Monday, April 16, 2012

Hormonal reductionism is as myopic as biochemical reductionism

Biochemistry-based arguments can be very misleading. Yet, biochemistry can be extremely useful in the elucidation of diet and lifestyle effects that are suggested by well-designed studies of humans. If you start with a biochemistry-based argument though, and ignore actual studies of humans, you can easily convince someone that glycogen-depleting exercise (e.g., weight training) is unhealthy, because many health markers change for the worse after that type of exercise. But it is the damage caused by glycogen-depleting exercise that leads to health improvements, via short- and long-term compensatory adaptations ().

Biochemistry is very helpful in terms of providing “pieces for the puzzle”, but biochemical reductionism is a problem. Analogous to biochemical reductionism, and perhaps one example of it, is hormonal reductionism – trying to argue that all diet and lifestyle effects are mediated by a single hormone. A less extreme position, but still myopic, is to argue that all diet and lifestyle effects are mostly mediated by a single hormone.

One of my own “favorite” hormones is adiponectin, which I have been discussing for years in this blog (). Increased serum adiponectin has been found to be significantly associated with: decreased body fat (particularly decreased visceral fat), decreased risk of developing diabetes type 2, and decreased blood pressure. Adiponectin appears to also have anti-inflammatory and athero-protective properties.

As a side note, typically women have higher levels of serum adiponectin than men, particularly young women. Culturally we have a tendency to see young women as “delicate” and “vulnerable”. Guess what? Young women are the closest we get to “indestructible” in the human species. And there is an evolutionary reason for that, which is that fertile women have been in our evolutionary past, and still are, the bottleneck of any population. A population of 100 individuals, where 99 are men and 1 is a woman, will quickly disappear. If it is 99 women and 1 fertile man, the population will grow; but there will also be some problems due to inbreeding. Even if the guy is ugly the population will grow; without competition, he will look very cute.

Jung and colleagues measured various hormone levels in 78 obese people who had visited obesity clinics at five university hospitals (Ajou, Ulsan, Catholic, Hanyang and Yonsei) in Korea (). Those folks restricted their caloric intake to 500 calories less than their usual intake, and exercised, for 12 weeks. Below are the measured changes in tumor necrosis factor α (TNF-α, now called only TNF), interleukin-6 (IL-6), resistin, leptin, adiponectin, and interleukin-10 (IL-10).

We see from the table above that the hormonal changes were all significant (all at the P equal to or lower than 0.001 level except one, at the P lower than 0.05 level), and all indicative of health improvements. The serum concentrations of all hormones decreased, with two exceptions – adiponectin and interleukin-10, which increased. Interleukin-10 is an anti-inflammatory hormone produced by white blood cells. The most significant increase of the two was by far in adiponectin (P = .001, versus P = .041 for interleukin-10).

Now, should we try to find a way of producing synthetic adiponectin then? My guess is that doing that will not lead to very positive results in human trials; because, as you can see from the table, hormones vary in concert. At the moment, the only way to “supplement” adiponectin is to lose body fat, and that leads to concurrent changes in many other hormones (e.g., TNF decreases).

Trying to manipulate one single hormone, or build an entire health-improvement approach based on its effects, is myopic. But that is what often happens. Leptin is a relatively recent example.

One reason why biochemistry is so complex, with so many convoluted processes, is that evolution is a tinkerer that is “blind” to complexity. Traits appear at random in populations and spread if they increase reproductive success; even if they decrease survival success, by the way ().

Evolution is not an engineer, and is not even our “friend” (). To optimize our health, we need to “hack” evolution.


J. Stanton - said...

I agree, Ned. Reductionism in general is very dangerous when we're talking about the many complex homeostases maintained in a human body.

There's way too much "science" out there which is wrong in the same ways population studies are wrong: "thin people tend to do X, therefore X makes you thin." Similarly, we get "thin people have lower levels of hormone Y, therefore Y makes you fat."

For a while insulin was fashionable; then leptin took its spot. Next up we have "every one of the trillions of cells in our bodies is a passive hand puppet of the hypothalamus, not an individual biochemical factory that expresses its own receptors and both ingests and excretes according to its own needs." I think we'll all have plenty of unknowns and controversy to write about for quite a while.


