8% reduction in mean serum cholesterol (0.5 mmol/l; p less than 0.01) and reductions in mean haemoglobin (0.3 g/dl; p less than 0.01)"

"Those affected report "better health" but they do have an increased risk of osteoporosis and mild anaemia. In contrast, they have a favourable cardiovascular risk profile that may afford protection from ischaemic heart disease and stroke"

"The important finding of a favourable cardiovascular risk profile in these individuals suggests that any screening programme of the general population would need to be carefully evaluated in terms of risks and benefits before its introduction"

That last snippet needs to be read very carefully.

To summarise: In Nottingham, undiagnosed coeliac disease is good for you. Never mind the occasional fracture, bowel cancer or auto immune neuropathy. And I'm trying not to grind my teeth at the stupid glee over lower than average total cholesterol (in a predominantly female population!). It's obviously better to die of bowel cancer than a heart attack. Well, if you're a Nottingham epidemiologist that seems to be the case.

Let's just head over to Northern Ireland for a while (rather than Sheffield, we want a more general overview this time). The first point is that the anti-endomysial antibody test is pretty rubbish. To quote McMillan et al:

"EmA-negative coeliac disease is common. Reliance on EmA testing to select patients for biopsy will result in significant underdiagnosis"

So obviously the benefits of coeliac disease, so popular at the Queen's Medical Centre, are more widespread than we realise! Certainly in Northern Ireland. Unfortunately there are certain benefits of occult coeliac disease which Nottingham forgot to mention, particularly death! Again from Belfast:

"Patients with coeliac disease or gluten sensitivity had higher mortality rates than the Northern Ireland population. This association persists more than one year after diagnosis in patients testing positive for anti-gliadin antibodies"

What is meant by "gluten sensitivity"?

"There were 1133 patients who tested positive for anti-gliadin antibodies and they were defined as gluten sensitive"

This later group would not even be considered by Nottingham as being unwell because they don't usually have gut pathology and their anti-gliadin antibodies come and go. How common is this category of sensitivity? McMillan again:

"The results establish that IgA antigliadin antibody prevalence is high at 5.7%"

That's one in eighteen people.

Using an antibody test. Antibody positive patients will only be the very big tip of a massive iceberg. One you start looking at how the innate immune system functions, with its NK cells that don't use antibodies, when challenged by gluten, you have to wonder whether anyone is immune to gluten damage.

You can guess what I think.

BTW If anyone got down to the comments of the gluten ataxia post and read those by Toxic, you can get an idea of how clued up Nottinghamshire seems to be when presented with a person suffering full blown, antibody positive, severe, multisystem gluten damage. They missed it. Lots of times. Not sure if Toxic attended the Queen's Medical Centre, but I'd guess so.

Peter

Physiological insulin resistance; Dawn Phenomenon

What is the Dawn Phenomenon (DP)? A nice simple definition is available from here:

"The dawn phenomenon is a term used to describe hyperglycemia or an increase in the amount of insulin needed to maintain normoglycemia, occurring in the absence of antecedent hypoglycemia or waning insulin levels, during the early morning hours. To be clinically relevant, the magnitude of the dawn increase in blood glucose level should be more than 10 mg/dL or the increase in insulin requirement should be at least 20% from the overnight nadir. Controversy exists regarding the frequency, reproducibility, and pathogenesis of the dawn phenomenon. Approximately 54% of patients with type 1 diabetes and 55% of patients with type 2 diabetes experience the dawn phenomenon when the foregoing quantitative definition is used"

OK, I lied about the simplicity.

If you go back to 1988 this group seemed to think that the Dawn Phenomenon was pretty straight forward and amenable to pharmacological management. In the early hours of the morning humans have a growth hormone (GH) surge. GH causes lipolysis, lipolysis releases free fatty acids. No muscle wants glucose when it has access to free fatty acids. Muscle thus becomes insulin resistant and blood glucose rises. They studied type one diabetics as doing this eliminates all of those messy insulin responses to glucose that normal people produce.

Give an anticholinergic, block the GH surge and you block the DP. All nice and simple.

Then this group, in 1992, went out to check if this was true and gave a bolus of GH, again to some type one diabetics. Any old time of day as far as I can tell.

As expected GH caused a rise in FFAs but no insulin resistance in this paper! Quite how they managed this is a bit beyond me. FFAs should produce insulin resistance. Both papers report comparable peaks in GH but neither gives an AUC for GH. It's difficult to compare FFA changes between papers.

