SYNDROME
X
by
Bill Beauman
Delivered to
The
April 29, 2002
©
2002, Bill Beauman
Syndrome X
I'm fat! I've always been fat. Mother told me I was long and lean at birth,
with lots of long, black hair. Well, so much for all that! I have been a fat
(and tow-headed) kid, a fat (and dark blonde) adolescent, and a fat (now
balding!) adult. I haven't seen 180 pounds (the proper weight for my height)
since I passed it at age 18, and I have been on some kind of diet every day of
my life that I can remember. The entire family was always on guard against
extra calories, because it was obvious that all of us had a weight problem.
There was never any bread and butter on the table, or dessert, or seconds.
Father was of "stocky" build with the excuse of needing lots of whole
milk for his stomach ulcer; Mother ate like a bird but was still plump; and my
poor sister used to make the whole house shudder when she would try to pound
the pounds off by flinging her hips onto the floor. All this worked, sort of:
we were always at least vaguely presentable never truly gross and my sister and
I both looked good at 18. But it took a constant, never-ending effort that is
difficult to maintain after leaving the nest, and regression was inevitable
after starting college. I tried every kind of diet there was low-fat and
low-carbohydrate, but mostly low-everything, by counting calories.
Unfortunately, I seem to have one of those excessively efficient, maximally
evolved metabolisms that our ancient ancestors needed in their uncertain times,
such that it took restriction to less than 800 calories per day for me to lose
weight. I'm sorry, but that's not living, that's torture, and I would rather be
dead than have to eat nothing but "leaves and twigs," as we used to
say of such extreme diets. I remember vividly the day in my mid- thirties when
I finally gave up trying to hold my gut in. It was an admission of defeat, an
acknowledgement of the ultimate failure of a lifetime of dieting, an expression
of despair, an entry into decades of depression. More recently, I have come to
make my own definition of "five by five" or "as wide as I am
tall": when I thread my belt through the loops on my pants, the buckle
clatters on the floor. That's not supposed to happen! Now I take pains to
prevent that hated sound, using expedients that would be comical if they
weren't so pitiful.
Of course, I understand perfectly that this is so only because I love to eat
and hate to exercise.
"So, exercise!" you say. "Control your intake!" Unfortunately,
I seem to have acquired an aversion to nearly any kind of strenuous physical
activity, which sprang from strange roots. It is more than simply indulging the
aversion everyone has to hard work; it is an application of the principle that
mental work is more valuable than physical work. I was taught from the earliest
age that if I wanted to avoid having to make my living the hard way by physical
labor I should study, study, study! That wasn't so difficult, since I had a
great talent for intellectual pursuits and absolutely none for athletics, and
over the years I came to avoid any activity that caused me to sweat. Even now,
the sensation of a rivulet of perspiration running down the back of my neck
still throws me into shudders of revulsion and triggers an urgent brushing-away
response as surely as if it were a true reflex. I even dislike sweaty sex! So
thorough was my rejection of manual labor that I recall a perverse pride in,
for example, not knowing what a Phillips screwdriver or ball-peen hammer was. I
still feel smug when showing ignorance about athletics and, by the way, where
did those extra arcs of paint on basket-ball courts come from, and since when
is it possible to make three points with one basket? (Those are rhetorical
questions I don't really want to know.) Of course, now, after more than 15
years with chronic atrial fibrillation, a heart rhythm described as
"irregularly irregular," and the beginnings of congestive heart
failure, exercise has now become a moot point. I literally can't walk and talk
at the same time, if either is going to be at all brisk.
So I grew up without learning to enjoy any sport or physical activity, while
excelling in my studies and music. We didn't get a TV until I was 16, so I
missed all the kiddie shows and never got into the habit of having it on all
the time as a background to life. Instead, I read. At age 6, I had a
life-altering experience when I plopped myself down on the folks' bed and asked
Mother, "What's an orange-outing ape?" You can imagine her perplexed
look. It turned out that I was bored with the library books available to me, so
I had made an arrangement with my sister such that she would let me read all
her upper-division library books before returning them. I was then traversing The
Complete Works of Edgar Allan Poe, and "The Murders in the Rue
Morgue" were committed by a mysterious orang-utan. I shall forever credit
my parents for not wringing their hands and shrieking, "Oh, our poor baby
may have been warped for life with such scenes of blood and violence!"
