There are several factors which affect the mix of fuels used by the body. The primary factor is the amount of each nutrient (protein, carbohydrate, fat and alcohol) being consumed and this impacts on the other three factors. The second determinant is the levels of hormones such as insulin and glucagon, which are directly related to the mix of foods being consumed. Third is the bodily stores of each nutrient including fat stores and muscle/liver glycogen. Finally the levels of regulatory enzymes for glucose and fat breakdown, which are beyond our control except through changes in diet and activity, determine the overall use of each fuel. Each of these factors are discussed in detail below.
There are four substances which man can derive calories from: carbohydrate, protein, fats, and alcohol. As stated above, the body will tend to utilize a given fuel for energy in relation to its availability and concentration in the bloodstream.
In general, the body can increase or decrease its use of glucose in direct proportion to the amount of dietary carbohydrate being consumed. This is an attempt to maintain body glycogen stores at a certain level. If carbohydrate consumption increases, carbohydrate use will go up and vice versa.
Protein is slightly less regulated. When protein intake goes up, protein oxidation will also go up to some degree. By the same token, if protein intake drops, the body will use less protein for fuel. This is an attempt to maintain body protein stores at constant levels.
In contrast, the amount of dietary fat being eaten does not significantly increase the amount of fat used for fuel by the body. Rather fat oxidation is determined indirectly: by alcohol and carbohydrate consumption.
The consumption of alcohol will almost completely impair the body’s use of fat for fuel.
Similarly the consumption of carbohydrate affects the amount of fat used by the body for fuel. A high carbohydrate diet decreases the use of fat for fuel and vice versa. Thus, the greatest rates of fat oxidation will occur under conditions when carbohydrates are restricted. As well, the level of muscle glycogen regulates how much fat is used by the muscle. Using exercise and/or carbohydrate restriction to lower muscle and liver glycogen levels increases fat utilization.
There are a host of regulatory hormones which determine fuel use in the human body. The primary hormone is insulin and its levels, to a great degree, determine the levels of other hormones and the overall metabolism of the body. A brief examination of the major hormones involved in fuel use appears below.
Insulin is a peptide (protein based) hormone released from the pancreas, primarily in response to increases in blood glucose. When blood glucose increases, insulin levels increase as well, causing glucose in the bloodstream to be stored as glycogen in the muscle or liver. Excess glucose can be pushed into fat cells for storage (as alpha-glycerophosphate). Protein synthesis is stimulated and free amino acids (the building blocks of proteins) are be moved into muscle cells and incorporated into larger proteins. Fat synthesis (called lipogenesis) and fat storage are both stimulated. FFA release from fat cells is inhibited by even small amounts of insulin. The primary role of insulin is to keep blood glucose in the fairly narrow range of roughly 80-120 mg/dl. When blood glucose increases outside of this range, insulin is released to lower blood glucose back to normal. The greatest increase in blood glucose levels (and the greatest increase in insulin) occurs from the consumption of dietary carbohydrates. Protein causes a smaller increase in insulin output because some individual amino acids can be converted to glucose. FFA can stimulate insulin release as can high concentrations of ketone bodies although to a much lesser degree than carbohydrate or protein.
When blood glucose drops (during exercise or with carbohydrate restriction), insulin levels generally drop as well. When insulin drops and other hormones such as glucagon increase, the body will break down stored fuels. Triglyceride stored in fat cells is broken down into FFA and glycerol and released into the bloodstream. Proteins may be broken down into individual amino acids and used to produce glucose. Glycogen stored in the liver is broken down into glucose and released into the bloodstream. These substances can then be used for fuel in the body.
An inability to produce insulin indicates a pathological state called Type I diabetes (or Insulin Dependent Diabetes Mellitus, IDDM). Type I diabetics suffer from a defect in the pancreas leaving them completely without the ability to make or release insulin. IDDM diabetics must inject themselves with insulin to maintain blood glucose within normal levels. This will become important when the distinction between diabetic ketoacidosis and dietary induced ketosis is made.
Glucagon is essentially insulin’s mirror hormone and has essentially opposite effects. Like insulin, glucagon is also a peptide hormone released from the pancreas and its primary role is also to maintain blood glucose levels. However, glucagon acts by raising blood glucose when it drops below normal.