Then, when you get down to the nitty gritty, you find that the second paper was quite careful to produce only a SHORT physiological burst of GH, shorter than occurs at night in humans. They were ONLY looking for the effect of GH on insulin resistance, so they had to keep FFA changes to a minimum. This looks to be a very carefully crafted sentence to me, it's the "summing up" in the abstract (the section of the paper which actually gets read):

"Since no significant effect on glucose metabolism was recorded, we do not presently find evidence to support a primary role for small surges of GH in the pathogenesis of the dawn phenomenon"

A translation might read:

"A bolus of GH which is significantly lower than that needed to produce the lipolysis necessary for the Dawn Phenomenon does not produce the Dawn Phenomenon"

People don't work like this! The nightly GH surge in humans does crank up FFAs. Eliminating this effect from your study won't help elucidate what's happening in the DP, except to say it's not GH per se, but it's still the down stream effects of GH that matter. The 1988 paper looks far more convincing to me.

Current thinking seems to have forgotten about FFAs but does come up with the concept that there is no drop in insulin levels involved. This is interesting in so far as Dr Bernstein suggests that rapid hepatic breakdown of insulin is the cause of the problem. I've yet to see any evidence of this mechanism, unusual for a Dr B idea.

The other main support for FFA involvement is the roll of eating in terminating the DP. This has been discussed many times on the Bernstein forum. Many type two diabetics develop a vicious DP on LC eating and, if they continue to fast through the morning, their blood glucose will just keep going up and up. Eating CARBS stops this, presumably the carbs get insulin high enough to get ahead of the effects of FFAs on muscle, while the extra insulin can shut down hormone sensitive lipase and so drop FFA production... This is physiological insulin resistance taken to pathological extremes.

It's interesting to speculate whether it is the facility to indulge in lipolysis to excess, possibly related to the absolute fat mass available or insulin resistance in those adipocytes, or failure of the cross talk between alpha and beta cells in the pancreas or failure of hepatic vagal nerve supply which makes the DP such a big problem in some diabetics but not in others. I don't know.

Also the how and why of bed time alcohol blocking the DP effect is another big unknown, but it seems to work for many diabetics. Whether this is an hepatic effect, a GH effect or a lipolysis effect seems wide open. Wine lovers with DP just seem grateful when it works for them. Evening alcohol incidentally also drops my morning glucose in to the 4 point something range.

So it looks to me as if the DP is an insulin resistance phenomenon by which GH induced lipolysis bumps up morning glucose. I think this is physiological. When lipolysis is one step ahead of the extra insulin production needed to keep blood glucose in an "acceptable" range you can easily end up with an elevation of FFAs, insulin and glucose all at the same time. In fact, broken insulin sensitivity might well do this, and so you end up with type two diabetes markedly worsened by a GH surge, every night...

Peter

When is a high fat diet not a high fat diet? Stuff via Fanatic Cook

Here's an interesting paper brought my way by Dave Lull who browses Fanatic Cook, a place I'm not likely to visit in my travels. Though perhaps I should, to keep an eye on what the carbophiliac people are up to...

This paper is another in which a Western/Cafeteria diet (45% fat, 40% carbs) is described as high in fat and, wait for it, low in carbohydrate. Assuming 2400kcal per day, that's 1000kcal of carbs or 250g/d. You can appreciate the level of intellectual honesty here, so of course the temptation is to bin the paper. No, WAIT.

There's some interesting stuff. Never mind the shifts in cholesterol levels (it was a cross over study with a low-fat high-carb period), these are exactly what you would expect. The study was careful not to check the LDL particle sizes and numbers otherwise they might have found the small dense LDL which would probably have predominated on the HC period. That is along side the lower HDL figure they did report on the HC phase. They were also careful not to look at glycosylation levels (HbA1c would be useless in a short study like this, but fructosamine looks at two weeks of glycosylation and would have been interesting) to see what was happening in the "eating" world, rather than during a glucose tolerance test. You don't put this sort of control in to nutrition studies because it might not get you the answers you want. High fat diets DO tend to produce higher fasting glucose levels and can even produce higher fasting insulin levels, as here, but 24h AUC for insulin and glucose would be lower. Fructosamine would have shown this. That's how come I can sit here with an HbA1c of 4.4% and a fasting glucose of 5.5mmol/l, higher some days. No suggestion anywhere that Vidon et al or Fanatic Cook see things this way. I do. Shrug.

So, not my type of study. But look at this, this is what grabbed me:

"Lower cholesterol concentrations occurred despite a higher cholesterol synthesis rate (P less than 0.05) and higher HMG-CoA reductase mRNA concentrations (P less than 0.05). LDL receptor mRNA concentrations were unchanged, LRP mRNA concentrations were lower (P less than 0.01)"

The molecular techniques are a bit beyond me to comment on, so I'm just going to believe Vidon et al, that cholesterol synthesis went UP on the high carbohydrate phase diet, plasma levels went DOWN and gene expression for the LRP went DOWN.

Now, they were looking at HMG-CoA reductase in white blood cells, not the liver, but they seem to think the same thing happens in both places:

"Because synthesis and secretion in the plasma pool increased, it appears that the lower plasma cholesterol concentrations were related to increased removal from plasma. However, the mRNA concentrations of 2 main lipoprotein receptors that control the clearance of cholesterol from plasma were unchanged (LDL receptors) or decreased (LRP)"

Now I find this very interesting. More cholesterol produced, less is taken up, yet plasma level drops.