Instead, within a short time I had unrestricted grade school and high
school library cards, plus the same for the Carnegie Library in town, plus a
set of encyclopedias on a shelf at home, plus my great-uncle's bound set of National
Geographics, complete from Vol. 1 in 1890! Treasures, all! I read the
encyclopedias straight through, from aardvark to zymurgy, and I pored over
every word and picture of the exotic places in those fabulous magazines. I
became a book-worm, and it has made a good direction for my life.
Then there's eating. God, I love food! For years I have been amazed by taste
mavens who think there are only four types of flavor receptors, recently
expanded to five with the discovery of taste buds for the amino acid glutamate
(as in monosodium glutamate). It informs the savory flavor of meat, called
"umami" by the Japanese scientists who discovered it.
A short digression on receptors: Receptors are large protein molecules that
float like icebergs in cell membranes. Each has a chemically reactive site on
the surface with the perfect shape and chemistry to accommodate a particular
"target" molecule, plus the ability to produce some kind of physical,
chemical or electrical change in itself or another molecule nearby. Several
hundred types of receptor are known in humans, and every cell contains the
genes for all of them, although only certain cells in certain places actually
produce, or express them. Taste buds are perfect examples. The sweet' receptor
protein is a huge molecule with a groove that is chemically hospitable to
sugars and other molecules with similar shapes or characters. When one of those
molecules contacts the active site, its presence there causes the whole
receptor protein to change its shape physically. An ion channel opens up as a
gaping hole through which a stream of calcium ions enters the cell, thereby
depolarizing the membrane and initiating a nerve impulse to the brain saying,
"Umm! Sweet!" Even though most authorities believe there is only the
one sweet receptor, slight differences in the structures of the various
sweet-tasting substances and the responses they produce enable most of us to
discern whether we are tasting plain table sugar, pure glucose or fructose,
honey, saccharin, cyclamate or aspartame.
Surely, there must be dozens, if not hundreds, of different kinds of taste
buds, to produce the myriad of marvelously complex, absolutely blissful taste
experiences some of us have with food. For example, people from Celera
Genomics, the company that beat the government's timetable for completing the
human genome, recently announced the discovery of nearly 1300 olfactory
receptor genes in mice, and I expect a similar breakthrough for our taste buds.
In addition, I do not accept the proposition that most of taste is actually
smell. Where's all the smell in a sugar cookie? I do not believe that the
fabulously complex taste of cookies and milk, or pesto sauce, or chocolate, or
you-name-it can be broken down to just salty, sweet, sour, bitter and umami.
Just recently it was reported that the umami receptor is activated by all of
the other amino acids, not just glutamate, and their flavors may be completely
different. For another example of a variable receptor, consider the one for
serotonin, a neurotransmitter in our brains that mediates "good"
feelings. The psychoactive drugs psilocybin, LSD and mescaline all share
serotonin's "backbone" structure and are thus able to activate the
serotonin receptor in some fundamental way, although the "highs" they
produce are completely different. I predict that the five kinds of taste buds
will soon be expanded to dozens, if not hundreds more, and that many or all of
them will be found able to register a wide array of variations on the basic
taste. I further suggest that some fat people may have inherited enhanced
sensory capabilities which make it harder for them to refrain from eating too
much of the wrong foods.
That brings me to my main topic, which is the influence of inborn factors on
the world-wide explosion of obesity, disordered fat metabolism with high
cholesterol levels and cardiovascular disease, and "insulin
resistance" leading to type II diabetes wherever people are rich enough to
overeat a combination of symptoms that has come to be called Metabolic Syndrome
or Syndrome X. 70 million Americans are at risk, and 10% of us will die of it.