Richard said...

I read this and thought for a moment, and then realized, if I’ve got this right, that the more in shape you are, the less fat you have, and the less fat you gain. So, on the other hand, the fatter you are, the fatter you get? So the way to lose fat is to lose fat? It may be true, and if so, it is both amusing and not very helpful.

I realize that this is based on reductionism, and as much as I want to keep that in mind, it strikes me that keeping things simple is a worthwhile goal.

Personally, I am a big fan of a Paleo diet, and of staying in shape, and it works for me. What I found highly amusing was the concept that exercise, in a gross sort of approach, like running, was not as effective for weight control as trivial and constant energy expenditure. And that it is difficult to get fat by eating too much. Again, what to do?

And one is torn by the idea of where this food consumption and fat regulation takes place? Is it the brain or at some hormonal level, or both, or one controlling the other? One yearns for clear answers and discovers instead that there is no answer at all. I would be much more distressed if I was not already in quite decent shape: 5’8” and 155 and about 10% fat, at age 67. I work out at the gym and play tennis six days a week.

On the other hand, increasing saturated fat consumption along with increasing green vegetables and eliminating or greatly reducing grains in the diet seems to have a beneficial effect over-all. We can ponder the mechanism, but it is effective when coupled with moderate or even minimal exercise. Although, it could be that not eating the grains decreases the desire to sit and sleep, and so in the end one expends more calories? I mean, who is making these decisions?

The whole thing strikes me as a black box sort of issue. But the key, to me, at the outset, was the idea that unless the human organism had the proper high fat diet, the body felt, or knew, with all the various feedback loops, that times were hard and that the body had to become more efficient in converting food to energy and store more fat as reserve energy, because it was facing hard times in hunting. If you could hunt and kill and eat fat animals why store very much excess fat on your body? Again, that is hardly a conscious decision.

john said...

This myopic mindset is often used to promote a certain kind of diet. I remember Anthony Colpo making arguments in favor of high carb diets based on the importance of thyroid hormone for bodybuilders. But while it's nice to have good thyroid hormone metabolism, how can we know without further info that a thyroid maximizing diet doesn't tank testosterone levels, which are shown to increase with increasing [saturated] fat intake; test levels are...umm...also pretty important for bodybuilders/athletes.

Thyroid-based arguments seem to be quite popular nowadays, with the implication that it is the "master hormone," and everything else falls into place accordingly.

George Henderson said...

Think about insulin though; insulin and all kinds of modulators of its effect are in fact useful medicines.
This kind of justifies a narrow focus on insulin sometimes; it seems less contingent than other hormones.
Even so, there are no master hormones.
Thyroid activity is as dependent on carb/fat ratio as is insulin.
The food is the master then.

Ned Kock said...

Synthetic insulin is indeed useful to many people, but widely misused. I would argue that most of the people who take it don’t actually need it. This includes some colleagues that I talk to on a regular basis.

It may surprise some readers that folks who are prescribed insulin are also encouraged to consume carbohydrates, at the same time.

In fact, without the carbohydrates, these same folks may experience serious hypoglycemic episodes as a result of their prescribed insulin injections.

George Henderson said...

Oh, I agree, absolutely. Low carb or ketogenic diets should be the first thing tried unless insulin production is determined to be zero, and even then.
The goal should be to minimise insulin needed, not mazimise carbohydrates tolerated.
My point was, that where a hormone clearly works as a stand alone drug, assessing its role in disease may not be excessively reductionistic, as it is demonstating reasonable independence of contingency.
Contingency, for example, is why individual cytokines are probably useless as drugs and their incidence in disease is often misleading.

Josh Almanza said...

Well said, Ned! I am on the same page.

jpatti said...

Modern insulin dosing is based on food intake. My own usage involves a "basal" insulin which handles what my liver does when not eating (and basal dosing is adjusted periodically); plus dosing for meals specifically based on both carbohydrate and protein content of what I'm eating.

And yes, I'm a T2, and still produce insulin, just not enough to overcome my insulin resistance.

