The obesity epidemic and how to beat it
This special mini-series tells you the latest on how metabolic interventions can make genes work to slim you down.
This series was first published in Science and Society 21.
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- The Obesity Epidemic
- How to Survive 40 Days Starvation
- How carbohydrates make fats
ISIS Report 12/02/04
How to Survive 40 Days Starvation
Some conventional health fears need to be questioned, as, like
fasting, they may contain health-restoring opportunities.
Dr. Mae-Wan Ho explains
Sources
for this report are available in the ISIS members site.
Full details here
Fear of ketosis
Ketosis is the dreaded condition of having too much of certain metabolic
products called ketones circulating in the blood. Generations of physicians
have been taught to be very afraid of it, because of the potentially fatal
episodes of ‘ketoacidosis’ in people with diabetes. In these
individuals, severe insulin deficiency causes fatty acids to pour out of fat
tissues and undergo metabolic conversion in the liver to the ketones, D-b-hydroxybutyrate and acetoacetate. The concentration of
ketones circulating in the blood can reach 25mM, upsetting the delicate
acid-base balance in the blood, so it turns severely acid. The body excretes
ketones in the urine, losing a lot of sodium and potassium ions in the process.
At the same time, the high blood glucose is also passed out of the body in the
urine together with a lot of water, leading to a drop in blood volume. All
these processes contribute to death, if untreated.
However, the fear of ketosis may be exaggerated, as milder forms of it
occur under other circumstances, and may have therapeutic potential. Such is
the claim of senior biochemist Richard Veech in the Unit of Metabolic Control,
in one of the National Institutes of Health in the United States. He has a
number of prominent veteran biochemists supporting his ideas, and, together,
they have written a fascinating review on the potential therapeutic uses of
ketosis.
How David Blaine could survive 40 days without food
Apparently, ketones in the blood can reach 5-7 mM in fasting subjects,
and this is essential to preserve glycogen in the muscles from breaking down
into glucose to feed the brain. Bouts of starvation may have been the normal
state of our hunter-gatherer ancestors, and so mild ketosis of modern humans
may be an evolutionary hangover, as it is almost unique to the human species.
Our brain consumes a disproportionately large amount of energy in our body. At
rest, 20% of the oxygen we take in goes to the brain, which is 2% of the body
weight. A further peculiarity is that ketones are the only other available
alternative to glucose for supplying energy to the brain. Ketones are the
secret to why humans, like magician David Blaine, can survive starving for
about 2 months instead of 2-3 weeks.
Therapeutic opportunities
The ability of the brain to use ketones was only once exploited for
therapeutic purposes. In the early 20th century, French neurologists
proposed fasting as a treatment for epilepsy on grounds that it was the result
of ‘intestinal intoxication’. A Wisconsin osteopath, Hugh Conklin,
subsequently successfully treated some epileptic children with a diet of only
water for 30 days. Russell Wilder, of the Mayo Clinic in the United States,
proposed that the beneficial effects of starvation in epilepsy could be
produced by a high fat/low carbohydrate diet, thus creating the "ketogenic
diet".
In one study, 150 severely epileptic children, averaging 400 seizures
per month, on a mean of 6.2 antiepileptic medications were placed on a
ketogenic diet consisting of 4 parts fat to 1 part protein, with almost no
carbohydrate. Thirty percent of the children had a greater than 90% decrease in
seizures and 3 became free of seizures.
But two problems arise in such ketosis therapy. First, eating even small
amounts of carbohyrate causes the release of insulin and an immediate drop in
ketone levels followed by seizures. Second, cholesterol increased from 168 to
220mg/100ml, with a decrease in high density lipoprotein, an increase in low
density lipoprotein and elevation of total triglycerides, putting the children
at slightly greater risk of atherosclerosis. In practice, this diet is rarely
used in patients over 17 years of age.
In one form of epilepsy resulting from a genetic decrease in GLUT1, the
major glucose transporter across the blood/brain barrier, ketones provide an
alternative energy substrate, compensating for the decreased glucose transport,
and hence ketosis therapy has been used.
The ketogenic diet has been used extensively in the treatment of
obesity, and like most other therapies, is only transiently effective at
best.
What’s so special about ketones?
The first clue that ketones are special came from observations in the
1940s that they were unique among 16 carbohyrates, lipids and other metabolites
tested on sperm in their ability to decrease oxygen consumption while
increasing mobility. This remained mysterious until Veech and his colleagues
found essentially the same effect in the perfused rat heart. Adding 5mM of
ketones to the glucose-containing perfusing fluid resulted in a 25% increase in
the heart’s pumping efficiency with a significant decrease in oxygen
consumption.
