The rise in triglycerides after an OFTT is actually chylomicrons (I'll use this term from here on) and gives us an idea of how good we are are putting fat in to use or storage. If we take any standard american chap and make him eat a standardised fat load there will be a surge of chylomicrons in his bloodstream, starting at a couple of hours after eating and going on for a few more hours.
So what determines the size of the rise in chylomicrons? As Dr Volek has pointed out, a ketogenic diet for six weeks markedly reduces your chylomicron concentration after an OFTT, ie you clear the chylomicrons from your blood stream more rapidly. This should hardly be surprising. If you have been in ketosis for 6 weeks you are hardly going to be running your metabolism on sugar. Fat comes in, fat gets used. But it still has to be transported.
How do we transport bulk fat from our gut to our butt? Dietary fat (medium chain triglycerides excepted) is ALWAYS transported in bulk as chylomicrons. "Regulated" fat, for metabolic needs, is ALWAYS transported as free fatty acids. These FFAs can be attached to albumin as their transport molecule in the plasma or can be accessed directly from chylomicrons via lipoprotein lipase, at the sites on the vascular wall where FFAs are needed by the tissues. But we can never transport all of a bulk fat meal as free fatty acids. Even when we are in ketosis. In ketosis we clear our chylomicrons faster because we are using a lot of fat. But we can never get rid of them altogether.
So if apoB48 containing chylomicrons kill, then fat kills. Post prandial chylomicrons kill. Even ketogenic diets kill. Eat anything to generate chylomicronaemia above 100mg/dl and you can kiss your coronary arteries goodbye. Gulp.
But how do we actually know that chylomicrons kill? From Denmark of course. Land of the Danish Pastry.
Denmark hosts The Copenhagen Heart Study. Just take 13,981 people, measure their non-fasting chylomicrons (described as "remnants"), record the results and watch who dies of heart disease and all cause mortality (bit risky that last one, but cardiologists were so naive back in the 70s) over the next 30 odd years. If chylomicrons kill, the higher the chylomicron count after a random meal, the more people should die, especially of heart disease.
Here are the "event" and death Hazard Ratios for men. Women are similar if not worse:
Random chylomicrons after a routine Danish breakfast or lunch are going to kill you. Heart disease. ApoB48. Simple. QED. Convincing enough to a cardiologist!
Woooooaaaaah, just a minute. This is observational. What are we observing? We are observing a group of people and they looked like this when they entered the study:
Look at hypertension incidence, diabetes incidence, physical inactivity prevalence and BMI splurge. All increase across rising chylomicron quartiles! Chylomicrons even make you smoke! They don't seem to make you alcoholic, a little disappointing that last one.
And you just thought apoB48 just caused heart disease!
Does anyone recognise the metabolic syndrome in these patient characteristics? Well I think that the size of your chylomicron surge after an average Danish pastry is determined by how far in to metabolic syndrome you are. However, the authors corrected for all of these factors and STILL chylomicrons kill.
The baseline characteristics recorded were crude in the extreme. Heavy drinking is defined as more than one drink a week (drinking two or more times a week is heavy)! But the fascinating one is diabetes. The definition of diabetes is anyone self reporting themselves as such, anyone who mainlines insulin (perhaps some body-builders got accidentally included here?), sulpha drug usage or having a random post prandial glucose above 11mmol/l.
Quick repeat: Anyone randomly detected with a blood glucose over
200mg/dl
(actually, over 198.2mg/dl) was classed as diabetic. Perhaps they missed a few diabetics in their multifactorial adjustments! But perhaps they don't think hyperglycaemia has anything to do with heart disease.
We know from Volek that if you eat a ketogenic diet your OFTT "improves". I'll just say that again. Elevated chylomicrons levels after a fat challenge reduce if you have been eating a VERY high fat diet. I think it is a reasonable extrapolation to say that a high carbohydrate diet might worsen OFTT results.
So in Denmark a high post prandial chylomicron count, which can be viewed as a surrogate marker for the metabolic syndrome, correlates positively with your risk of heart disease. The hallmark of metabolic syndrome is hyperinsulinaemia. If that hyperinsulinaemia is inadequate to maintain normoglycaemia in the face of carbohydrate consumption then HbA1c rises and other nasty hyperglycaemic stuff happens. And the bulk fat transport gets the blame. Certainly in Copenhagen and perhaps other places too!