Here's an ad hoc hypothesis as good as anything in the paper:


Some receptor other than the LDLr or the LRP is taking up the LDL cholesterol.


Lets have a guess at which one, let's guess at the oxidised cholesterol receptor. There is at least one short term intervention study showing that small reductions in total fat calories in the diet increase the level of oxidised LDL in the blood, markedly. There was a 15% difference in the fat content of the two diets in Vidon's study. Oxidised LDL is eaten by macrophages, using the oxLDL receptor. They become foam cells in fatty streaks.

Perhaps the cholesterol levels drop as it's all now in foam cells on the arterial walls????

Never forget the American paradox. According the Vidon et al there must a sharp reversal of those benefits associated with increasing fat from 18% of calories through to 32% (p less than 0.001 for trend by quartiles) if you extend it to 45%. Duh.

Maybe, maybe not.

Peter

Ketosis links

There are a couple of posts on ketosis and brain function on Emma's blog that warrant a read, especially with Failsafe additions (read Emma, I don't know much about Failsafe). Ketogenic diets are in the news in the UK for epilepsy management at the moment. With the list of neurotransmitter effects that Emma details there is very clear cut logic to looking down this route for a fairly wide range of brain problems. As well as epilepsy and bipolar disorder I've heard anecdote on Dr Bernstein's forum for Tourette's. Obviously there is a certain amount of stuff about gluten/casein (A1 I presume) and schizophrenia.

Peter

Weight loss when it's hard 5. Son of diazoxide

Life can be mean to you, just on a random chance basis. Sometimes bad stuff just happens.

Imagine what it's like to be planning a study, let's say on the use of a drug for managing atopic dermatitis in dogs, and you've struggled to recruit 20 participants. After the randomisation process you notice that you've ended up having recruited eight West Highland White Terriers (all with pink toes, sweaty armpits and sore ears, many Westies live with atopy) in to the treatment group (n=9) and a heterogeneous mix of healthy mongrels in to the placebo group (n=11). Oh dear. This is a real problem and can happen with small group-size studies. At this point you should consult a statistician or perhaps your group leader, before staking your career on the outcome of this particular study. Suicide is not usually needed, even if considered.

So poor old Due, the first author of a paper produced by Astrup's group in Denmark, struggled through 280 potential participants for his (or her? Dunno) diazoxide study before eventually finding 47 people who conformed to the entry criteria. Twelve of these said get lost. So 35 people started the study. Randomisation and drop outs gave n=13 in the diazoxide group and n=18 in placebo group by the end of the study.

Due got bitten by his patient groups and doesn't appear to even realise it happened! Whoever did the statistics on the participant characteristics of this study noted that the diazoxide group had an average fasting insulin level of 157 pmol/l where as the placebo group had a level of 119 pmol/l, with p less than 0.001 for the difference. Yes, I counted and recounted the number of zero's in this p value. It's not a typo. Oh dear! This never made it in to the discussion, it never even made it in to the results section, just in to a table, so I assume Due never noticed! ! ! ! It must have gotten past two scruntineers too.

Within one week of starting the drug there was a significantly greater drop in the average insulin level of the diazoxide group. Of course there was, this is what the drug does. Even Due noticed this. Because of the way the results table is laid out we only get the differences, down by 50 pmol/l in the diazoxide group, by 5 pmol/l in the placebo group. Again p less than 0.001 when comparing the changes. What Due didn't do was compare the insulin levels at this point BETWEEN groups. The diazoxide group is going to be in the region of 107 pmol/l and the placebo group at this point would be around 114 pmol/l.

I defy anyone to find a statistically or biologically significant difference between the fasting insulin levels at this point.

By the end of the study the fasting insulin values were about 100 pmol/l on diazoxide plus semi starvation versus about 80 pmol/l on semi starvation alone in the placebo group. I've no idea what the p value for the differences between groups might be at this point and Due certainly isn't going to tell us.

Going to table 2 we find that the diazoxide group, which ran a fasting insulin level of just over 100 pmol/l throughout the study lost 4.9kg and the placebo group, which ran a fasting insulin which started at 115 pmol/l and which probably dropped continuously to 80 pmol/l and so probably averaged just below 100 pmol/l, lost 6.4kg.


An aside:

At this point it is certainly worth noting from table 2 in Alemzadeh's paper that the initial fasting insulin levels were the opposite way round to those in Due's paper, tending to emphasise the diazoxide effect (204 pmol/l in the placebo group vs 168 pmol/l in the diazoxide group). Checking the bottom left hand graph of figure 2 shows that this difference was not statistically significant. We have to decide for ourselves if it was biologically significant.



Back to Due's paper:

Averaged over the bulk of the study the placebo group probably had slightly lower insulin levels that the diazoxide group and lost slightly more weight. All non significant, but with no significant difference between insulin levels, why should you expect any significant difference in weight loss?