Today 80% of Americans are considered overweight, and half of those are
pathologically obese. 80% of people diagnosed with Syndrome X are obese, but
only 10% of the obese will develop Syndrome X. We all know people who can eat
lots of the most fattening foods and never gain an ounce, and most people have
felt for a long time that that ability must be due to a special genetic
endowment of some kind. Significant strides in explaining that have been made
just in the last couple of years, and I'm going to bring you up to date
tonight.
Just over a year ago, the March 30, 2001 issue of Science, the premier
scientific journal published in America, carried an article by corresponding
editor Gary Taubes entitled "The Soft Science of Dietary Fat," which
resulted in a fire-storm of angry recrimination from mainstream nutritionists
which raged for a full year. He wrote that the association between low-fat
diets and enhanced quality and length of life has been established only in
little steps details of the deposition of cholesterol, for example, or the
effect of this or that nutrient on blood pressure, but nobody had put it all
together and evaluated the overall, long-term effect of improved diet on health
and longevity.
In 1988 the U.S. Surgeon General's office committed to produce a definitive
report on the dangers of dietary fat; in 1999, after eleven years of internal
strife, they cancelled the project, saying it was too complicated a topic. Pfff!
The truth is, they had initiated the project with a preconceived expectation of
the results (highly unscientific!), and they were reluctant to publish
conclusions they knew would be unpopular. But others have done so. In 1987 a
group at Harvard University published results from a large study in Framingham,
Mass., the largest such study ever undertaken. Buried among the pages were data
showing that individuals at high risk of heart disease smokers, for instance
could expect to live only one year longer by shunning saturated fats;
healthy nonsmokers might live an extra three days to three months! The
next year the Surgeon General's office funded a study in San Francisco,
expecting it to contradict the Harvard study, but it did not. They found that
changing diet would delay 42,000 deaths each year, but the average
person would benefit by living only three to four months longer. To be
precise, a woman who otherwise would expect to die at age 65 could expect to
live two weeks more after a lifetime of careful eating. If she lived to
be 90, she could expect 10 more weeks of life. A third study, done at
McGill University in Montreal, came to virtually identical conclusions. Taubes
reported that the Surgeon General's office tried to squelch publication of the
San Francisco study, but the editors of the Journal of the American Medical
Assn. defied them. But they might as well not have published it hardly
anyone has cited the work anyway. These results have been totally ignored by
mainstream physicians and nutritionists.
So who did pay attention? Fringe elements like Dr. Robert Atkins, that's who.
He was so vociferously vilified by the mainstream AMA/FDA axis that I had
always trusted that I did not buy or read his first book. Now, after reading
Taubes' article, I sought out Dr. Atkins' New Diet Revolution,
written 20 years and 25,000 patients later, and it was a revelation. His
explanation of Syndrome X is that the easy availability of refined
carbohydrates and simple sugars in the modern world has deranged our carbohydrate
metabolisms and overwhelmed the ability of insulin to control it. Until very
recently in human evolution there were no refined carbohydrates at all,
anywhere, and the only simple sugars anybody ever came across were in fruits
and honey. Now, instead of water, we give our babies bottles of fruit juice
(either real or flavored sugar-water) just to keep their little mouths quiet
and occupied. Then we feed them white bread, ketchup that's 15% sugar, soft
drinks that are 12 to 18% high-fructose corn syrup, potato chips that have been
processed to the liquid state and then molded into perfect forms, to say
nothing of all the cakes, pies, cookies, candy, ice cream and gums that are so
readily available. All of these cause glucose to flood into the bloodstream and
stimulate the release of insulin. In addition, fructose, the fruit sugar, seems
to have a particularly bad effect: instead of acting like glucose, fructose
goes directly to the liver to make fatty acids, which are then dumped into the
blood-stream. The effect of snacks and "grazing" all day also keeps
the system continuously awash in glucose, insulin, and fatty acids. The control
system was not designed by evolution to cope with such an intense and sustained
onslaught, and we should not be surprised that it would falter in so many
people. Some Pacific islanders were so biochemically unprepared for the
gustatory advances of civilization that more than half of Togo and Fiji
Islanders now suffer from full-blown type II diabetes. The Pima Indians in
Arizona are in even worse shape.
