AGE RAGE and ALE: small dense Krauss

While I was looking through some of the references cited by Krauss in his discussion paper about the roll of omega 3 fatty acids in the lowering of triglycerides, I came across this paper from 1999 on the effects of high and low fat diets on LDL subclasses. I read the abstract, re read it and read it again, scratching my head. Then I slogged through the whole paper. I just couldn't make out whether Krauss considered saturated fats to produce atherogenic changes in plasma lipids or not. After reading the paper I still couldn't decide what his conclusions were! Here are some quotes from the discussion:

"Change in dietary saturated fat was associated positively with mass of larger LDL particles and with peak LDL particle diameter and LDL flotation rate. These results suggest, therefore, that feeding saturated fat is associated with increased mass of larger LDL"

I think this means that saturated fats make "good" bad cholesterol. What do you think? What do you think Krauss thinks? Can you tell?

"In the present study, correlation analyses revealed significant positive relations of change in intake of the long-chain saturated fatty acids myristic and palmitic acids with change in plasma concentrations of large LDL particles. These findings are consistent with studies showing that, of the long-chain saturated fatty acids, myristic and palmitic are the most hypercholesterolemic"

Gasp, saturated fats are hypercholesterolaemic. Good or bad? Surely hypercholesterolaemis is bad? Keys said so. But large LDLs... atherogenic or benign????

"In summary, the present study showed that changes in dietary saturated fat are associated with changes in LDL subclasses in healthy men. An increase in saturated fat, and in particular, myristic acid, was associated with increases in larger LDL particles (and decreases in smaller LDL particles [did you spot this inset???? It matters]). LDL particle diameter and peak flotation rate were also positively associated with saturated fat, indicating shifts in LDL-particle distribution toward larger, cholesterol-enriched LDL"

Now, would you eat something which produced "cholesterol enriched" particles?

"Although there is a possibility that a subset of large LDL particles may be atherogenic (46), earlier results (37) point to a differential benefit of low-saturated-fat diets on LDL concentrations in individuals who have an atherogenic lipoprotein profile denoted by a predominance of small LDL particles"

What on earth does "a differential benefit of low-saturated-fat diets" mean? Your guess is as good as mine on that one. Answers on a postcard to Hyperlipid.

From the results, from whence it didn't seem to make it to the discussion, except in that little inset in brackets I highlighted:

"During the high-fat diet, saturated fat was correlated negatively with mass of smaller LDL particles"

What does this mean? Isn't that good? Does this mean the small dense LDLs are less dense?

As far as I can see, saturated fats improve every lipid marker they looked at BUT just look at this comment, again from the discussion:

"An increase in dietary saturated fat has been associated with the progression of CAD independent of LDL-cholesterol concentrations (56), and in cross-cultural studies, higher intakes of dietary saturated fat are associated with higher prevalence rates of CAD (57)"

Translates as: Never mind the lipid paramenetrs, saturated fats are BAD. Full stop. I think it's called nailing your colours to the mast.

BTW Ref 57 is Keys. Scraping the barrel a bit there!

So what did I do? I was beginning to doubt anything I'd read about lipid particle sub types, so I googled something along the lines of "LDL particle size CAD" or the like.

This was the first hit. Really, no kidding.

It's clear cut, cutting edge science from 1994:

"The lowest quintile--those with the smallest and most dense LDL particles--had more than three times the risk of heart attack as the quintile with the largest LDL particles"

Classic quote from: Ronald M Krauss, circa 1994.

Hmmmmmmmmm

Peter

Familial Hypercholesterolaemia and glucose

Just as an aside from hepatic lipids. This study is about heart disease within a group of people with heterozygous FH. The full text doesn't say much more than the abstract. Here are the two punch lines:


"The combination of DM [diabetes mellitus] or IGT [impaired glucose tolerance] with FH was associated with a further increase in the prevalence of CAD"

and

"total cholesterol levels were not significantly different [ie between normal, IGT or DM affected people with FH]"

The basic conclusion I get from the study is that if you take a group of statin naive FH "victims", it's not the variation of LDL cholesterol level in their bloodstream which determines CV disease, it's the degree of glucose dysregulation which seems to matter within the group.

Now what I want to know is if a heterozygous FH person maintained chronic and rigid normoglycaemic, 24/7 and so kept their blood glucose always below, say 5.0mmol/l, would they have ANY CVD above that of a non FH person under the same circumstances. Especially if they were omega 6 fatty acid restricted....

Mutations of the gene for the LDL receptor seem to be common and to come in an enormous number of flavours. If it was so very important to have two fully functional copies of the gene I would expect it to be much more highly conserved.

Peter

AGE RAGE and ALE: VLDL degradation and Fish Oil

OK, this is the direct link to figure 1 of Krauss' commentary paper. I just want to run through what seems to be happening and some of the consequences. Best to have the picture open alongside Hyperlipid.

Top left is the nucleus, then there's the stack of endoplasmic reticulum, then a newly synthesised lipid particle stuck on the outer surface of the ER. There is an interesting initial particle labelled I receiving "lipids" (another post there) which goes on to become that unlabelled particle on the outer surface of the ER (call it a nascent lipoprotein). The nascent lipoprotein has two arrows leading away from it representing two metabolic options. The upper arrow goes to a particle labeled III. On this pathway the particle receives saturated fatty acids which, at step V, stop it being destroyed. Destruction is termed PERPP, and the line from PERPP has a flat end meaning its blocked, and the legend "+SFAs" is shown as doing the blocking (by the little curved arrow). Got it? This SFA loaded particle is exported as an IDL (bad) or a large LDL (good). Luckily the IDL appears, on this diagram, to convert to the large form of LDL. But IDL may only be bad if secreted post prandially, I don't know, life is so complex in the ad hoc world of the lipid hypothesis!


Summary so far: Basic particle plus SFA gives the "good" version of "bad" cholesterol. Don't you just love these terms.


Now go back to that nascent lipoprotein and follow the alternative pathway shown by the downwards arrow. This leads to particle labeled IV, having accepted a lipid droplet via the curved arrow. Remember the lipid droplet. It might matter later. Anyway, there is then a dashed arrow showing possible secretion of this particle. If secreted it becomes a large VLDL particle.