Diazoxide is not a slimming drug. It reduces insulin levels, which is what allows the weight loss. Whether you drop insulin levels by starvation, diazoxide and starvation, LC eating or becoming muscle bound, insulin is what matters. No differences in insulin, no differences in weight loss.

Of course, it is possible that Due and Astrup were fully aware of what they achieved and thought long and hard about how they presented their results. I don't think so. I sincerely hope not. Stupidity is much more pleasant to consider than deviousness.

Peter



PS I'm not going to discuss the discussion. Due doesn't really discuss anything there anyway, just re states his results, recapitulates those of the original diazoxide paper without understanding where or how the differences in outcome arise and then states that diazoxide is useless for weight loss. There is no synthesis or understanding of what is going on. Probably due to working under Astrup.

PPS It's worth noting that semi starvation DOES drop insulin levels and does increase insulin sensitivity (Matsudas index from 5.91 up to 8.31 in this study) and so does lowering insulin with diazoxide plus semi starvation (Matsudas index up from 5.18 to 9.27). I wonder what 8 weeks of hypocaloric LC eating would do, or even weight stable LC eating...

Weight loss when it's hard 4. Coming soon; son of diazoxide

Particular thanks to both Mark and Stephan for copies of the diazoxide paper by Astrup's group. Looking forward to posting on this one but not sure how time will pan out in the next couple of days! But just goes to show, you REALLY do need the full text, otherwise you get the impression that the two studies conflict each other, and that Astrup is, well, I'd better not put down my opinion of Astrup!

Look here:

The Danish diazoxide group: Can't write a discussion or understand their own results-

Due A, Flint A, Eriksen G, Møller B, Raben A, Hansen JB, Astrup A.

Location: Research Department of Human Nutrition, Royal Veterinary and Agricultural University, Frederiksberg, Denmark


Compare that group to the Danish flavanoid wash out group-who fought tooth and nail to publish a controversial result:

Young JF, Dragstedt LO, Haraldsdóttir J, Daneshvar B, Kall MA, Loft S, Nilsson L, Nielsen SE, Mayer B, Skibsted LH, Huynh-Ba T, Hermetter A, Sandström B.

Location: Department of Human Nutrition, The Royal Veterinary and Agricultural University, DK-1958 Frederiksberg C, Denmark.


Anyone spot any overlap at all between the group members? Two sorts of researchers perhaps, one with a better eye to future funding. Oh, did I say that?

Peter

Weight loss when it's not hard 3. Oops

You just have to be careful. You know what it's like, you're up at 6am with your son, get a quick creamy cocoa as you spoon his breakfast in to him, then it's play play play, then he goes to nursery and you've got to tear down the higgledy piggledy fence, get a decent gate, buy the timber, get it all cut, fitted, creamy cocoa, realise the carport post is so far off of vertical you have some more post fitting to do, run out of time, get your son from nursery, sort out the blog while he naps, play play play, have a hyperlipid supper, sort out the blog while your wife goes to Pilates, do the same thing the next day pretty well identically, but get the verticals vertical, back pack your son to playground play play play, especially the slide, another high fat supper, do some gardening somewhere along the line, sort the blog.

Suddenly you realise you've skipped some calories by accident.

Calories in, calories out. You don't weigh 65kg. That was 48 hours ago. Now 63.8kg is more where it's at despite the gluten free almond based chocolate sponge cake (mmmm, bad carbs in the icing) we had after supper last night. Bodyfat's still at 11% but that's at 9am, it'll be down by this afternoon as it always drops through the day. Except today I'll eat.

YOU HAVE TO REMEMBER TO EAT!

Peter

Weight loss when it's hard 2. Diazoxide

I just thought I'd put this post up as it's fairly topical at the moment.

We all now know that macronutrient ratio is irrelevant, insulin is irrelevant and all that counts is calories. Calories in, calories out, fat people are lazy gluttons. So let's play.

You can simply reduce insulin secretion using diazoxide. Find enough obese people willing to put up with the hunger generating regime supplied by Slimfast and semi starve them for 8 weeks. Half can have a placebo, half get diazoxide in addition to Slimfast starvation. Figure 1 in the results is where you want to look. The idle porkers starving on Slimfast plus diazoxide lost significantly more weight in 8 weeks than the idle porkers starving on Slimfast alone.

It looks to me as if the diazoxide group had lost 10% of bodyweight and were still loosing. The Slimfast alone group were stalled at about 4.5% bodyweight loss. Note also that the diazoxide group lost 9.3kg of fat vs. 3.6kg in the placebo group.

That is, diazoxide produced an excess fat loss of about 5.8kg in eight weeks. That's 100g per day. Or about 900kcal of fat. Every day.