Dr. Atkins made the point that the modern toxic diet became excessive in fats
at about the same time as the rise of refined carbohydrates. When the rates of
heart disease, cancer, obesity, and insulin resistance began to soar, the
medical establishment focused on fats as their scapegoat; others like Dr.
Atkins picked the carbs. He calls sugar and other foods with a high glycemic
index "metabolic poisons." (That is, those that are digested quickly
and cause rapid glucose and insulin release. In addition to simple sugars and
refined flour, both our beloved potatoes and the pristine, polished white rice
that most Asians insist on have extremely high glycemic indices.) His approach
to dieting is to simulate the diet of our ancient hominid ancestors before the
advent of agriculture: what fruits and vegetables they could gather, plus meat,
meat, and more meat. Hardly any grain. The only carbohydrates they got were
from fruits and vegetables, plus the glycogen stored in the flesh of animals
well-fed enough to have any. A good steak today may contain up to 50% glycogen,
which is a storage polymer of glucose similar to starch, but until the
appearance of animal husbandry and herding, food animals were so stressed by
chasing or being chased that their meat didn't have much glycogen. That's what
Dr. Atkins orders his patients to do: cut out the carbs almost entirely, down
to less than 40 grams per day at first (that's two slices of bread), so that their
muscles (and also their livers) become depleted of glycogen and are forced
to resort to burning fats for energy. There is no need to restrict fats they
are so powerful at producing a sense of satiety that most people naturally
consume less than they did before starting to diet.
An interesting side-note to the Atkins Diet is that one can purchase little
chemical test strips to monitor one's progress: a normal byproduct of the
break-down of fats is the production of intermediate waste products known as
"ketone bodies," mostly acetone, which are excreted in the urine and
can be detected. A positive test means the diet is working: fats are, indeed,
being burned instead of carbohydrates. Ketones are also excreted via the lungs,
and we have known about "acetone breath" among diabetics for ages.
People with true type I diabetes are often in a state of "metabolic
ketosis," as it is called, and they reek of acetone. An unfortunate
diabetic friend of mine was once jailed for drunk driving and nearly died of
neglect because the police didn't recognize the smell, but his only crime was
poor planning and the resulting insulin shock.
Because of the connection with type I diabetes and its dire consequences,
metabolic ketosis has always been seen as a condition to be avoided at all
costs. However, Dr. Atkins insists that intentional, controlled metabolic
ketosis as a treatment for type II diabetes is an entirely different matter and
is perfectly safe. He has records from 25,000 patients to prove it.
Type I diabetes is caused either by an inborn genetic error that results in
defective insulin molecules, or an autoimmune condition in which the special
beta cells in the pancreas are destroyed so that no insulin is produced at all;
type II diabetes is the late-onset, "acquired" type that now accounts
for 90 to 95% of all diabetes. Since it can be treated with diet, the Puritans
among us thought that meant it must also be caused by diet specifically,
overeating and a high-fat diet and it came to carry the same pejorative baggage
that now follows obesity. However, now it seems that seems that type II
diabetes may be just as genetic in its basis as type I.
We know what causes type I diabetes, but type II is still a mystery. Both
diseases are characterized by a failure of the mechanism for controlling blood
sugar. When sugar from the food we eat appears in the blood, glucose receptors
in the brain produce hormones that stimulate the special cells in the pancreas
to secrete insulin, which circulates in the blood and interacts with its
receptor on the surface of cells that need glucose. There it acts like a key to
unlock or activate the receptor so that the sugar can enter. Without insulin's
action, glucose builds up in the blood to dangerous levels that damage tissues.
The kidneys do their best to get rid of the excess sugar, but they ultimately
fail. Unfortunately, when the liver dumps sugar into the blood it also dumps in
fatty acids specifically, the dangerous low-density lipids that stick to and
clog blood vessels. That's one connection between diabetes and heart disease:
while being a primary regulator of carbohydrate metabolism, insulin is also a
secondary regulator of fat metabolism.