While large LDL particles are good guys, large VLDLs are not. In fact they are the precursor to the evil incarnate particle, the small dense LDL. Like Darth Vader, only without the pre death conversion to the good side. Secrete and die.

Fish oils to the rescue! There is an arrow from the PERPP "destructaparticle" system pointing straight to this evil particle, joined by a little "n-3 PUFA-ox" which destroys the evil large VLDL before it ever gets secreted. Less of the large VLDL means less of the small dense LDL. More joy on blood results. Not only do triglycerides drop, it's the evil fraction of triglycerides which drop.


To summarise this pathway: Basic particle plus lipid droplet gives you bad VLDLs and small dense LDLs, unless aborted by omega 3 lipoxidation product (malondialdehyde is claimed but I'll get on to signaling molecules eventually).


All of that is pretty straight forward but it doesn't give us any insight in to anything except how to improve lab numbers.

Here are the nitty gritty questions.

1. Where did the SFAs come from? This is easy. Just follow Krauss' refs and you will find it's diet. Another post there needs writing.

2. Where did the lipid droplet come from? Well, lipid droplets in the liver vary from normal physiological amounts through to hepatic lipidosis. Hepatic lipidosis is a routine feature of the metabolic syndrome. We know that fructose is converted to lipid as rapidly as possible in the liver. We know that insulin inhibits the release of all VLDLs from the liver. Combining fructose with a glucose source (to raise insulin) seems a good way to generate hepatic lipid and block it's release. The bigger the dose and particularly the more continuous the ingestion, the more lipid droplets are likely to form. Sucrose or HFCS would do the job nicely. So might alcohol. Alcohol is interesting. Low doses improve insulin sensitivity and high doses do the opposite. The histpathology of non alcoholic hepatic steatosis is indistinguishable from alcoholic steatosis. They are the same condition. Keeping those lipid droplets in your liver seems a good way to get hepatic lipidosis and subsequent cirrhosis.

3. Where are the lipid droplets going? Well, if you dose up on fish oils the answer is nowhere! Lipid droplets should be off-loaded as small dense LDL precursor particles, the large VLDLs. You're not going to release them if you're on high dose fish oils! So you are trading the drop in "bad" LDLs for a rise in hepatic lipidosis. Are you going to mangle your liver to make Krauss happy? Yes?

Now let's go back and look at the high dose fish oil study from back in 1991.



Here are the triglyceride effects of 30ml fish oil a day for three weeks. Without vitamin E some omega 3s still get to the liver and trigs (probably large VLDLs in this case) drop from 2.6 to 2.0mg/dl. Modest and not statistically significant. Have a wash out period and do it again, but this time preserve the omega 3s with vitamin E. The drop is 48% this time, p<0.01, enough to warm the cockles of a cardiologist's heart.

Remember, these absent triglycerides should have contained lipid droplets which the liver wants rid of. I find it fascinating to see that, in the post washout/pre omega 3+vitamin E session, that the trigs were up at 3.4mg/dl, quite a bit higher than the 2.6 at the start of the study. Is this the liver off loading lipid droplets retained during the first section of the study? With trigs down at 1.8mg/dl by the end of the high dose vitamin E section, how much hepatic steatosis is going on?

Now look at this table, especially insulin and glucose. You'll have to click to enlarge.



All of these FBG values are scarily high, so these volunteers are on the edge of diabetes. What happens when you load up on fish oils? Insulin: No significant change at any time. FBG; both fish oil sessions show increased FBG! For low dose vitamin E section the change had p<0.05, for the vitamin E protected phase it had p<0.001.

That smells of insulin resistance to me and hepatic lipid overload is the easiest explanation.

Aha! So the Greenland eskimo, who refuse to die of cancer on 15g/d of EPA+DHA, must all have been dropping like flies from hepatic cirrhosis. Or type 2 diabetes. Apparently not. This dose of fish oil appears to be fine, just so long as you are not making lipid droplets in the first place. That means no sugar and no excessive alcohol. Remember modest dose alcohol improves insulin sensitivity, so zero alcohol is not needed. The Greenland eskimo were VERY low carb.

So where does that leave fish oil supplements? I think if you have a problem with alcohol they are very bad news and you should be absolutely minimising all forms of PUFA, unless you really want cirrhosis. If you are eating to the ADA or AHA sucrose ladened guidelines and already have "mysterious" raised liver enzymes, you will make an already appalling job worse.

If you are LC and low PUFA in the first place, or even just eating a diet which doesn't generate hepatic lipidosis (minimal sucrose), I think there are advantages to modest dose fish oils for long term changes in insulin sensitivity (another post needed). Dropping your triglycerides in the short term is not one of them, unless you are in to treating numbers, in which case; come back torcetrapib, all is forgiven!

Peter

PS Let's just clarify: There is no "good" or "bad" bad cholesterol. You can fuel your metabolism with saturated fat, and the "good" bad cholesterol goes up as a marker. It's the saturated fat which is really good. Or you fuel your metabolism on sucrose, which raises "bad" bad cholesterol. Stuff the cholesterol. It's a marker you are being evil to your metabolism by eating sucrose, which is what does the damage.

Conditioning Research on bad carbs

Just a 10 second post:

Chris over at Conditioning Research just emailed this link to me. You're all reading Conditioning Research I hope. There'll be a full post over there on it some time soon.

Enjoy.

Peter

OK, now back to the incredible publications from Krauss. He's really getting in the way of signalling molecules for vascular disease.

Rheumatoid arthritis and fasting

Many moons ago (it seems) Bloggeier sent me a pdf of a paper in which a group of researchers made a serious attempt to look at the roll of food allergies in rheumatoid arthritis. They went deeper than simple food challenges, antibody counts and skin prick allergy testing. They looked in to the small intestine, I won't go in to how, and found that people with rheumatoid arthritis have food allergies. Lots of food allergies. Never mind the levels of antibody in the blood, local reaction in the gut picked up far more allergies than it seems fair for anyone to have. Food seems to be important in RA.