So what's going on. It's pretty obvious really. This is not a metabolic ward study and the subjects cheated. Must have done. Stands to reason. These are free living people. How can any bloke on a 1570kcal per day diet walk past the gym without slipping in and spending an hour doing bench presses? OK, he promised to keep his exercise unchanged but really, no one will ever own up to having a 900kcal/d gym habit like that.

Or maybe the placebo group cheated. It's pretty obvious that 1570kcal of Slimfast will have you pogged out all day, no room for even a teensie weensie little donut, but hell, if they're half price you might force one down or maybe that will be 10 donuts......

But it's funny that the gym sneaks and the donut moonlighters ended up in separate treatment groups.

Or maybe, just maybe, you could just accept that in the real world, outside a meatball ward, sorry, metabolic ward, the level of insulin in your blood stream influences your rate of weight loss, specifically your rate of fat loss.

BTW The folks in this study are clearly pathological liars too. Any trainer being told that a fatty can maintain a BMI >30 on 1900kcal per day will be snorting in their whey protein shake. You know calories in calories out, yawn.

The placebo group lost 64g of fat per day, which is about 600kcal. This was on 1570kcal/day. So, just by arithmetic, they should previously really have been eating 1570 + 600 = 2170kcal/d to have been weight stable. They claimed to have been eating 1953kcal/d. That's not so far out given the accuracy of food tables. Maybe these were the honest ones.

But the diazoxide group lost 1660kcal/d of fat every day while eating 1570kcal/day of "food" (Slimefast). Does this mean that they had originally been eating 1570 + 1660 = 3230kcal/d to maintain their weight pre study? Now these people claimed 1977kcal/day. Lying porkers. You can't trust anyone. Least of all a fatty. But then everyone lies according to Gibney!

Let's get real. I think both groups ate just 1570kcal/d and skipped the gym. The diazoxide group used all of those calories PLUS 1660kcal/d of their own fatty tissue. The placebo group appeared to use that 1570kcal plus 600kcal of their own fat, but this is an average over time. They lost more than this initially per day, but by the end of the study they didn't look to be loosing any weight at all on those 1570kcal. By week eight they USED 1570kcal/d and that was it. They hadn't lost much weight anyway and now they were weight stable on the same energy consumption that had the diazoxide group loosing consistently. And this was at a much lower energy intake than they had possibly "under reported" at enrollment.

To go back to that apparent idiot Taubes, the problem with fat people is that they do not have access to their fatty tissue. It's only "there" as an energy source when insulin levels are low enough to allow HSL (hormone sensitive lipase) to work. Slimfast drops insulin a bit compared to the SAD, in this study from 204pmol/l to 174pmol/l (neither statistically significant nor biologically significant, after a few weeks anyway). Slimfast plus diazoxide dropped insulin from 168pmol/l to 108pmol/l (statistically p<0.01, biologically weight loss continued).

So where did the energy go to in the diazoxide group, and why did the placebo group stop loosing weight on a marked calorie deficit? Thermodynamics rules. No evaporating calories.

Well, a calorie is a calorie is a calorie. You can't burn what you ain't got. On Slimfast alone (I suspect low fat, low protein, some carbs to keep insulin up almost as much as the SAD) stored adipose tissue is just not available. Lugging around a body with BMI of >30 takes calories. If you don't have the calories, you don't do this. No sneaking to gym for this group, and I bet they were dreaming of donuts by week six, if not before.

In the diazoxide group there were significant periods of time when fatty tissue was available to supply calories because insulin was low. Use it AND loose it, calories that is. Lifting a 150kg body takes calories. If they are available, you can do it, you do do it. You don't need a gym when you weigh this much and have found access to all of that energy in your adipose tissue. Just moving around more makes a difference. I weigh 65kg. Putting on a back pack weighing 85kg would cripple me. I'd burn some calories. Heavy people live with this, shifting about takes energy. A lot. You don't have to change your basal metabolic rate. Just how you move.

So just to summarise this paper. Caloric restriction failed in about 7 weeks. Equal caloric restriction plus lowered insulin levels allowed on going weight loss throughout the study period.

Now, imagine the insulin drop without the diazoxide and without the hunger generated by Slimfast. Eating 1570kcal of steak, curly kale, bacon, scrambled eggs, double cream etc etc. The rest of your calories can come from that enormous supply of fat in your abdomen first, then on your bum. Forget about hunger.

You might even have the energy to go to the gym. After all, with all those adipose calories available, you can afford the energy to work out.

Peter

Weight loss; when it's hard

This post is a set of jottings on weight control when it's difficult. It's essentially unreferenced and was produced in response to the enquiry by Windmill/Windmum (same person) in the comments after this previous post.

Many posts ago I mentioned the thought that it was probably perfectly possible to gain weight on a low carb/high fat diet, provided there were adequate calories involved. Because insulin appears to be very important in controlling the activity of lipoprotein lipase, that enzyme which gets fatty acids out of lipoproteins and in to fat, there has to be some other way of doing this transfer when insulin levels are low.