Since insulin resistance and full-blown type II diabetes develop gradually, the
cause may or may not be an inborn genetic flaw. I predict that the cause will
soon be reported to be a progressive poisoning of the insulin receptors by
other similar molecules that accidentally lodge at the active site where
insulin should go. At least nine types of confounding fat molecules have
already been documented. Thus, type II diabetes is a malady of the insulin
receptor. The receptors in affected individuals may be genetically defective
such that they are more susceptible than normal to fouling by extraneous
chemicals, or it may be that the receptors are structurally perfect but the
fouling chemicals are more prevalent because of something in the contemporary
Western diet. This illustrates a general rule: there are always at least two
ways in which a hormonal system can fail: the hormone may be defective or
absent, or its receptors may be defective or absent or compromised in some way.
Several hormonal systems affecting obesity and diabetes have recently been
discovered. The first was leptin, a hormone produced by fat cells, themselves,
which was a big surprise. Who would have thought that fat could be an endocrine
organ! There are leptin receptors in the hypothalamus region of the brain,
where both appetite and the deposition of fat are controlled. People with
excess leptin in their blood eat less and store less fat than normal, assuming
the receptors are functional. If their leptin production is compromised or its
receptors are nonfunctional, they eat more and get fat. Predictably, leptin's
action is even more complex than that, with effects on taste perception as
well: in mice, at least, injected leptin causes the sweet receptors on the
tongue to be less responsive to sugar, and they eat it continuously without
ever reaching satiety. Finally, leptin affects the expression of literally
hundreds of different genes that control growth, maturation, and even immunity.
Another hormone newly found in fat cells is called resistin because it seems to
cause insulin resistance. No one knows exactly why it exists, what turns it on,
or precisely how it works. Maybe the molecules that progressively foul insulin
receptors are resistin mimics.
Then there's adiponectin, another protein hormone secreted by fat cells, which
somehow opposes resistin and enhances insulin action and also reduces
triglyceride levels in the blood. If adiponectin is absent or defective,
circulating fat levels soar and insulin resistance grows. Another protein
called Tumor Necrosis Factor-alpha accompanies adiponectin and has nearly the
same effects.
The discovery of hormones produced by fat cells has inspired a new
pharmaceutical strategy to prevent obesity and insulin resistance: inhibit or
prevent the formation of the fat cells in the first place. The most promising
target is a class of peculiar little peptides known as "zinc fingers"
that reside in the nucleus, in direct association with the DNA that comprises
the genes.
Another newly-discovered hormone is called ghrelin, for Growth Hormone
RELeasing factor. It is produced by the stomach, and its receptors are found in
the hypothalamus, where appetite is controlled. But in addition to promoting
the release of growth hormone, ghrelin also causes laboratory mice to deposit
more fat in response to their increased appetite. Scientists hope to manipulate
it to control both obesity and cachexia, the "wasting syndrome" that
afflicts many with chronic illnesses.
There are many, many other hormonal systems that interact to influence fat and
carbohydrate metabolism, but it will not be useful to expound on all of them
here. Who wants to hear about obscure proteins like peroxisome proliferator
activated receptor-delta, or malonyl or acetyl coenzyme A, or
11-beta-hydroxy-steroid dehydrogenase-type1? Suffice it to say that there are
literally thousands of genes that control various aspects of Syndrome X, and
each one is susceptible to inheritable imperfections. Achieving and maintaining
one's ideal weight is anything but a simple matter of restricting intake and
exercising.
Before I close, there are two other aspects of the problem that need to be discussed.
One is diet, or more specifically, special chemicals that can be consumed as
foods or supplements to improve one's chances of beating chronic obesity and
type II diabetes. One is the so-called "good trans fats," which used
to have the reputation of raising serum cholesterol presumably a bad thing.
However, a particular mixture of essential dietary fatty acids known as
conjugated linoleic acids or CLA has been shown to fight cancer, enhance
immunity, and help rid the body of fatty plaques that clog blood vessels. They
were first found in hamburger and have since been shown to be part of all
animal fats. The richest dietary source? Cheese Whiz! No kidding!
