Having discussed the basics of fuel utilization, ketone body formation and ketosis, it is now time to examine in detail the adaptations which occur in shifting the body away from glucose and towards fat metabolism. The primary adaptation occurs in the brain although other systems are affected as well.
There is a common misconception, especially among bodybuilders, that ketosis is indicative of protein breakdown when in fact the exact opposite is the case. The development of ketosis sets in motion a series of adaptations which minimize body protein losses during periods of caloric deprivation. In fact, preventing the development of ketosis during these periods increases protein losses from the body.
The adaptations to ketosis are complex and involve most systems of the body. As with the previous sections, smaller details are ignored for this discussion and interested readers should examine the references provided. Rather, the major adaptations which occur in the body’s tissues, especially the brain, liver, kidney and muscle are described The adaptations to ketosis have been studied in great depth during periods of total starvation. While this is an extreme state, the lack of food intake makes it simpler to examine the major adaptations. To help individuals understand the adaptations to ketosis, the metabolism of the body is examined during both short and long term fasting. The following sections address in detail the effects of ketosis on glucose/protein requirements as well as the effects on fat and ketone use.
Starvation and the ketogenic diet
In one sense, the ketogenic diet is identical to starvation, except that food is being consumed. That is, the metabolic effects which occur and the adaptations which are seen during starvation are roughly identical to what is seen during a ketogenic diet. The primary difference is that the protein and fat intake of a ketogenic diet will replace some of the protein and fat which would otherwise be used for fuel during starvation.
The response to total starvation has been extensively studied, arguably more so than the ketogenic diet itself. For this reason the great majority of data presented below comes from studies of individuals who are fasting. With few exceptions, which are noted as necessary, the metabolic effects of a ketogenic diet are identical to what occurs during starvation.
Although it is discussed in greater detail in a later section, the critical aspect of developing ketosis is the quantity of carbohydrates in the diet and carbohydrate restriction mimics the response seen with total fasting (1-3). The amounts of protein and fat are less critical in this regard.
A brief overview of the adaptations to starvation
Before looking in detail at the adaptations to starvation, we will briefly discuss the major events which occur. Starvation can be broken into 5 distinct phases. In the first phase, during the first 8 hours of starvation, the body is still absorbing fuel from previous meals. Within 10 hours after the last carbohydrate containing meal, roughly 50% of the body’s total energy requirements are being met by free fatty acids (FFA).
In the second phase, the first day or two of starvation, the body will rely on FFA and the breakdown of liver glycogen for its energy requirements. Liver glycogen is typically gone within 12-16 hours.
In the third phase, during the first week of starvation, the body will drastically increase the production of glucose from protein and other fuels such as lactate, pyruvate and glycerol. This is called gluconeogenesis (the making of new glucose) and is discussed in detail below. At the same time, tissues other than the brain are decreasing their use of glucose, relying on FFA and ketones instead. This helps to spare what little glucose is available for the brain. During this phase, protein breakdown increases greatly.
The fourth phase of starvation is ketosis, which begins during the third or fourth day of starvation, and continues as long as carbohydrates are restricted. The major adaptations during ketosis is increased utilization of ketones by the brain. The final phase, which begins in the second week, is marked by decreasing protein breakdown and gluconeogenesis, as the major protein sparing adaptations to ketosis occur. With the exception of the initial hours of carbohydrate restriction (phases 1 and 2), each of the above phases is discussed in more detail below.
Changes in hormones and fuel availability
Although some mention is made in the discussions below of the adaptations seen during this time period, most of the major adaptations to ketosis start to occur by the third day, continuing for at least 3 weeks (4-6). During the first 3 days of fasting, blood glucose drops from normal levels of 80-120 mg/dl to roughly 65-75 mg/dl. Insulin drops from 40-50 µU/ml to 7-10 µU/ml (5,7,8). Both remain constant for the duration of the fast. One thing to note is that the body strives to maintain near-normal blood glucose levels even under conditions of total fasting (5). The popularly held belief that ketosis will not occur until blood glucose falls to 50 mg/dl is incorrect. Additionally, the popular belief that there is no insulin present on a ketogenic diet is incorrect (7).
One difference between fasting and a ketogenic diet is that the slight insulin response to dietary protein will cause blood glucose to be maintained at a slightly higher level, approximately 80-85 mg/dl (1). This most likely occurs due to the conversion of dietary protein to glucose in the liver.
At the same time that insulin and glucose are decreasing from carbohydrate restriction, other hormones such as glucagon and growth hormone are increasing, as are the levels of adrenaline and noradrenaline (7,10-12). Cortisol may actually decrease (13). This increases the rate of fat breakdown and blood levels of FFA and ketones increase (6,8,10,14,15).
Although the liver is producing ketones at its maximum rate by day three (14), blood ketone levels will continue to increase finally reaching a plateau by three weeks (6). The decrease in blood glucose and subsequent increase in FFA and ketones appear to be the signal for the adaptations which are seen, and which are discussed below (16).
In addition to increases in FFA and ketones, there are changes in blood levels of some amino acids (AAs). Increases are seen in the the branch chain amino acids, indicating increased protein breakdown (1, 17-19). As well, there are decreases in other AAs, especially alanine (1, 10,17-19) This most likely represents increased removal by the liver but may also be caused by decreased release of alanine from the muscles (16).
Changes in levels of the other amino acids also occur and interested readers should examine the references cited. Blood levels of urea, a breakdown product of protein also increase (1). All of this data points to increased protein breakdown during the initial stages of starvation.
By the third day of carbohydrate restriction, the body is no longer using an appreciable amount of glucose for fuel. At this time essentially all of the non-protein energy is being derived from the oxidation of fat, both directly from FFA and indirectly via ketone bodies (20).
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