Chris found the enzyme, it's ASP. You can read more here. ASP is Acylation Stimulating Protein. Let's stick to ASP.

This is completely logical. Those of us who eat combined high fat with LC tend to have rather low levels of insulin in our blood stream. Low levels of insulin mean low levels of activity in the lipoprotein lipase just outside our fat cells. If there was no other way of getting fat out of chylomicrons or VLDL particles and in to adipocytes, we LC eaters would be as chronically hypertriglyceridaemic as a diabetic on a low fat diet. No one would want that.

In to the gap steps ASP, which allows us to store the fat from our current meal as adipose tissue for use in the time before our next meal. On intermittent fasting or once daily eating we HAVE to store an awful lot of fat until we next eat. ASP gets fat in to adipocytes for us, without needing an insulin spike. Good.

What gets the fat out of adipocytes? That's hormone sensitive lipase (HSL from here onwards). Actually, even in HSL knockout mice it is quite possible to get fat out of adipocytes and in the circulation. Which system does this I've no idea and, because none of us is a HSL knockout mouse, I don't much care! If HSL is really working well, it will do the job.

So, say we are eating once daily, we can assume ASP will store any fat we eat in excess of our immediate needs, tucked in to our adipocytes. What reduces our weight is when the release of free fatty acids (FFAs) from our adipocytes via HSL is greater than the input via ASP.

Getting FFAs out easily means optimising the activity of HSL. That means lowering insulin. Low insulin allows HSL to work effectively. An effective HSL supplies FFAs to allow our metabolic activity requirements to be met from adipocytes. A freely available energy supply from adipocytes should reduce the need to obtain energy from food, ie less hunger. Ineffective HSL means you need to eat more, because your fat cells are hanging on to their contents. To paraphrase the whole of Good Calories Bad Calories in one phrase:

Excess weight is the result of a failure of adipocytes to release energy, hunger is needed to supply any shortfall needed for metabolism.

Working on this basis, the requirement for weight loss must be to minimise insulin. This allows metabolism to run on the surplus of adipose tissue energy released over dietary energy consumed. On a high fat diet with low insulin levels ASP will still rapidly store most meal derived fat, HSL will subsequently release it as needed.

Ultimately weight loss boils down to lowering insulin levels. So we end up with a need for minimal carbohydrate. On the Optimal Diet basis that would be the lowest amount for a sedentary person to avoid ketosis, say 0.5g/kg of "ideal" weight. If a person is well adapted to a LC/high fat diet then protein requirements can be as low as 0.8g/kg ideal weight. Protein metabolism requires some insulin response and any excess protein will be mostly converted to glucose, which requires a considerable amount of insulin to be used. Fat intake should be relatively low (by Kwasniewski standards only!) to keep total calories below those needed by our metabolism, otherwise ASP will store more fat than HSL will release. HSL will only ever release enough FFA for the metabolic needs in a healthy person.

On top of that basic plan, the basal metabolic rate must be normal. If a person is hypothyroid they will require far less FFAs for their metabolism and so HSL will adjust to this and minimise fat break down. ASP won't, so a high fat diet will produce weight gain if calories are in excess of metabolic needs. Correct and well monitored thyroid medication is needed for this. As most common thyroid problems seem to be auto immune in origin, avoiding gluten seems like a good idea, if it isn't always a good idea. Which it is. BTW both hypo and hyper thyroidism appear to cause insulin resistance. That seems a bit bizarre to me, but there you go.

There seem to be a few teaks available. Tinkering with insulin sensitivity may be worthwhile. If your muscles need a certain amount of insulin to dispose of a given amount of glucose, then the pancreas will produce that insulin. In addition to helping the muscles take up glucose that insulin will inhibit FFA release from adipocytes. Resistance exercise seems to be the best way to increase insulin sensitivity. Doing this shifts that same given amount of glucose on less insulin. Less insulin means less inhibition of HSL, so easier fat loss.

Improving insulin sensitivity can also be achieved by avoiding medication which interferes with the action of insulin. There has to be a balance here. If dumping your antidepressant makes you suicidal, don't do it! Most blood pressure medications can be gradually reduced as blood pressure tends to normalise on LC eating. Corticosteroids are a real bugbear. Again, if they are life saving you have no choice, keep taking them and accept the weight they make you carry. If you are corticosteroid dependent, never forget that acute withdrawl can be fatal.

If you live as far north as Finland then checking and correcting your vitamin D status would be well worth while.

Anyone reading Chris or Emma's blogs will realise that aspirin, and possibly other related salycilates from plants, cause the pancreas the secrete extra insulin. Avoid. Gluten and wheat germ agglutinin (both from wheat, barley and rye) are (or contain) insulin mimetics, avoid. Casein stimulates insulin secretion, avoid. Pharmaceutical NSAID probably do the same as salycilates, avoid if possible.

