Science in Society Archive

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

  1. The Obesity Epidemic
  2. How to Survive 40 Days Starvation
  3. How carbohydrates make fats

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

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.

Article first published 12/02/04



Sources

  1. Veech RL, Chance B, Kashiwaya Y, Lardy HA and Cahill Jr GF. Ketone bodies, potential therapeutic uses. Life 2001, 51, 241-7.
  2. Hoshi M, Takashima K, Noguichi M, et al. Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinaseI/ glycogen synthase kinase 3beta in brain. Proc. Natl. Acad. Sci. USA 1996, 93, 2719-23.
  3. Ho MW. Dietary interventions for Alzheimer’s & Parkinson’s. ISIS News 2001, 9/10

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