Let's stop bashing those poor apoB48 molecules.
Peter
As on a number of other occasions, thanks to Dr Davis for pointing to both of these studies even if I completely disagree with his interpretation of what is happening in Copenhagen. Lipophobes have such strange yet fascinating ideas. But then I love Goth stuff too.
17 comments:
Peter, nice follow-up to the previous post.
After my comment there, I have been thinking. Endothelium gaps are around 25 nm in diameter. And what is the typical size of LDL particles:
http://healthcorrelator.blogspot.com/2010/02/large-ldl-and-small-hdl-particles-best.html
It is now becoming clear. The Devil created LDL particles to kill us, and since they were not doing a good enough job, the Devil also created chylomicrons.
Michael the Archangel, who dislikes the Devil, and usually takes a hands-on approach to dealing with those he dislikes, gave us HDL.
This theory probably needs some adjustments and refinements based on analysis of refereed research, and consultation with the Most Interesting Man in the World.
But I am pretty confident it will pass the test of time, unless it doesn’t.
Keep in mind that although the increases in the postprandial lipid levels were slightly lower in the people who had been on a ketogenic diet in Volek's study, they still weren't zero. Not sure how high they were as the axis is mislabeled.
And not everyone sees the reduction that he saw.
What we need is studies that show *why* high PP lipids are related to heart disease.
Do the lipids themselves cause heart disease? In that case, lowering them through various means would help.
Or are they simply markers for an underlying condition such as metabolic syndrome that is causing the heart disease? In that case, lowering them through various means wouldn't make any difference.
Ned,
LOL
what about a number of studies showing impaired endothelial function as measured by flow mediated dilation and other measures after dietary fat, but not dietary carbohydrate ingestion (at least not if it is low glycemic carbs)? There seem to be quite a lot of studies like this on google scholar/pubmed and both ornish and esselstyn cite these as a big factor in their conviction in the benefits of low-fat diets. Would be grateful for your thoughts on this topic.
One conclusion that could be made as well, is that you get diabetes, smoke more and drink more with old age.
More lipoterror tactics?:
"Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats"
http://tinyurl.com/yb6b7ap
Mainstream press is reporting it with headlines like "Fatty foods may cause cocaine-like addiction" (CNN).
This from the study's observation that rats fed a diet "of bacon, sausage, cheesecake, pound cake, frosting and chocolate" developed "compulsive-like feeding behavior in obese but not lean rats" and that "overconsumption of palatable food triggers addiction-like neuroadaptive responses in brain reward circuits and drives the development of compulsive eating."
somehow I doubt it was the bacon and sausage . . .
http://circ.ahajournals.org/cgi/content/full/97/17/1695?ijkey=c523f654bef401e109edcf3d6de2d9fd7f8ac181
"Although the primary objective was to increase forearm glucose concentration, systemic insulin levels increased significantly during the dextrose infusion in the initial protocol (see "Results"). Insulin is a known vasodilator,23 24 and several lines of evidence suggest that insulin-mediated vasodilation is achieved via endothelial release of nitric oxide; insulin-mediated vasodilation is inhibited by the nitric oxide synthase antagonist, WG-monomethyl-L-arginine (L-NMMA),25 26 and concomitant insulin infusion augments local vasodilation to methacholine"
"Insulin is a known vasodilator." Less insulin (or less action of insulin --physiological insulin resistance)="impaired" endothelial function.
Thanks Donny, except that high glycemic index carbs, which should provoke more insulin release than low-glycemic carbs result in greater fmd:
http://linkinghub.elsevier.com/retrieve/pii/S0735109709010687
Okay, David, but we're not talking about carbs vs. carbs here, we're talking carbs vs fat. I'm not real excited about the difference in insulin and glycemic reaction between low and high glycemic carbs; I don't eat much of either.
High carb, if you're insulin sensitive, opens your arteries right up. For some reason, I'd say if you eat glucose, and everything's working right, your arteries need to open wider than they would be during a low insulin, fasting condition.
Eating a bunch of fat, you're not changing much, compared to the fasting state; you're still mostly burning the body's preferred fuel, which is fat. (Mine prefers fat, anyways.) The insulin-induced vasodilation just plain isn't necessary in the fat-fed state.
Besides which,
"Thanks Donny, except that high glycemic index carbs, which should provoke more insulin release than low-glycemic carbs result in greater fmd:"
That's just the point. Insulin induces vasodilation; which should improve flow-mediated dilation.