Ketones, like glucose, go into the mitochondria where oxidation
reactions take place to supply energy for all living activities, but at a
different point of entry. Glucose, a 6-carbon molecule is first broken down to
3-carbon pyruvate, which enters the mitochondrion, and is converted by pyruvate
dehydrogenase enzyme to acetyl coenzyme A, which goes into the tricarboxylic
acid (TCA) cycle, the main energy-generating chemical dynamo common to all
organisms that depend on oxygen.
The ketones, however, enter the mitochondrion directly, where
b-hydroxybutyrate is converted to acetoacetate, then
acetoacetyl coenzyme A, which is converted to acetyl coenzyme A.
At various points in the TCA cycle, electrons are abstracted from the
metabolites and passed across an electron-transport chain releasing some of the
energy in each step. Ketones essentially widens the energy gap in a particular
part of the electron-transport chain – between coenzyme Q and cytochrome
oxidase - thereby generating greater energy release as electrons travel across
that gap. This, says Veech and colleagues, will have the effect of increasing
the energy gradients of the major inorganic ions between the outside and the
inside of the cell, making the cell more highly charged electrically, which may
be related to the role of ketones in treating epilepsy.
Additionally, ketones caused a 16-fold elevation in acetyl coenzyme A,
the main entry point to the TCA cycle, which will have the effect of increasing
the rate of energy supply, and greater energy efficiency.
These effects of ketones are precisely the same as those resulting from
saturating doses of insulin, except that insulin works by increasing glucose
transport into the heart through GLUT4, the glucose-transporter in the cell
membrane.
It dawned on Veech that ketosis, the physiological response to insulin
deprivation during starvation, is actually mimicking the effects of insulin by
generating equivalent effects. Ketones are in fact bypassing the block in
glucose transport, and even stimulating synthesis of glycogen in the muscle
cells.
Ketosis as treatment for Alzheimer’s and Parkinson’s
diseases?
The accumulation of ‘amyloid peptides’ both inside and outside
brain cells is a hallmark of Alzheimer’s disease. Earlier research by
Hoshi and coworkers have shown that a fragment of the beta chain of amyloid
stimulates the activity of glycogen synthase kinase 3b, an enzyme that adds a phosphate group to pyruvate
dehydrogenase, thereby inhibiting it, and blocking the entry of pyruvate into
the TCA cycle. The amyloid fragment was also found to inhibit the formation of
acetyl choline, a major neurotransmitter, probably because the block in
pyruvate dehydrogenae decreases the concentration of citrate, an intermediate
in the TCA cycle and also a precursor of acetyl choline. Adding the amyloid
peptide fragment to cultured neurons from the hippocampus killed the cells.
Ketones are the answer to removing the block, and as ISIS has reported
in 2001, Veech and coworkers found that adding ketones protected the neurons
from the amyloid peptide fragment. Similar treatment was also effective in a
cell model of Parkinson’s disease, which involves another defect in the
mitochondrial energy generating enzyme reactions.
Other conditions that may be addressed by ketones include
Freidreich’s Ataxia, a genetic defect in a mitochondrial protein involved
in iron transport, various forms of insulin resistance, and cognitive
disorders.
Veech believes that the benefits of ketones are best produced by a diet
that include ketones, and not those that generate ketones in the body, as they
tend to unbalance it (see below). The problem is that one can’t give a lot
of ketones directly, because they are too acidic, so one way is to produce a
ketone esters, where the acidic groups are neutralised.
Veech tells me enthusiastically that he has just received a contract to
produce these ketone esters as a way to induce significant ketosis without
feeding high fat and low carbohydrate, and further down the line, to test the
diet on people with different kinds of disease.
What’s wrong with all the diet fads?
"The Atkins diet has certainly stimulated interest in low carbohydrate
diets. It is however a misnomer to call the diet ketogenic, but rather it
should be called ketouric. There are small amounts of ketones in urine, but
because of the high protein in the diet, the blood levels of ketones are really
quite low." Veech says.
Low carbohydrate diets are not new, and have been tried with variable
success. But, for these diets to work, one must cut insulin secretion to very
low levels, as in the condition of starvation described earlier. For more on
how diet affects metabolism, read "How carbohydrates make fats", this
series.
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