Life, Risk & Biomarkers

Let's start out with a little nostalgia, eh?  Before video games, there was a time when humans played boardgames, like Life and Risk.

Newman & Kramer play Risk on the subway!

While life and health is not a war strategy game, we are constantly bombarded with health advice based on observational studies associating risk factors with certain parameters.   From these, we are advised to eat or avoid eating certain foods, acceptable levels of radiation exposure, etc. are determined.

Cardiovascular disease is a huge killer, and for many, a first heart attack is it.  So as sentient beings cognizant of our mortality we'd like to know our risk of dying in this manner and strategies to minimize risks.   But here's a semi-absurd example of this.  Men are at higher risk of dying from CVD than women, but would a sex change operation lower his risk?

When I was 19 I had my first cholesterol test for an employment physical (since I would be working with certain chemicals and such, this unusual process was required.)  The company nurse informed me my cholesterol was on the high end of normal, and offered up the standard dietary advice of the day.  On my next test a couple of years later, I learned my TC was high because I have high HDL.  Pretty much all my life doctors have looked askance at my lipids but mostly I've been spared "the talk" primarily because of the HDL, and because I've only ever been borderline high.  Over the years, my cholesterol levels -- all of them -- seem to track with my weight, not with my diet.

Let's take triglycerides since they are such a poorly understood biomarker.  Everyone agrees that high fasting triglycerides are a risk factor, right?  In the fasted state, triglycerides are pretty much synonymous with VLDL particles produced in the liver.  In Where do triglycerides come from?  Part I, I discussed a radio-label study that looked at the mechanism of carbohydrate-induced increases in fasting triglycerides.  Was it increased de novo lipogenesis (DNL, converting carb to fat), increased VLDL secretion (from esterification of fatty acids from all sources), or decreased clearance of VLDL particles?  The answer, contrary to what "low carb science" tells us, is the latter -- decreased clearance of VLDL.  Here's the graphic of the results using normal men, and those with endogenous (genetics) hypertriglyceridemia.  While the high carb diet changed things slightly for the production of VLDL in normal men, and significantly more for the HTG subjects (the "missing" VLDL is addressed in the other blog post), the elevated fasting trigs were attributable to reduced clearance.

So ... we have a lot of observational studies that show fasting trigs are a significant biomarker for CVD risk.  So let's say my fasting trigs are 100 and I go on a low carb diet and they drop to 50 in a month.  The next month I switch to a traditional carbohydrate heavy Pima diet and my triglycerides soar to 150.  And let's say based on some meta-analysis,  50 puts me in a low risk category, 100 normal, 150 moderate risk of perhaps 20% greater risk of developing CVD.  Heck, forget diet and let's say I had trigs at 150 and took DrugX to drop them to 50, am I healthier?

The triglyceride data include a subset of the population genetically predisposed to HTG, and these people may have a genetic make-up that predisposes them to CVD based on what's causing their higher TG production, or related defect, not the TG themselves.  Carbohydrates don't increase the secretion of VLDL, they slow the clearance.  Now this may or may not be a good thing or a bad thing, but is a "normal" person who's trigs go up on a high carb diet increasing their personal risk of CVD?  After all, their numbers now put them in a different range.  How about the much-vaunted greater reductions in trigs on LC diets?  Now compared to the general population, this puts the same person, with the same genetics and metabolism in a lower risk category.  Or is there anything at all to triglyceride levels in all but this subset that over-produces them?   If you give an HTG person a drug to slow VLDL secretion, are they healthier because their trigs go down?

Given how variable and volatile such lipid profiles can be, and how conflicting various risk analyses are as to the predictive value of this or that biomarker, I personally, would rather rely on whatever measures come down the pike that look for actual physical manifestations of developing CVD, or measure rates of production, clearance, etc., rather than such biomarkers.  Because I don't believe that if my trigs can be changed in a month on a diet, I've altered my risk "overnight" in terms of a lifetime.  And the point of going through the mechanistic stuff above is that I think it is more important to understand why one might have a disturbance in some metabolic process.

Realize that those biomarker ranges are vs. the population as a whole consuming varied diets but some "average" SAD.   If one is to draw any conclusions on their health based on such biomarkers, it would seem prudent to consume an average SAD (doesn't need to be junk food BTW) for at least a month prior.  Then at least you're comparing your Granny Smith apple to all apples.  But every day we hear how this or that biomarker not so good after all.  A email circular landed in my Inbox just the other day questioning the usefulness of ApoB, and there was that study discussed on the news about how endogenous over-producers of HDL (maybe I'm one?) are not "protected" against CVD.