Coconut oil is interesting. It has a reputation for assisting weight loss, but if gavaged in to the stomach of a chow fed lab rat it will decrease blood glucose and increase blood insulin levels. You don't want to increase your insulin levels if you want to loose weight. There are other plus and minus sides to coconut oil, but I'd keep life simple and avoid it.

That's quite a list. There are probably loads of other tweaks that I've not thought of...

If you are in the same position as Windmill, that must all be pretty depressing to read. If you want to adjust your weight downwards to where you would like it to be, you are stuck with a pretty extreme version of the Optimal Diet, low but adequate in protein, low in carbs, probably eaten as starches as part of the evening meal, fine tuning your thyroid meds and replacing coconut oil with lard. Lard at a moderate level that is. Do everything practical to maintain your insulin sensitivity.

This seems to work (from an off blog comment from Windmill).

The trouble is that it is HARD. This is not OD as myself or Stan eat it. This is kitchen scales, bathroom scales, portions, calculations, limitations, problems eating out, vegetable avoidance, cheese avoidance, gluten avoidance....... Arghhhhhhh

So there is a trade off. It's one hell of a big trade off. Some of us (most of us probably) have it easy, certainly easier than Windmill. But ultimately there is that balance between fats in to adipocytes and fats out of adipocytes. ASP and HSL. Even worse, there is a trade off between what you know you can do, that you have already done successfully in the past, and the real bind of allowing your diet to rule your life and putting some pretty draconian limits on your eating. Does anybody want to do this? Long term, for ever? That's a very personal decision.

Also the final thought must be: What is the healthiest weight, personal preferences aside?

I don't think we know.

Peter

Lipoprotein(a) and genetics

There's a diagram of the structure of human Lp(a) here. The apolipoprotein(a) molecule is the curvy bit partly wrapped around the lipid particle. The section which varies on a genetic basis is the number of repeats of the kringle IV type 2 (shown in black). There can be as few as 10 repeats or more than 50. The rule of thumb, within a given population, is that the lower the number of repeats there are, the higher your total plasma Lp(a) is likely to be. NB comparisons between populations are notoriously difficult. Better control your variables and stick to one population.

It almost looks as if the liver wants a certain number kringle IV repeats in the circulation. If there aren't many kringle IVs in the gene, the liver puts more whole protein molecules out to get the number up. Each protein is attached to a single LDL cholesterol particle. Short repeats mean more individual apo(a) proteins are needed to get the number up, which means a higher Lp(a) concentration. It's not a complete equalisation of kringle IV repeats, but that's the general organisation.

The vegetarian Bantu have two things which are special about their Lp(a).

The first is that, despite considerable intermarriage with fishing Bantu, they are genetically short on the kringle IV repeat front so, naturally, they produce more apo(a), attach each to an LDL, so have higher Lp(a) levels across the board compared to their more carnivorous cousins.

The second is that, if you control for this effect by selecting and comparing two genetically apo(a) matched groups, one veggie and the other fish eating, the difference decreases but is still significant.

What can you make of this? The first thing must be that there is a selection pressure to maintain the differences in apo(a) genetics. Either the fishermen don't need much Lp(a) or the vegetarians need lots. I think the vegetarian environment is such that people with high Lp(a) are more likely to survive.

Second follow on is that the extra Lp(a) from the genetics of the vegetarians is not enough. There is some scope for "pushing" Lp(a) levels up or down from the level you might expect from the genetics of apo(a). The vegetarian environment requires higher Lp(a) than the fishing environment.

We know from intervention studies such as DELTA that a simple change of 7% of calories in the SAD from saturated fat to carbohydrate will increase Lp(a) levels by 20%. What does this mean?

If you subscribe to the "Lp(a) is a suicide lipoprotein" theory, you have to conclude that replacing saturated fat with carbohydrate makes your liver want you dead, by 20% more than it did when you ate butter.

Using monounsaturates instead of saturated fats is not quite as bad, the hepatic homicide lipoprotein only goes up by 11%.

The other way of looking at the changes is to suggest that your liver either monitors your macronutrient intake (you think it doesn't?) or some marker of vascular damage. If you do something which is either is outright damaging, or which is sensed as potentially damaging, your liver acts to save your life. If it "perceives" that you need more Lp(a), you get it.

What each of us gets in terms of the genetic number of kringle IV repeats is probably determined by where our personal ancestors lived. Not much we can do about that. What ever we do to tweak this background level of Lp(a) production is up to us.

From the DELTA study it's pretty clear that no one is going to drop their Lp(a) by eating "healthy" monounsaturates or carbohydrate. From the fish oil study we can see that you won't get any joy from adding omega 3 fatty acids either. I've not seen the effect of omega 6s on Lp(a), but I'd guess they're probably as bad as carbohydrate.

