Having quantitatively examined the adaptations which occur in terms of glucose use and nitrogen losses during starvation, the mechanisms behind the ‘protein sparing’ effect of ketosis can now be discussed.
The question which needs to be answered is what mechanisms exist for ketones (or ketosis) to spare protein. There are at least four possible mechanisms through which ketogenic diets may spare protein, three of which are well established in the literature, the fourth less so.
They are discussed in more detail below.
Decreasing the body’s glucose requirements
This is arguably the primary mechanism through which ketosis spares nitrogen losses.
This adaptation is discussed in detail in the previous sections and is well established in the literature. To briefly recap, by shifting the body’s overall metabolism to fat and ketones (especially in the brain), less protein is converted to glucose and protein is spared (6,27). This mechanism is not discussed in further detail here.
It should be noted that preventing the development of ketosis, either with drugs or with the provision of too much dietary carbohydrate, maintains the nitrogen losses during starvation (31).
That is, the development of ketosis is a critical aspect of preventing excessive nitrogen losses during periods of caloric insufficiency. This suggests that non-ketogenic low-carbohydrate diets (frequently used by bodybuilders) may actually cause greater protein losses by preventing the body from maximizing the use of fat for fuel.
Decreased nitrogen excretion via the kidney
The kidney is a major site of ketone uptake and the buildup of ketones in the kidney has at least two metabolic effects (32). The first is an increase in urinary excretion of ketones, which can be detected with Ketostix ™. The second is an impairment of uric acid uptake.
The excretion of ketones through the kidneys has an important implication for nitrogen sparing. The kidney produces ammonia, which requires nitrogen, as a base to balance out the acidic nature of ketones and prevent the urine from becoming acidic. This is at least one possible site for an increase in protein losses during ketosis (32). In all likelihood, the increased excretion of ammonia may be the basis of the idea (long held in bodybuilding) that ketone excretion is indicative of protein loss.
As ketosis develops, however, there is an adaptation in the kidney to prevent excessive ammonia loss. As blood ketone concentrations increase, the kidney increases its absorption of ketones. If this increased absorption was accompanied by increased ketone excretion, there would be further nitrogen loss through ammonia production.
However urinary excretion of ketones does not increase, staying extremely constant from the first few days of ketosis on. Therefore, most of the ketones being absorbed by the kidney are not being excreted. The resorption of ketones appears to be an adaptation to prevent further nitrogen losses, which would occur from increasing ammonia synthesis (16,32). This adaptation has the potential to spare 7 grams of nitrogen (roughly 42 grams of body protein) per day from being lost (32).
Directly affecting protein synthesis and breakdown.
As stated, it is well established that protein breakdown decreases during the adaptation to total starvation and one of the mechanisms for this decrease is a lessening of the brain’s glucose requirements. It has also been suggested that protein sparing is directly related to ketosis (5,26).
As well, many popular authors have suggested that ketones are directly anti-catabolic but this has not been found in all studies.
As described previously, muscles will derive up to 50% of their energy requirements from ketones during the first few days of ketosis. However this drops rapidly and by the third week of ketosis, muscles derive less only 4-6% of their energy from ketone bodies (22). This becomes important when considering the time course for nitrogen sparing during ketosis.
Several studies have examined the effects on protein breakdown during the infusion of ketone bodies at levels that would be seen in fasting or a ketogenic diet. Of these studies, three have shown a decrease in protein breakdown (33-35) while two others have not (36,37). One study suggested that ketones were directly anabolic (38). One oddity of these studies is that the infusion of ketones (usually as a ketone salt such as sodium-acetoacetate) causes an increase in blood pH (36,38), contrary to the slight drop in blood pH which normally occurs during a ketogenic diet.
At least one study suggests that the rise in pH is responsible for the decrease in protein breakdown rather than the ketones themselves (36); and sodium bicarbonate ingestion can reduce protein breakdown during a ketogenic diet (39). However, since blood pH is normalized within a few days of initiating ketosis, while maximal protein sparing does not occur until the third week, it seems unlikely that changes in blood pH can explain the protein sparing effects of ketosis.
It should be noted that these studies are different than the normal physiological state of ketosis for several reasons. First and foremost, the mixture of ketone salts used is not chemically identical to the ketones that appear in the bloodstream. Additionally, the increase in pH seen with ketone salt infusion is in direct contrast to the drop in pH seen on a ketogenic diet suggesting a difference in effect. Therefore, ketones produced during metabolic ketosis may still have a direct anti-catabolic effect.