Okay, I see that high carb/low carb thing was a typo. Never mind that last bit. Although the high glycemic carbs might have caused more of a peak and valley effect, explaining the lessened flow mediated dilation at the two hour point with the glucose vs cornflakes.
@David and Donny
The cardiologists use fmd as a proxy for atherosclerosis, but they are mistaken in this.
They are confusing cause for effect.
fmd is impaired as a result of intimal thickening and and atherosclerosis. The smooth muscle can't relax very well.
Cardiologists use this observation to conclude that whatever decreases fmd in the short term must therefore be a cause of atherosclerosis.
This is kind of like observing that those with advanced atherosclerosis have higher blood pressure, so anything that raises blood pressure in the laboratory causes atherosclerosis.
Like the clean and jerks I did today that transiently elevated my blood pressure so that I could keep perfusing my brain and not pass out. Or the increase in sympathetic tone when I got out of bed this morning that had the same purpose.
A cardiologist might propose that weight lifting or getting out of bed in the morning will lead to atherosclerosis.
Like transient changes in blood pressure, fmd is a homeostatic regulatory mechanism. It can be affected or perturbed by pathology, but not everything that changes either one is pathology.
Dr Harris --thanks for getting right to the point. I tend to take the scenic route, and sometimes I forget where I was going. And that's when I'm not manic. (Public service message; Glutamine and creatine have both been implicated as triggers of mania. Starting on both of these supplements at the same time, especially if bipolar or schizophrenia runs in your family, is probably a bad idea.)
I thought that it was the relative ease of oxidising that made small LDL particles bad, rather than their size.
Do chylomicrons oxidise easily?
Are the Extravasation & Inner Life animations on Harvard BioVisions relevant to this discussion?
Chinese to English translation of the post above, by Google translator:
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Thanks for the insightful comment Mao 1!
http://diabetes.diabetesjournals.org/content/49/4/597.abstract
--------------------------------
Atherosclerosis is the major complication of diabetes. Accumulating evidence indicates that lipoprotein lipase (LPL) produced by macrophages in the vascular wall may favor the development of atherosclerosis by promoting lipid accumulation within the lesion.
We previously demonstrated that high glucose stimulates in vitro murine and human macrophage LPL production.
--------------------------------
It doesn't sound like chylomicrons and ldl etc, just pelt their way into the artery wall, it sort of sounds like they're welcomed in with open arms.
I'm pretty sure I'm not manic right now, but this is still looking sort of like a lipid storage disease.
Nigel Kimbrun said "I thought it was the relative ease of oxidation that made small LDL particularly bad, rather than their size."
It is indeed true that small dense LDL oxidizes more readily than native LDL. Ox-LDL then displaces eNOS from caveolae of the endotheliaum (which native LDL does not do) and proceeds to emit free radicals which damages the endothelium. The displacement of eNOS results in a reduction in NO production which results in vasoconstriction and further impairs endothelial function.
Small dense LDL is more easily oxidized in part because, as found in the following study, it has already been partially oxidized as indicated by the redox status of coenzyme Q10 in total LDL which shows a higher ratio of oxidized to reduced CoQ10.
http://www.ncbi.nlm.nih.gov/pubmed/9012647
None of this bad stuff happens in the presence of high enough levels of HDL cholesterol. HDL cholesterol protects the endothelium in more than a dozen ways, including inhibiting the emission of free radicals by ox-LDL, preventing displacement of eNOS from caveolae thereby enhancing NO production, and reverse cholesterol transport of ox-LDL.
The highly atherogenic LDL pattern B of small, dense LDL particles exists only in the presence of relatively low HDL and high TG. High TG levels result in increased TG content of HDL which impairs HDL function.
Adopting a high saturated fat diet resulted in my HDL increasing from 55 to over 100 (ten year average), and TG decreasing from 130 to 50. I therefore eat the chicken skin without fear.
Nigel, Jack C:
I think that Peter has implied that in his post (and other posts), although I cannot speak on his behalf.
Surely one cannot possibly believe that evolution made the typical size of LDL particles and endothelium gaps nearly the same, if LDL particles were not meant to cross that wall.
If one wants to believe that LDL particles were made to kill us, here is a good theory to adopt:
http://healthcorrelator.blogspot.com/2010/03/ldl-chylomicrons-hdl-and.html
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