Low carb is NOT the answer. I low carbed for TWO DECADES after my diagnosis, usually under 50g carb/day, with a monthly "cheat" meal (not a day, just a MEAL). And after that two decades, my bg went up over 300 FASTING and would not go down, even after 2 and 3 day fasts. Thus my insulin use.

Low carb is like saying that the head gasket on your car is leaking, so you should try not to drive it very much so it lasts longer. Yeah, if your body can't handle sugar, you should avoid it, obviously. But that isn't the ANSWER.

Cause my hubby can eat 1/6th of a double-layer chocolate cake in one sitting and his bg never goes above 120. Mine goes over 300 when FASTING FOR SEVERAL DAYS unless I take insulin! His body does things VERY different than mine does.

And BTW, I was raised by a nutritional freak who was afraid of sugar before it was fashionable anjd fed us yogurt and whole grain bread when only one brand of either existed (she was an Adele Davis fan); he was raised in a bakery and NEVER ate fresh produce in his life, tomatoes were a component of ketchup, not a vegetable to him. This effects our behavior today; I eat WELL over 10 lbs of fresh produce every week, and get maybe 1-2 pounds into him. So... no, diet is not the answer.

I'm not implying insulin is the answer either. I can keep my bg under control with insulin, but high serum insulin is inflammatory in itself. So I get to choose between the damage from high bg or the damage from high insulin, EITHER of which correlate to MI more highly than HDL/LDL profiles do.

And I've had an MI, so avoiding risk is pretty big for me. Maximizing vitamins A, D3 and K2 in diet and supplemental CoQ10, aspirin and fish oil are huge for me.

I've thought LOTS of things were "the" answer.

Several years of eating a better diet, with the right fats (minimizing omega6 and overall PUFAs while maximizing omega3s and MCT) has not yet fixed my insulin receptors.

Leptin was interesting, and the Zucker rats, but... no good answer there either. That's just another "resistance" I have. If it came before insulin resistance, so what? Still no ANSWER to the problem.

Symlin (synthetic amylin) did not improve my glucose control and the research on that was SO freaking kewl. I mean, I was nearly orgasmic over that stuff. Mind-boggingly cool stuff. But... I added 3 extra shots per day for several months and saw NO difference whatsoever.

Adiponectin is darned exciting too, but too far away for me to try yet. Was telling hubby today that it'll probably wind up available to patients right after I die. Heh.

It's all wheels-within-wheels. A causes B which causes C which causes D which causes A. It's all feedback loops.

I've had severely low cortisol (to the degree of being bedridden for nearly a year), severe rT3 issues with the resultant fatigue, and managed to fix both of those with hormones, which I later weaned off of.

Cause when your endocrine system is messed up, it's like driving with your car out of alignment, the more you drive, the more the rest of the vehicle gets messed up.

Synthetic hormones are a stopgap, not an answer. But I don't know what the answer is and don't think anyone else does either.

George Henderson said...

is intermittent fasting ever an option when using insulin?

The Salk study found the body stores fat while eating and starts to burn fat and breakdown cholesterol into beneficial bile acids only after a few hours of fasting. When eating frequently, the body continues to make and store fat, ballooning fat cells and liver cells, which can result in liver damage. Under such conditions the liver also continues to make glucose, which raises blood sugar levels. Time-restricted feeding, on the other hand, reduces production of free fat, glucose and cholesterol and makes better use of them. It cuts down fat storage and turns on fat burning mechanisms when the animals undergo daily fasting, thereby keeping the liver cells healthy and reducing overall body fat.

The daily feeding-fasting cycle activates liver enzymes that breakdown cholesterol into bile acids, spurring the metabolism of brown fat - a type of "good fat" in our body that converts extra calories to heat. Thus the body literally burns fat during fasting. The liver also shuts down glucose production for several hours, which helps lower blood glucose. The extra glucose that would have ended up in the blood - high blood sugar is a hallmark of diabetes - is instead used to build molecules that repair damaged cells and make new DNA. This helps prevent chronic inflammation, which has been implicated in the development of a number of diseases, including heart disease, cancer, stroke and Alzheimer's. Under the time-restricted feeding schedule studied by Panda's lab, such low-grade inflammation was also reduced.

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