I've had this paper lying around for ages but pretty well ignored it due to its vegan/vegetarian stance. I really shouldn't let my biases stop me thinking about interesting stuff. Before I get on to the main jist of this post I'd just like to point out that this group also looked at antibody counts against Proteus mirabilis during their intervention diet and the antibody counts dropped in some subjects. This is important if you have followed Ebringer's work on bacterial mimicry as a trigger for auto immune diseases. There is a protein sequence on the surface of P. mirabilis that is remarkably similar to certain sequences on the HLA molecules associated with RA in humans. The diet changes, used over a year, ONLY helped those people in whom the antibody titre to P. mirabilis dropped. Look at it this way, you could eat a totally allergy free diet, say a cocktail of amino acids and glucose, and P. mirabilis could assemble those amino acids in to an allergenic protein.... Neat hey? RA is associated with antibodies to P. mirabilis and this holds true in various countries around Europe. I'll come back to this later.

Back to the study. They starved their subjects for the first 7 days. As far as I can see they used a water fast. It produced dramatic improvement.

The same group looked at ketosis without calorie deficit and it didn't work, though I don't know what components were used in the less than 40g of carbs per day which were allowed. This may be important, especially if gluten was included in the carbs. In a separate study they looked at various cells in the immune system after a 7 day fast and found that CD4+ lymphocytes, the ones I chatted about here, went sleepeebyes after a fast.

What's happening during a fast? Well, you're not getting any food! So for food allergens it's an absolute, total and complete elimination diet. Then your GUT BACTERIA aren't getting any food either. In fact, your gut bacterial count is likely top drop like a stone when you fast. If you are remotely lucky your P. mirabilis count will also drop and your CD4+ cells might start ignoring both proteus and your HLA DR1 and DR4 molecules.

So fasting is good news. Personally I've only ever played with fasting for 48 hours, in a spirit of companionship with a friend who was fasting for non specific arthritis. We both did 48 hours and, because we were both already in full ketosis, it was easy. That included cooking carbs for my children over that 48 hours. I don't know how easy it would be to extend this to 7 days, and my willpower might be markedly influenced by the size of the RA gorilla sitting on my shoulders. It worked for the non specific arthritis BTW (which has never been worked up and could be rheumatoid).

But no one can fast for ever and expect to stay healthy.

Assuming the improvement occurred, as it really should, anecdote and Kjeldsen-Kragh's work supported, how should you break the fast?

I'd suggest with a single food substance of absolutely no allergenic potential and of no use to P. mirabilis. Beef dripping comes to mind. I discussed long chain fatty acids and starving your gut bacteria in the fiaf posts. The colon, home to P. mirabilis, is anaerobic. Nothing can be done here with a fatty acid. Fatty acids only do oxidation, never fermentation. Aesthetically I guess clarified butter might taste better but watch the casein and lactose. Next would be to add some protein. Not much, say 40 grams as a maximum. You want it all absorbed and none to get through to the colon. Egg yolks first, whole eggs next. If you are still ok you are set up. You can live on eggs and clarified butter. How big is the gorilla?

After that it's a matter of introductions and seeing what happens. In general animal protein won't make it to the colon, cereal protein will always and pulse protein is not worth the risk.

Unless you want to stay in frank raging ketosis some carbs are going to be needed. That's a tricky one. Obviously any fiber will feed colonic bacteria. No fiber. Simple sugars with absorption slowed by a high fat meal might do the job. Optimal icecream comes to mind. A peeled potato might do a reasonable job too, as chips if you like.

It feels a bit odd sitting here musing about a disease as nasty as RA when I don't have it. Having read a little about RA, it seems that musing without the disease is infinitely preferable to musing with the disease.

Peter

AGE RAGE and ALE: VLDL degradation and Krauss

When you are waiting for a paradigm shift, you look at the old school dinosaurs with incredulity. One such dinosaur is Krauss. Who is Krauss? Well, you know that time worn phase of Churchill's:


"Man will occasionally stumble over the truth, but most of the time he will pick himself up and continue on"


That man is not really Krauss. Krauss is more like a little kitten, just beginning to use a litter tray and making such a mess trying to bury the truth that it doesn't manage to cover it effectively... The smell is pretty much a give away and someone has to empty the litter tray anyway.

This is Krauss burying the unsavoury truth about low carbohydrate diets as best he can, taken from the abstract.


"Moreover, beneficial lipid changes resulting from a reduced carbohydrate intake were not significant after weight loss"


The kitten's litter tray had to be emptied by Feinman and Volek, who know the truth when they smell it. You can read the full text here but this is the summary:


"Although some effort is required to disentangle the data and interpretation, the recent publication from Krauss et al. [1] should be recognized as a breakthrough. Their findings, presented in Figures 1-5, make it clear that the salutary effects of CR [carbohydrate restriction] on dyslipidemia do not require weight loss, a benefit that is not a feature of strategies based on fat reduction. As such, Krauss et al. [1] provides one of the strongest arguments to date for CR as a fundamental approach to diet, especially for treating atherogenic dyslipidemia"


Don't you just love that first phrase! So that's Krauss, just an introduction. Bearing in mind that all of these people live within the lipid hypothesis.

Why focus on Krauss? Well he wrote this commentary on the paper teasing apart the mechanism of the fasting triglyceride lowering effect of fish oils.


Here is the title of his commentary:


Hold the antioxidants and improve plasma lipids?


It never ceases to amaze me how someone who knows so much about the detail of VLDL production can be so stupid. The first thing is that back in the 1990s the original fish oil work showed that adding vitamin E actually increased the hypolipidaemic effect of fish oils. Maybe Krauss doesn't read old stuff from the wilds of scandinavia. Giving vitamin E by mouth is not remotely the same as dropping some vitamin E or desferroxamine on to cultured liver cells in a petri dish. Ancient practical work makes that crystal clear.