Possibly the biggest argument against the idea that ketones are directly anti-catabolic is the time course for changes in nitrogen balance. Most of the infusion studies were done on individuals who had been fasting for short periods of time, overnight or a few days. The major decrease in nitrogen sparing does not occur until approximately the third week of ketosis, at which time muscles are no longer using ketones to any significant degree (22,40). All of the above data makes it difficult to postulate a mechanism by which ketones directly affect muscle protein breakdown. In all likelihood, contrary to popular belief, ketones are not directly anti-catabolic.
Affecting thyroid levels
A fourth possible mechanism by which ketosis may reduce protein breakdown involves the thyroid hormones, primarily triiodothyronine (T3). T3 is arguably one of the most active hormones in the human body (42-44). While most think of T3 simply as a controller of metabolic rate, it affects just about every tissue of the body including protein synthesis. A decrease in T3 will slow protein synthesis and vice versa. As a side note, this is one reason why low carbohydrate diets are not ideal for individuals wishing to gain muscle tissue: the decrease in T3 will negatively affect protein synthesis.
The body has two types of thyroid hormones (42). The primary active thyroid hormone is T3, called triiodothyronine. T3 is responsible most of the metabolic effects in the body. The other thyroid hormone is T4, called thyroxine. Thyroxine is approximately one-fifth as metabolically active as T3 and is considered to be a storage form of T3 in that it can be converted to T3 in the liver.
T3 levels in the body are primarily related to the carbohydrate content of the diet (44-46) although calories also play a role (47-49). When calories are above 800 per day, the carbohydrate content of the diet is the critical factor in regulating T3 levels and a minimum of 50 grams per day of carbohydrate is necessary to prevent the drop in T3 (44,48,49). To the contrary, one study found that a 1500 calorie diet of 50% carbohydrate and 50% fat still caused a drop in T3, suggesting that fat intake may also affect thyroid hormone metabolism (50).
Below 800 calories per day, even if 100% of those calories come from carbohydrate, T3 levels drop (47). Within days of starting a ketogenic diet, T3 drops quickly. This is part of the adaptation to prevent protein losses and the addition of synthetic T3 increases nitrogen losses during a ketogenic diet (1). In fact the ability to rapidly decrease T3 levels may be one determinant of how much protein is spared while dieting (51).
Hypothyroidism and euthyroid stress syndrome (ESS)
There are two common syndromes associated with low levels of T3 which need to be differentiated from one another. Hypothyroidism is a disease characterized by higher than normal thyroid stimulating hormone (TSH) and lower levels of T3 and T4. The symptoms of this disease include fatigue and a low metabolic rate.
The decrease in T3 due to hypothyroidism must be contrasted to the decrease seen during dieting or carbohydrate restriction. Low levels of T3 with normal levels of T4 and TSH (as seen in ketogenic dieting) is known clinically as euthyroid stress syndrome (ESS) and is not associated with the metabolic derangements seen in hypothyroidism (1). The drop in T3 does not appear to be linked to a drop in metabolic rate during a ketogenic diet (17,52).
As with other hormones in the body (for example insulin), the decrease in circulating T3 levels may be compensated for by an increase in receptor activity and/or number (1). This has been shown to occur in mononuclear blood cells but has not been studied in human muscle or fat cells (53). So while T3 does go down on a ketogenic diet, this does not appear to be the reason for a decrease in metabolic rate.
The primary adaptation to ketosis (as it occurs during total starvation) is a gradual decrease in the body’s glucose requirements with a concomitant increase in the use of free fatty acids and ketones. The main adaptation which occurs is in the brain which shifts from deriving 100% of its fuel from glucose to deriving as much as 75% of its total energy requirements from ketones. Thus the commonly stated idea that the brain can only use glucose is incorrect.
A large increase in the breakdown of body protein during the initial stages of starvation provides the liver and kidney with the amino acids alanine and glutamine to make glucose.
However, there is a gradual decrease in protein breakdown which occurs in concert with the decreasing glucose requirements.
Although the exact mechanisms behind the ‘protein sparing’ effect of ketosis are not entirely established, there are at least four possible mechanisms by which ketogenic diets may spare protein. These include decreased glucose requirements, decreased excretion of ketones from the kidneys, a possible direct effect of ketones on protein synthesis, and the drop in thyroid levels seen during starvation.
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