Another group of naturally-occurring fats with powerful effects on obesity are
the fatty acid ethanolamides, especially the one derived from the oleic acid in
olive oil. Never mind the chemical terms; the important thing is that it is a
natural analogue of the chemical that our bodies makes to interact with the
cannabinoid receptor the receptor that the compounds in marijuana activate to
produce its "high." In fact, it poisons the cannabinoid receptor and
prevents the ravenous appetite known as "the munchies," which usually
accompanies getting high on grass. When fed to lab rats, they eat less and convert
more of what they do eat into protein.
These consumables also illustrate my last point: there are many
inter-connections between the factors that produce obesity and Syndrome X and
other systems in the body, and they are absolutely fascinating. For example,
the cannabinoid receptor is also expressed on dendritic white blood dells,
which are part of the immune system. Similarly, dendritic cells in the blood
and the "beta" Langerhans cells in the pancreas that produce insulin
both express an antigen called lectin, thus connecting those systems.
Another aspect of the connection between Syndrome X and the immune system is
seen in the correlation with specific infections. The antigenic signature of
oral bacteria is very often found in atherosclerotic plaques following oral
surgery, and it is now standard practice for dentists and oral surgeons to
prescribe antibiotics to fight any bugs that might get into the bloodstream.
More recently, at least two adenoviruses that affect people have been tied to obesity.
There appear to be multiple mechanisms, still unknown, underlying the role of
viruses in fat accumulation. Thus, DNA and genes from other organisms are also
implicated in Syndrome X.
Even more fascinating is the cholesterol connection between Syndrome X and
Alzheimer's disease. All cell membranes are composed of a double layer of fat
molecules free fatty acids, triglycerides, and lots of cholesterol. Thus, any
cellular growth or repair is impossible without adequate fat resources. In
addition, nerve fibers in particular are sheathed in layers of fat from special
cells, which insulate nerve impulses from outside interference until they get
to where they're going. That means cholesterol is absolutely necessary for
proper functioning of the nervous system, including the brain. Since it's so
important, it's not surprising that the body would have its own mechanisms for
maintaining cholesterol balance, regardless of diet. On the other hand, since
cholesterol comprises most of the fatty plaques of atherosclerosis, it's not
surprising that "statin" type drugs that inhibit cholesterol
synthesis have become mainstays of treatments for fighting Syndrome X. They
have been around long enough for some statistics to emerge, and it now seems
that drugs like Zocor and Lipitor reduce the risk of Alzheimer's by some 70%.
When I heard that a year ago I said "Sign me up!" and have been
taking Lipitor ever since.
Finally, it is my pleasure to report a new wrinkle in the "French
Connection" between wine consumption and superior cardiovascular health,
in spite of their rich diet. The polyphenols in red wine undoubtedly do some
good as antioxidants, but it turns out that alcohol from any source is
beneficial because it boosts the concentrations of the "good" cholesterol
and inhibits the formation of blood clots. Now the benefits of moderate alcohol
consumption are extended to the brain: both ordinary dementia and Alzheimer's
disease are reduced by half or more. The therapeutic dosage is estimated to be
three to four drinks per day. Hallelujah! Ain't science grand?
These discoveries have led to an explosion of new research on diabetes,
obesity, carbohydrate metabolism, fat metabolism, and appetite modulation. The
situation in which we fatties find ourselves is, in fact, exactly the opposite
of the former simplistic and insulting theory that obesity is due to nothing
more than moral weakness the self-indulgent overconsumption of the wrong foods.
Now we know that there are literally dozens of hormones and their receptors,
plus scores of newly-found biochemical pathways involving hundreds of enzymes,
each of which can affect no, determine how much of what kinds of food we
eat and how our bodies process it. There are thousands of specific genetic
flaws that have profound effects, and for many of us, trying to control weight
the old way, by counting calories and avoiding dietary fat, is not merely
ineffective but self-destructive. Just a week ago I got permission from my
cardiologist to begin the Atkins Diet, and the Ketostix already show me to be
in metabolic ketosis. So, we'll see whether I will be able to button my jacket
again come October. Meanwhile, don't call me fatty! or late to dinner.
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