The other bizarre lack of perception is that it is BECAUSE saturated fats are not prone to peroxidation that they don't drop VLDL counts. He actually says this. For goodness sake. The man knows so much. He almost understands, but never quite. Saturated fats don't drop VLDLs, specifically because there is no need for the body to panic about saturated fat based VLDLs entering the blood stream. They don't peroxidise. Maybe Krauss has never heard of Kitava, unless he sees it as a potential market for mass stain medication...Sugar coated VLDLs may be another matter, whatever their lipid content.

And then of course you have to ask whether lowering triglycerides with fish oil does any good at all. The answer to that seems to depend on which study you cite. In some they help, in some they don't. But Krauss can't see beyond a lab number.

Peter

Physiological insulin resistance: Clarification of FBG

This is a cheat "copy-paste" entry trying to clarify the difference between a fasting blood glucose of 5.5mmol/l in an insulin resistant SAD eater and a FBG of 5.5mmol/l in a LC very high fat eater running their metabolism on free fatty acids. The original exchange is in the comments section of this post. Here we go:


Peter,

I've read again you post "Helicobacter and glucose" and yes, the Hisayama study suggested an increase in Fasting Plasma Glucose (FPG) to be a risk factor for gastric cancer (Helicobacter Pylori positive).

A modest increase in the FPG, but not a "modest increase" in the incidence of gastric cancer.

7.2 gastric cancers per 1000 person/years in the high FPG (> 5.8 mmol/l) vs. 2.2 per 1000 person/years in the low FPG (< 5.3 nmol/l) in men.

In women 2.5 per 1000 person/year in the high FPG vs. 0.8 per 1000 person/years in the low FPG.

More than three times higher incidence?!?

Good if you have a low FPG. Ok, but do you have a low FBG if you're on a LC diet?

I don't want to spoil the party to many LCers here, but I read on this Blog that "LC eating rapidly induces insulin resistance" and that "elevated non esterified fatty acids induce physiological insulin resistance and a higher than expected FBG level.".

Uhmm... Bad news for LCers who carry their "beast"?

p.s. - Peter, you said: "This carbohydrate derivative may be more important than sugar for H pylori gastritis, though perhaps NOT IN THE GASTRIC CARCINOGENESIS ASPECT".
I don't understand. Why "not in the carcinogenesis aspect"? Could you explain?

Thanks again.

Marco




Reply

OK, here we go.

A LC eater has a FBG of 5.5mmol/l, technically pre diabetic, but blood insulin is 3.5 IU/ml. This is VERY low. Glucose is in very short supply but blood glucose is maintained by physiological insulin resistance, ie the muscles are full of triglycerides assembled from free fatty acids (NEFA) from lipolysis. The LC eater has breakfast, with enough protein from his eggs or particularly casein from his yoghurt to raise insulin from 3.5 IU/ml to 5.0IU/ml. This inhibits lipolysis enough to reduce NEFA in the bloodstream, intramuscular triglycerides fall and muscle insulin sensitivity returns. There's minimal glucose coming from the gut and so plasma glucose drops to between 4.0 and 5.0mmol/l, probably nearer 4.0mmol/l. It fluctuates between 4.0 and 5.0 after and between each LC meal. In the early hours of the morning there is a growth hormone surge and NEFA from lipolysis peak early morning to give insulin resistant muscles and an elevated FBG.

MEAN glucose over 24h will be in 4 point somethingish, HbA1c will be between 4 and 5%. INSULIN will probably average out around 5-10 IU/ml, averaged out over 24h.

A SAD eater has a FBG of 5.5, prediabetic, because he is prediabetic. His muscles and liver are permanently and pathologically insulin resistant. His pancreas is cranking out 50 IU/ml of insulin to just keep that FBG in the 5.5mmol/l range. He eats bagels, jam and a large mocha for breakfast and his blood glucose hits 15mmol/l. His pancreas ups the insulin output as high as it can get it, perhaps to 150 IU/ml and just manages to to get blood glucose back down to 5.5mmol/l before lunch. Lunch is pasta and the cycle repeats.

Mean glucose over 24 hours will be between 7 and 12mmol/l. HbA1c might just hover around 7%. INSULIN will average 100 IU/ml over the 24 hours.

Helicobacter lives on the hydrogen from flatus, so is present in far too high a number for health in our flatulent carb eater and chronically irritates the gastric lining. Insulin-like Growth Factor-1 (IGF-1) receptor is over expressed and converts disorderly proliferation of gastric mucosa in to gastric cancer. See here.

Insulin acts on IGF-1 receptor to achieve this transformation.

A high carb eater with FBG of 5.5mmol/l implies chronic hyperinsulinaemia, 24/7 and is looking for something to die from.

A LC, very high fat eater with a FBG of 5.5mmol/l implies they haven't had breakfast yet. They are not going to be hyperinsulinaemic at any stage. Unless they eat a bagel instead of their normal bacon and eggs that is. If they do this their blood glucose will hit 10mmol/l before insulin can shut down lipolysis and get the muscle accepting glucose.

It's NOT the FBG of 5.5mmol/l that matters. It's what that means about insulinaemia if you are eating a rice based diet. It's bad. The Kitavans eat a sweet potato based diet, are not insulin resistant and have FBG of 3 point something.

Does that clarify matters? Did I screw up in terms of clarity in the posts on physiological insulin resistance and H. pylori? If so, I'd better get a new post up!

Thinking in terms of FBG = 5.5mmol/l = huge cancer risk is thinking like a cardiologist. Don't go there. Think why, think holistically.

Peter

AGE RAGE and ALE: VLDL degradation

Malonyldialdehyde (MDA) is a small molecule formed by the random oxidation of a polyunsaturated fatty acid. The exact chemistry seems quite complex but needs, as an absolute minimum, two double bonds in the fat molecule, three omega numbers apart. But a feature of organic chemistry makes the free radical attack much more successful if there is a third double bond, located three omega numbers away from that bare minimum pair. So linoleic acid, that good old omega 6 fatty acid, can form some MDA because it has a double bond at the omega 9 position and at the omega 6 position, but it struggles to do it. Alpha linolenic acid, with its third double bond down at the omega 3 position, really allows MDA production to get going. That's chemistry. There's the briefest of summaries here.