Based on recent studies I've read about the role of glyceroneogenesis regulating esterification in the liver, I think the lowering of trigs with VLC is probably just because glyceroneogenesis competes with gluconeogenesis for substrates.  Glyceroneogenesis is a truncated form of gluconeogenesis, but gluconeogenesis is the more important pathway when push comes to shove.  So in a VLC state your liver is more interested in keeping blood glucose levels high enough than it is in performing its recycling role in the TAG/FA cycle.  You have the same fatty acids circulating around, but fewer esterified into triglycerides due to reduced G3P production in the liver.  Healthier?

Now again, this is my personal opinion, but IMO, lipid profiles are most useful to track for yourself, compared to yourself, on your habitual diet.  If all of a sudden your VLDL starts rising or your HDL dropping or something like that, that would be an indication something's going on.  And I believe they can be informative as to the benefits of dramatic changes in one's diet.  Many people at Paleo Hacks have reported through the roof LDL levels from eating lots of butter and/or coconut oil (ahem Jimmy Moore, your near 400 TC levels are only mysterious to you).  Most people see improvements on LC -- usually associated with weight loss.  But some do not even when losing weight -- were I one of those I'd stay far far away!

In the mean time, while "they" sort out the magical biomarker you can bet the farm on that you'll live a long and healthy life, the best biomarker out there is the mirror and your brain.  A healthy diet shows outwardly though some things take many years to show outward symptoms.  This is where you have to use your brain -- scrubbed clean of all denial -- as to how you feel.   Health and well being shows through your eyes, and I'm not talking about whether or not a person has nice eyes.  And there's that puffiness of inflammation or age-inappropriate emaciation and sagging.  That was the dig against Gillian McKeith but some of the Nigella Lawson pics show the kind of inflammation I'm talking about.  And since Jimmy Moore is fond of posting pictures of others and commenting, it makes him fair game.  My hubs was shocked to learn he was only 40 and he's aged more than 8 years worth if you ask me.  He looks remarkably better in recent pics than on the LC Cruise -- a lot less puffy.  Likely half of his recent weight loss is inflammation-associated water.  His fellow hater of this scumbag hater, OTOH, is the personification of the puffiness I'm talking about.  In just about every picture from the cruise she's got that "look" and you know what I mean.  It's a darned shame because she's a pretty woman (and I'd kill for that hair even as much as I like my own!) and only serious denial has someone proclaiming the healthfulness of how she's eating or trying unsuccessfully to eat.  Many, many of the MDA success stories are improved inflammation with nominal weight loss -- likely because the list of foods to remove from one's diet includes some usual suspects, and that's a good thing.   But demonizing one and now two macronutrients because many problematic factors are associated with some carbohydrate containing foods ... too far by a mile.

 In this game of "pick the biomarker" , I'll go with outward appearances, fully aware that mine fall far short of perfect, and non-denial based general feeling of well-being.  Perhaps it's time for fat biopsies to look for macrophages or crown-like structures, or routine liver screenings or more sophisticated mechanistic tests rather than more sophisticated lipid profiles.   But I think the mirror and our brains are probably the best tools we got. In this game of Life and Risk.


Woodey said…
"....the mirror and our brains are probably the best tools we got."

After a year of LC/Paleo (is there really a difference?)I looked in the mirror and said, "Lame". So I plugged my brain back in and started to question the "science" of Taubes, Naughton, Moore, Wolf and the myriad of other opinion science people out there. In the end it lead me to places like Carbsanity and I got my life back in order. Decompressing from a cult or cult-like movement is challenging and I have had my struggles with it, but like today I went shopping and bought some nice pineapple (on sale for $1 each) without giving it a second thought about the evil carbs and sugars that are in them.

Here is an example of common sense and how useful it has been since before the birth of modern science, mass printing and all the a**holes who peddle their opinions via the internet and books: I tool a West Civ. class about a year ago and read a book called "Pericles Of Athens And The Birth Of Democracy"
by Donald Kagan.

One of the things the author discusses is the war the between Sparta and Athens, in doing so he mentions the Spartan leader Lycurgus and the laws he created for Spartan society. One of them was that they should not eat more than they needed. The reasoning behind it was that if one ate too much that became lazy and got fat. There's more too those laws and I do recommend reading the book. Anyhow the point is that even before we became enlightened with modern science, people knew that eating more than you needed made you fat.

Slice it dice it, wrap it up in shiny packaging, the bottom line is if you eat more calories than you need you will put on the pounds. Cut through all the crap and opinionated science, that is the bottom line, even the Spartans who believed in all sorts of supernatural mumbo jumbo knew that.