As I see it Lp(a) is a very interesting lipid. I think it's hard to get much information from a single measurement in isolation, but changes in Lp(a) probably give you marks out of 10 for your changes in food choices. "Healthy" oils and carbohydrate score you zero. These are likely to damage your vascular system as judged by your liver's increased output of Lp(a). A surrogate for vascular damage would be the increasing blood pressure with age seen in the vegetarian Bantu, probably related to their 82% carbohydrate diet, and so they will need more Lp(a). They get it.

Down at 70% carbs the fish eating Bantu cope well and don't have degenerating arteries to raise their blood pressure, so they don't need so much Lp(a). They don't make it.

I'd predict that substituting beef dripping for both carbohydrate and olive oil would give you the lowest Lp(a) concentration within your genetic window.

Peter

PCOS and LC; is pregnancy a side effect?

This review dropped out of Pubcrawler today. How to get pregnant if you have PCOS.

"Fat should be restricted to < or =30% of total calories with a low proportion of saturated fat"

Of course it must, what else would you expect? Now here's the real giggle:

"High intake of low GI carbohydrate contributes to dyslipidaemia and weight gain and also stimulates hunger and carbohydrate craving"

I'm sure it does, but who would have expected the low fat brigade to realise this? I can't get the full text to see if this is a typo (it MUST be!), but if not, you can't eat fat and you can't eat low GI carbs. Sounds like sugar on your veggie burger is all that's left! The abstract gives no indication of how likely you are to conceive if you follow this advice. I don't think I'd trust it as a form of contraception but...

Of course you could always try living within the limits of your insulin resistance, but (gasp) you might have to eat >30% of calories from fat. This was a pilot study. Only five of the eleven women completed the 24 weeks on the diet. Which diet?

"They were instructed to limit their carbohydrate intake to 20 grams or less per day for 24 weeks"

Result?

"Two women [out of five] became pregnant despite previous infertility problems"

For anyone who might not want to get pregnant, you do have to do something more than eat LC for pregnancy to happen... and be female!

Peter

Lipoprotein(a), a prickly subject

Convergent evolution is a fascinating subject. Lipoprotein(a) has been independently evolved at least twice, not only to produce a remarkably similar (but not identical) molecule each time, but on both occasions it has been by a modification of the same gene, that for plasminogen. The two groups with well characterised Lp(a) are of course old world primates (including man) and the hedgehog. You thought the non primate was the guinea pig? Well, I've not been able to find any replication of Pauling and Rath's work with lipoprotein(a) in guinea pigs and the people who did the work with hedgehogs have looked for the apoprotein(a) gene in guinea pigs, pretty thoroughly... and without success.

What is lipoprotein(a)? It's perhaps best described as a super LDL. Just imagine taking a lethal LDL particle and wrapping it up in a second protein, apo(a), which is not only specifically designed to bind the whole lipid particle to the fibrin present in a blood clot, but which also inhibits clot dissolution. On top of that (could it get worse?) apo(a) is heavily and specifically glycosylated with a sticky sugar coating which will bind to the arterial wall. Hmmmm, if you wanted to clog an artery with lipid, this has got to be your glue!

A quick trip to St Tiggywinkles Hedgehog Hospital would be expected to reveal cages of recuperating hedgehogs, victims of strokes, aortic aneurisms, heart attacks, peripheral vascular disease, all of the problems associated with elevated Lp(a) in humans. In truth my guess is that most of them (the hedgepigs) will actually be victims of road traffic accidents, lung worm infection (a killer in hedgehogs) and late summer birthed toddlers who won't overwinter successfully in the wild.

Perhaps Lp(a) in hedgehogs is different to Lp(a) in humans. It has certain structural differences, but it still acts in as an inhibitor of clot dissolution in models based on human tissue. The fact that it doesn't seem to cause vascular problems in hedgehogs is all the more surprising when you realise that it is THE bulk lipid transport particle in hedgehogs!

The other very strange thing about Lp(a) is that it tends to be rather good for you if you (as a human) make old bones:

"lipoprotein(a) elevation in centenarians, in the absence of other coronary artery disease risk factors, appears as a positive survival factor"

It's worth noting that many of the risk factors for heart disease are turned on their head anyway in the elderly, once you look at all cause mortality. If you are over 65 years old, white or African-American then better think twice about popping that statin! You might end up in that lowest quartile of LDL cholesterol, maybe down at 60mg/dl:

"hispanics had the best overall survival, followed by African-Americans and Whites. Whites and African-Americans in the lowest quartiles of total cholesterol, non-HDL cholesterol and low-density lipoprotein cholesterol (LDL cholesterol) were approximately twice as likely to die as those in the highest quartile"

Just to simplify, low LDL cholesterol=death. That got missed out of the conclusion line! For hispanics, all lipids were irrelevant once you cracked 65 years of age, ie high LDL is not protective in elderly hispanics, nor is it a problem. Of course this is only New York, things may be different in other places. Maybe.

Well, that got me side tracked. Back track with Lp(a) next post.

Peter