So omega three fatty acid supplementation will increase MDA production. Adding vitamin E will largely eliminate this effect in the short term and the theory is that the vitamin E protects the omega 3 fatty acids in the chylomicrons en route to the liver. So more undamaged PUFA reach the liver, which has a greater impact on fasting triglycerides (VLDLs). This much comes from this paper.

But what I found really interesting is what happens within the liver itself. This paper comes up with some answers. The VLDL particles are manufactured as per normal, but if there is enough lipid peroxidation, the particle is degraded and never released. The liver appears to use iron to generate MDA from PUFA as a decider as to whether to release the VLDL particle or degrade it. The more MDA generated within the liver cell, the lower the plasma VLDL levels drop.

Why should that be? The liver makes a VLDL particle, tests how stable it is in terms of lipid peroxidation, and refuses to release any VLDLs deemed too unstable. This peroxidation is what omega 3 fats do, far better than omega 6 fats do it. The message I get from this is that our liver does not want lipid peroxidation prone VLDLs being released in to the circulation. So, if we accept that VLDLs from carbohydrate are stable (palmitic acid based) lots can be safely released. Render then unstable with fish oil and they, and their components, stay in the liver. Is this good or bad?

Well, taking fish oil makes your fasting triglyceride value look like it belongs to a LC eating person, even though you may not be a LC eating person. Does your cardiac risk belong to the the LC person or the mixed diet person? Draw the comparison with torcetrapib. Fantastic lipids, increased death risk. Now look at atrovasatain, quite "good" lipids and permission to trade in your heart attack death certificate for a cancer one, with the same date. Then look at LC eating and wonder about the blank cause of death and date.

Where do fish oils fit in to this spectrum? Dropping your triglycerides is treating a number. Fine for cardiologists. Eating like a Greenland eskimo requires strict LC in addition to 15g/d of EPA+DHA. This is a double triglyceride lowering approach but one which, in addition, dramatically minimises the glycation of apoB containing lipoproteins too. Is it the LC, the low trigs or the changes in tissue lipids which helps reduce CV risk? The mixed diet eating person with fish oil induced LC style triglycerides may well be munching lots of fruit as healthy low fat snacks to stave off hunger pangs between mixed meals. VLDL gycation?

If you have already lived your way to a heart attack, just "doing" EPA+DHA at 3.5g/d is as effective as 4g/d of corn oil for prevention of that second heart attack within the next 12 months! It's okay, unless you are one of the 25% of heart attack victims in each group re infarcting. Of course the fasting triglycerides were MUCH lower in the omega 3 group...

So do I think fish oils are useless? Not at all, but I think that using them as a tool to manipulate a number is, well, not a good idea. I do know that low dose EPA+DHA seems to benefit me, at around 1g/day. Whether this is "treating" the amount of omega 6 fatty acids I get from chicken and pork, I wouldn't like to say. But there's a lot more to omega 3 supplements than meets the eye.

What does seem lacking to me is convincing evidence of toxicity. The Greenlanders (back in the 1950s) were at low CV risk on high omega three intakes and I think it's reasonable to assume they were at the same low cancer risk as the Inuit described by Stefansson, see Stephan's post here. So I don't rate omega 3 as coming with the same toxicity as omega 6s.

There's another post on hepatic VLDL stability testing, but I'll call it a day on this rambling entry...

Peter

Helicobacter and hydrogen

This one just has to jump the queue of posts, it had me cracked up. Thanks to Marco for the abstract and press release, the full text doesn't say anything much you can't get from those two sources.

Here's the gist of it:

If you are eating to one of those complex carb high fiber diets beloved of Ornish and his ilk, your flatuses (flati?) may be room clearing, but you're probably healthier if you just drop them and run. Clamping tight to save embarrassment could seriously damage your health, as could eating the high fiber diet in the first place of course. The only significant source of hydrogen in your body is colonic fermentation of carbohydrate by bacteria.


Helicobacter is a harmless or potentially beneficial commensal in your stomach, unless you feed and feed and feed it with, guess what? Hydrogen. This carbohydrate derivative may be more important than sugar for H pylori gastritis, though perhaps not in the gastric carcinogenesis aspect. Looks like it might also be a preferred energy source for assorted serious nasties, here's the speculation from the press release:


"Though unstudied, it's possible that this hydrogen could serve as an energy source for pathogens in other areas of the body, including the lungs and internal organs.

Since the amount of hydrogen produced in the colon varies based on diet, and since the researchers have shown that H. pylori uses this hydrogen as an energy source, something as simple as a diet change could affect virulence and persistence of this and other pathogens"



I don't think it's practical to eliminate all fiber from your diet. The absolutely indigestible fiber from grains can go very easily as cereal avoidance is a major step towards health, but getting rid of all remaining vegetable fiber is more difficult. I suspect having some hydrogen in your blood stream is probably normal. I've heard in various places on the net that LC eaters do still produce some flatus (but it's usually odourless) so must be making some hydrogen and methane, but the amount is low. So too will be the molecular hydrogen in their gastric mucosa.

So be tolerant if a whole grain fiber derived room clearer gets you. It's there for health purposes. Better out than in.

Peter

Food: steak and kidney casserole

One pound diced beef, two pig's kidneys, one onion, one carrot, tin of tomatoes, few mushrooms, garlic, salt, pepper plus a little water to just cover. Simmer for three hours (I like my meat to melt in the mouth).

OK, spot the hidden mistake?

This is what I cooked and I only realised when I was turning it off to let it stand over night: There's NO BUTTER or DRIPPING in the pot!!!! I'm out of dripping at the moment so, as a matter of some urgency, I threw in the remains of a part used 250g block of butter. Probably about 100g. This stew will probably do three portions, might freeze some and take it to work. There is no way to cook eggs at work, so usually I have cream and chocolate for lunch but the occasional cold serving of casserole is nice. People seem shocked to see me eat "ordinary" food.

Hee hee. I always explain that the meat is for show, the fat is what I'm eating.

Peter

Food: Optimal ice cream

One pint of double cream, six egg yolks, about 10 drops of vanilla and sweetener to taste.