"But I have a condition."....yeah its called bigbuttitis. Now put down the twinky, grab a carrot and go for a walk. Use your brain and stop looking for some dips**t with a book to tell you otherwise. Cause then you spread that persons stupidity to others and it spreads like a disease.

I guarantee that if you take a group of chubs and put them through Marine Boot Camp they will get in shape and drop some pounds. Why? Because they will eat less and move more. That is unless you are Private Pyle and try to sneak in a jelly donut!
P2ZR said…
But the Marine boot camp thing (not saying you're advocating it) is where much of the resistance to the MM of ELMM comes from. These boot camp-type classes are based on the premise of 'exercisical' S&M--that you're not making any progress unless you feel like the effort is going to make you die (and don't you dare even involuntarily show your distress, you weak SOB). This isn't even factoring in that a lot of these classes take place very early in the morning, which is a truly huge *physiological* hurdle for those who are not super-early-morning people--largely (though not exclusively) through no fault of their own.

MM is more sustainable when it's *enjoyable*, or at least not a source of stress. And really, it's just unwise to have people stressing out over MM, due to the simple fact that people are less productive (at work, at home--which in turn can affect work) when they have to expend mental energy dreading workouts. Granted, when you're out of shape, very few forms of MM will be appealing because the least exertion feels awful, but that's the getting-into-shape curve, and there's really a form of enjoyable MM for everyone.
P2ZR said…
'Slice it dice it, wrap it up in shiny packaging, the bottom line is if you eat more calories than you need you will put on the pounds.'

But somehow, it's a mortal offense to suggest that substances that stimulate overconsumption, such as MSG, are doing so via dopaminergic (reward) pathways--instead, it absolutely *must* (gawd help us if this is not true) be due to effects upon insulin signalling. Nevermind that subjective feelings of hypoglycemia (with which I'm unfortunately very familiar) don't actually track well with clinical hypoglycemia (reactive and otherwise) wrt. BS levels. Oh no, no...the feelings of sh*tiness in response to certain food ingredients--that seem as if they can be alleviated only by eating more--just can not, not, NOT (!!! I tell you!) be due to messed up reward circuits in the brain. Because acknowledging so is TANTAMOUNT to equating overeating with gluttonySlothAndMoralDecrepitude! (No non sequitur there, really...just swallow my proclamation hook, line, and sinker. Demagoguery = truth, didn't cha know?!)
Sanjeev said…
> subjective feelings of hypoglycemia (with which I'm unfortunately very familiar) don't actually track well with clinical hypoglycemia (reactive and otherwise) wrt. BS levels
try, just TRY saying that to a Taubesian's face. oof.

Make sure you're wearing a Dexter type welding shield when you do it to avoid the phlegm, sputum sure to come your way.
Steven Hamley said…
In regards to testing Doug McGuff has said something along the lines of

"If the number is bad, eat healthy, and if the number is good, eat healthy"
P2ZR said…
Urgh, spittle...eww.

P2ZR dons protective gear and, using a 10m fishing rod, dangles a glucometer to Taubesian.

Taubesian: "I don't need no glucose measurements, I friggin' KNOW that I'm hypo!"

P2ZR manages to prick Taubesian with dangled glucometer, getting a reading that flashes in his/her face. Not clinical hypoglycemia.

Taubesian: "Liar!!! You and yer damn machine are lyin'! I can FEEEEEEL[??!!?!?!] the insulin stuffing my fat cells to the gills*!!!!!!!!!!"

P2ZR runs for her life.

*Yes, adipocytes possess gills. They are aquatic parasites that, with the abetting of Zeh Nefarious Insulin, sequester glucose and summarily alchemize it into infinitely many lipid molecules.
Woodey said…
Those are some good points P2ZR. Personally I would not recommend boot camp to anyone, but my point was that if you put someone in a strict setting where they have set meals and only so much food per meal, combined with exercise and just moving in general that change will occur. I don't believe that everyone would become thin as a rail, some are built to carry extra weight.

This is what makes me mad about living in a shallow society, everyone wants to look like the person they see on the tv, magazine ads, and movie screen. Its just no reality, so we put all of this pressure on ourselves to be something we aren't. It makes for fertile ground for every dingbat or scammer that wants to prey on society's insecurities.

Imagine how many people like Jimmy Moore, Gary Taubes, or even Jack Kruse (remember him?) would go away if the masses really understood nutrition and felt comfortable with their body. That fact that people listened to a guy who injected himself with a virus and insisted freezing his a** off made it go away and helped him lose weight (don't forget super buff as well) is just flat out retarded. Yet the minions went along with it, which tells me people are so desperate they went and killed common sense.