JK uses about 60g (100g to a litre) of sucrose. This is wayyyyyy too sweet for me, 20g is usually plenty. I also like it made with honey, about 20ml of liquid honey is fine. Sweetener users can adjust stevia/saccharin etc to taste. I just use some of my carbs to sweeten it.

Blend it up in a food processor and transfer to an ice cream maker. I can manage quite a lot of this before I hit fat overload and it's always tempting to push my fat tolerance limits with it... Just in a spirit of exploration of course!

Peter

Pork in green salsa and random dessert

Last night we made Optimal ice cream because, well, no reason. You need a reason to make ice cream????? Anyway, breakfast was a little informal today...



After that nutritious start we had some rubbish to finish off. Squiggs discovered the raspberry canes and though we expected the birds to get most of the berries this year (first crop) he beat them to it. Every morning. He likes raspberries so much that occasional shop bought ones are allowed. Though he only likes certain types...



Tonight's meal was belly pork in green salsa. Our own tomatillos, green peppers and chillis are all eatable at the moment, so the salsa was almost home made. The belly pork was prepared as for carnitas but then fried in the salsa sauce.


Salsa sauce: Tomatillos, green peppers, green chillis, garlic. Coarse blend, fry in butter, add the pre cooked belly pork and simmer for 20 minutes. Quantities are basically what you feel like! Just before serving add cream. Lots, just adjust your calories to your needs. Salt and pepper help.


We've never had tomatillos before this year, but the flavour is so good we can understand why the Mexican post docs we know (a) rave about them and (b) take whatever supply we can spare!



Even Squiggs was defeated by the left over ice cream so we used it this evening as a base for a few raspberries and poured hot chocolate sauce over it (melted 85% cocoa solids chocolate diluted with double cream). This dessert was totally, utterly and completely unnecessary. But yummy!

Low fat vegan anyone?

Peter.

OK, tomorrow's steak and kidney casserole is simmering and Nirvana is on the CD player. Time to make a start on omega 3s, Krauss and VLDLs. And a glass of wine.

AGE RAGE and ALE: low fat!

Just to finish on glycation before moving on to signaling molecules, I'd like to add to Dave Dixon's comments about meal timing and chylomicron peaks after the segragation post. Let's just have a quick think about a serious low fat diet, using real food, say as eaten on Kitava or by the non vegetarian Bantu. These people are up at 70% of calories from carbohydrate. They tend to have the typical elevated fasting triglycerides of carbohydrate based diets, but not the heart disease associated with similarly elevated triglycerides in Western populations. Fasting triglycerides are VLDL particles released from the liver to move carbohydrate derived lipid to adipose tissue or muscle. They may have some PUFA from chylomicrons which have been taken up by the liver. They're certainly not chylomicrons in healthy people.

What's happening on the glycation front here? Post prandially there will be a marked glycation hot spot in the portal vein. This is unavoidable on a high carbohydrate diet. Insulin will rise and insulin promptly inhibits the release of VLDL particles from the liver. Same principle as we went through in this post, using all night glucose bingeing to "treat" hypertiglyceridaemia.

So, post prandially there are minimal chylomicrons due to the low fat content of the diet and VLDL secretion is inhibited. This is a neat way of separating glycation after a carb load from contact with any apoB containing lipids. As glucose uptake tails off, insulin falls and the processed glucose beyond acute needs can be shipped out as VLDLs, primarily as saturated fat which won't generate lipid peroxides anyway.

So there is some scope for genuine low fat diets to avoid glycation problems. You can have your fasting VLDLs up at 3.0mmol/l, just so long as they are full of palmitic acid and don't have sugar all over their apoB100 tags. You'll barely have a chylomicron anywhere to be seen at any stage, so who cares about that apoB48 tag?

It's the three times daily mix of sugar and soy oil (with fridge raid at 3am) which sets the scene for vascular catastrophe. The apoB counts might be the same in Kitava as in the USA, but the sugar coating and rancid fatty acid contents on and in those apoB tagged particles may be very different.

Peter

AGE RAGE and ALE: fasting

Jan Kwasniewski hates fasting. I'm not so sure it's as simple as this, there are some aspects which might be beneficial.

I started thinking about fasting when Dr Davis put up this post.

I'd just like to put this in to the perspective of glycoxidation. Let's look at glucose and lipid metabolism under a fast. There is no glucose uptake from the gut. The portal vein is no longer a glycation hot spot, the systemic circulation has only basal glucose too. Arterial endothelial cells are not undergoing hyperglycaemia induced apoptosis. This minimises the need for foam cell formation as there is essentially no damage needing repair.

Chylomicrons are not being produced at all, the liver is depleted of carbohydrate and so puts out a minimum of VLDLs. However many VLDLs and subsequent LDLs are actually produced, they will not be exposed to aggressive glycation conditions. If the liver does continue to produce significant levels of VLDL, they will be based either on fats synthesised from residual glycogen stores or free fatty acids derived from adipose tissue. That is, mostly saturated with some monounsaturated. So VLDLs will be deficient in PUFA and not prone to glycoxidation. PUFA supply will be limited to hepatic stores and whatever is present in adipose tissue, ie not a lot.

Bulk lipid for energy supply will be derived from adipose tissue lipolysis and be (a) mostly saturated fatty acids and (b) in free fatty acid form. You cannot glycate free fatty acids without direct free radical attack. No amino group on a FFA to form that horrible Schiff base.

From the perspective of someone who regards arteriosclerosis as a repair process gone horribly wrong, fasting has a lot to offer in the short term, with death in the long term. LC high saturated fat diets mimic fasting in several ways: There's never a lot of glucose in the portal vein and the chylomicrons based on saturated fats are pretty well glycoxidation proof. Fat gets stored as adipose tissue after each meal and is released as free fatty acids on demand. Metabolism mostly runs on free fatty acids. The big difference is that there is no (premature!) death if the diet is sustained for more than a few months!

Peter

AGE RAGE and ALE: segregation

Both glucose and fructose are transported from the gut to the liver via the portal vein. I've never seen papers which have measured the concentration of either of these sugars in the portal vein, but the determinants must be rate of uptake from the gut, strongly influenced by dietary load, and splanchic blood flow, a high flow carrying the sugars at lower concentration per unit uptake. Ultimately this blood flow must carry the highest plasma glucose concentration and absolutely the highest plasma fructose concentration in the body, especially in the aftermath of drinking a giant Pepsi. Or maybe after a detox dose of Kiwi fruits.

Fatty acids come as mixtures. Even beef dripping carries a small load of PUFA. Nuts more so, seeds like those from Sunflowers much more so. Humans eat all of these in variable quantities. They are broken down by lipase, absorbed in to intestinal cells and reassembled in to triglycerides to be secreted as chylomicrons. Chylomicrons are the bulk transport system used to get lipid, including the PUFA, from the diet to the muscles, fat and the liver. A chylomicron is labled with a marker protein. It's a truncated form of that good old apoB100 used by the liver to mark the VLDLs destined to become LDL particles. The truncated protein is called apoB48. It starts life as an apoB100 but gets a socking great chunk cut off between transcription and particle assembly. It looses the LDL receptor interacting section but keeps the AGE triggered switch. No one seems to have looked at how glycation of chylomicrons acts in terms of receptor attachment to deliver lipid to muscles, or it's interaction with the "LDL-like" receptor which allows it to be recycled by the liver. I'll bet both actions get mangled by glycation. It does seem reasonable to assume that glycation allows chylomicrons to interact with RAGE, the receptor for glycated lipoproteins on mesothelial cells, in particular macrophages. These are the cells which make foam cells as part of atherosclerotic lesions.

This seems to be a feature of all apoB containing lipoproteins which have been glycoxidised. Obviously you would expect this to be a problem in the chronic hyperglycaemia of diabetes.

If your dietary carbohydrate intake stays within the capability of your liver to handle effectively, avoiding systemic hyperglycaemia, there is no need for foam cell formation. Avoiding chylomicron glycation under these physiologically normal circumstances, ie when you don't need foam cells, is likely to be beneficial. That's what happens.

The body actually puts chylomicrons in to the lymphatics which drain the gut, not in to the portal vein. They then pass down the thoracic duct and directly in to the venous circulation, avoiding the portal vein and its glycating environment. Mixing bulk lipids with bulk sugars gives bulk glycoxidation. Evolution has segregated them.

I'd always wondered why the digestive system was arranged this way. Now at least I have some idea.

Peter

When is a high fat diet not a high fat diet? Masai part 2

Many many thanks to Dave and Hege for the text of the paper. What does it say?

OK, they did a single 24h dietary recall and they ain't telling us anything about the results except for diet "type" predominant in each group. So they have discovered the Masai eat low carb high fat, the Bantu subsistence farmers eat high carb, low fat and urban Bantu probably eat junk. I simplify.

They also noticed the Masai walk a long way everyday and the urban Bantu don't. Cracking stuff this.

They took random bloods and found exactly what you would expect, deteriorating lipids from the "excellent" values from the high fat/LC Masai down to the "worst" lipids of the urban Bantu. If you believe the sort of lipids they're measuring are "good" or "bad" per se. They forgot to check HbA1c.

After that it's an ad hoc hypothesis that walking makes a lethal dose of saturated fat give you the "best" lipids in Africa. A bit like saying the French are protected from heart disease by all that red wine they drink.

The job of observational studies is to generate hypothesises. This one generates an ad hoc hypothesis to explain a non existing paradox. The well known effects of high fat low carb diets on blood lipids have been documented in the obesity and diabetes literature so many times now that you wonder why Mbalilaki has not been sacked on publication of this study for ignorance of the current intervention studies. Just pubmed Volek or Westman to catch a few.

How do you sum up this paper? Line one of their introduction:

"Despite overwhelming evidence for a link between intake of saturated fat and coronary heart disease... blah blah blah"

Translation: Haven't read the literature.

The Norwegian Centre for International University Co-operation and the Swedish Council for Working Life and Social Research funded her jaunt to Africa. I hope she enjoyed it as much as we did our walking safari in Kwazulu Natal in pre Squiggs days.

She wins hands down over Gibney.

This girl will go far.

Peter

In the Drankensbergs, nice hill walking.

When is a high fat diet not a high fat diet? Masai

Just a quick post to comment on this paper from a link emailed to me by Dave Lull.

It turns out that eating saturated fat is fine if you burn 2500kcal above basal metabolic requirements. Phew. That must be an awful lot of saturated fat being burned off to make it safe.

I only have the abstract of this paper, so can't get much of an idea of the size of the blinkers worn by the authors. They look pretty enormous from the here. In fact my window faces East and from Berkshire (far inland in southern England) I think I can see the tops of their blinkers way over there on the other side the North Sea (can't see any surf, must be flat, it is August).

If we go back to 1980 and another of my favourite idiots, we have Gibney's abstract here. He's now a major noise in Irish obesity promotion. He explains that it was the Masai's, and I quote:

"variable and generally low energy intakes"

that kept them healthy.

Now does 2500kcal over BMR count as a generally low intake? Why would variation in intake protect against IHD and the demon hypercholesterolaemia?

It's competition time. Who is the bigger idiot, Gibney or Mbalilaki? I know, I know, it's impossible to decide. You can stop trying now.

Equally difficult is to decide if Mbalilaki will do as well in influencing nutrition policy as Gibney seems to have done. Just pubmed him to see how well he has done for himself since 1980. They probably both know how to get on pretty well as dietitians. But as scientists? The biggest mistake I can see in the press release is to describe Mbalilaki et al as scientists.

Peter

PS if anyone has access to the full text of Mbalilaki's paper I'd be interested to see if she "forgot" to check sugar intake of the "high fat" urban Bantu. I would expect her to have skipped it and so to snatch the idiot's crown from Gibney by a gnat's whisker. Please don't let her disappoint me.

Playing with salt and water

While we're talking about the risks of low salt and high water intakes, this hit the news today: You want to try a "detox" diet?

Don't!

It's arguable whether a detox diet is more or less likely to precipitate a hyponatraemic crisis than either Ecstasy or psychogenic polydipsia (a psychosis). Never forget the massive press misinformation about Leah Betts. This is what really happened to her:

"Hyponatraemia is an uncommon complication of MDMA ingestion. Only a few cases have been reported. The death of Leah Betts achieved wide publicity in the popular press, and it became clear that fatal water intoxication can be precipitated by excessive water drinking in ecstasy users. Fifteen cases were identified between August 1994 and December 1995 by the National Poisons Information Service (London), with serum Na+ concentrations of <130 mmol litre–1. The clinical pattern was remarkably uniform, with initial vomiting and disturbed behaviour, followed by drowsiness and agitation and, in seven cases, epileptiform convulsions. Drowsiness, a mute state and disorientation were observed for up to 3 days (Hartung TK, Schofield E, Short AI, Parr MJA, Henry JA, unpublished)"

Detox time or too much water after taking E at a party? Neither is beneficial and both can be fatal. Play safely!

Peter

Update

Well, here I am briefly. Things have pretty much ground to a halt on Hyperlipid. What has happened is that my boss has broken his little finger, in to lots of little pieces (pushbiking is pretty dangerous!). The steel pin, support dressing and full time sling don't seem to be doing much good so he's off work for 6 weeks and I've gone from working one day a week to working full time. Then our other primary surgeon is on study leave for his surgery ticket and our full time internal medicine slanted vet is off sick... So this is the first time I've logged on to do anything other than check work emails.

I'm just finishing week four out of six... By the time I get to answer comments people will probably will probably have forgotten they posted them! Still, it pays off a chunk of the mortgage.

So apologies for the lack of activity and replies.

BTW the off sick vet is really interesting. Anaemia to the point of hyperventilation after climbing the stairs and recurrent major infections. Ah, Weight Watchers and wholemeal bread! People love these wacky diets, play at your own risk!

Peter

AGE, RAGE and ALE; oxLDL

This is the abstract from a discussion paper, it's not in pubmed for some reason but I have the pdf lying around my hard drive. It's just an opinion piece but quite well referenced.


Oxidized Low-Density Lipoproteins and Atherosclerosis
S. Ylä-Herttuala1,2, T. Pakkanen1, P. Leppänen1, T. Häkkinen1

Basic research has provided strong evidence that LDL oxidation plays an important role in atherogenesis. Several mechanisms have been identified which can lead to LDL oxidation in vivo. Clinical and epidemiological studies have provided circumstancial evidence that oxidized LDL may be involved in the progression of atherosclerotic vascular disease. Better understanding of mechanisms that lead to LDL oxidation or protect LDL against oxidative damages shouldhelp the development of new strategies for the prevention of cardiovascular diseases. J Clin Basic Cardiol 2000; 3: 87–8.

Just look at this table of comparison between LDL lipoproteins and oxLDL lipoproteins.

If you are measuring the size and numbers of your LDL particles, you might also want to look at their oxidation state too. Perhaps it matters more? Are the small dense LDL particles so associated with atherosclerosis also the most AGEd and ALEd?

Here's the table, click to enlarge



If you had the choice between lots of minimally oxidised LDL and a small amount of highly oxidised LDL which would you choose? Low fat diet anyone, or maybe just more sugar on your soya oil fried donut? Mmmmmmm, yumeeee.

Peter

AGE, RAGE and ALE: The ALE of LDL

I looked at glucose reacting with amino groups of proteins in the last post on the formation of AGEs. Apart from protein, cell membranes and the surface membrane of lipoprotein particles contain lipids. These form the classical lipid bilayer of biological membranes. The lipids of the bilayer come in a mix of saturates, mono unsaturates and PUFA. The exact mix of saturates to monounsaturates is largely determined by stearoyl-CoA desaturase, the enzyme which puts double bonds in to saturated fats to give monounsaturates.

Interestingly this enzyme appears to be under the control of insulin and activity goes up in insulin resistant states. That's another subject.

The PUFA composition is largely diet determined.

While boiling sugar with butter gives toffee, the situation in vivo seems more complicated and the initial generation of damaged lipids (ALEs, advanced lipoxidation end products) seems to involve an amino group. These are freely available from molecules like phosphatidylserine in cell (or lipoprotein) membranes. They provide the nitrogen for the formation of that horrible unstable Schiff base and its subsequent decay. The decaying base triggers oxidation/reduction reactions which hit double bonds in surrounding fatty acids, leading to ALE formation.

There's a good summary in this paper.

I just loved the chemistry in the introduction with stuff about electron spins, the pi antibonding level and other stuff that sounds really fancy. I think it means that molecular oxygen leaves PUFA alone without a transition metal or a pre formed free radical to get things going.

Until you add glucose that is.

Now I have two complaints about this paper. First is that some of the glucose concentrations used would make the ADA blanche. Not even an ADA diabetologist would suggest a blood glucose of 500mM (ie 500mmol/l). The 200mM used to oxidise the LDL particles would have had an intact human being in hyperglycaemic coma too. This is aggressive corner cutting on a time basis I guess. They did do some work down at 5mM.

Second is that they thanked Scott Grundy for helpful discussions. If you don't know who Scott Grundy is then you haven't read enough about the cholesterol con. Big black mark to the paper.

Third is that they used oleic acid for a lot of the work. They do comment that PUFA are 10-30 fold more oxidisable than oleic acid but PUFA didn't fit their protocols. They also forgot to mention that saturated fats just won't randomly oxidise at all in biological systems. No double bonds. But who would expect that sort of information from a cardiologist?

Did I say two complaints? Fourth...

So this paper is a bit rocky.

But what I do like about it is that it appears to show that glycation is what converts an LDL cholesterol particle in to an oxLDL particle. They're not the same. This is compatible with the recent study using low fat diets to (accidentally) raise the levels of oxLDL in intact humans.

Seems like sugar is what oxidises the PUFA in LDL to give oxLDL.

Avoid sugar, PUFA or both. Seems sensible to me.

Peter

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