Glucagon’s main action is in the liver, stimulating the breakdown of liver glycogen which is then released into the bloodstream. Glucagon release is stimulated by a variety of stimuli including a drop in blood glucose/insulin, exercise, and the consumption of a protein meal.
High levels of insulin inhibit the pancreas from releasing glucagon.
Under normal conditions, glucagon has very little effect in tissues other than the liver (i.e.
fat and muscle cells). However, when insulin is very low, as occurs with carbohydrate restriction and exercise, glucagon plays a minor role in muscle glycogen breakdown as well as fat mobilization. In addition to its primary role in maintaining blood glucose under conditions of low blood sugar, glucagon also plays a pivotal role in ketone body formation in the liver, discussed in detail in the next chapter.
From the above descriptions, it should be clear that insulin and glucagon play antagonistic roles to one another. Whereas insulin is primarily a storage hormone, increasing storage of glucose, protein and fat in the body ; glucagon’s primary role is to mobilize those same fuel stores for use by the body.
As a general rule, when insulin is high, glucagon levels are low. By the same token, if insulin levels decrease, glucagon will increase. The majority of the literature (especially as it pertains to ketone body formation) emphasizes the ratio of insulin to glucagon, called the insulin/glucagon ratio (I/G ratio), rather than absolute levels of either hormone. This ratio is an important factor in the discussion of ketogenesis in the next chapter. While insulin and glucagon play the major roles in determining the anabolic or catabolic state of the body, there are several other hormones which play additional roles. They are briefly discussed here.
Growth hormone (GH) is another peptide hormone which has numerous effects on the body, both on tissue growth as well as fuel mobilization. GH is released in response to a variety of stressors the most important of which for our purposes are exercise, a decrease in blood glucose, and carbohydrate restriction or fasting. As its name suggests, GH is a growth promoting hormone, increasing protein synthesis in the muscle and liver. GH also tends to mobilize FFA from fat cells for energy.
In all likelihood, most of the anabolic actions of GH are mediated through a class of hormones called somatomedins, also called insulin-like growth factors (IGFs). The primary IGF in the human body is insulin like growth factor-1 (IGF-1) which has anabolic effects on most tissues of the body. GH stimulates the liver to produce IGF-1 but only in the presence of insulin.
High GH levels along with high insulin levels (as would be seen with a protein and carbohydrate containing meal) will raise IGF-1 levels as well as increasing anabolic reactions in the body. To the contrary, high GH levels with low levels of insulin, as seen in fasting or carbohydrate restriction, will not cause an increase in IGF-1 levels. This is one of the reasons that ketogenic diets are not ideal for situations requiring tissue synthesis, such as muscle growth or recovery from certain injuries: the lack of insulin may compromise IGF-1 levels as well as affecting protein synthesis.
There are two thyroid hormones, thyroxine (T4) and triiodothyronine (T3). Both are released from the thyroid gland in the ratio of about 80% T4 and 20% T3. In the human body, T4
is primarily a storage form of T3 and plays few physiological roles itself. The majority of T3 is not released from the thyroid gland but rather is converted from T4 in other tissues, primarily the liver. Although thyroid hormones affect all tissues of the body, we are primarily concerned with the effects of thyroid on metabolic rate and protein synthesis. The effects of low-carbohydrate diets on levels of thyroid hormones as well as their actions are discussed in chapter 5.
Cortisol is a catabolic hormone released from the adrenal cortex and is involved in many reactions in the body, most related to fuel utilization. Cortisol is involved in the breakdown of protein to glucose as well as being involved in fat breakdown.
Although cortisol is absolutely required for life, an excess of cortisol (caused by stress and other factors) is detrimental in the long term, causing a continuous drain on body proteins including muscle, bone, connective tissue and skin. Cortisol tends to play a permissive effect in its actions, allowing other hormones to work more effectively.
Adrenaline and noradrenaline (also called epinephrine and norepinephrine) are frequently referred to as ‘fight or flight’ hormones. They are generally released in response to stress such as exercise, cold, or fasting. Epinephrine is released primarily from the adrenal medulla, traveling in the bloodstream to exert its effects on most tissues in the body. Norepinephrine is released primarily from the nerve terminals, exerting its effects only on specific tissues of the body.
The interactions of the catecholamines on the various tissues of the body are quite complex and beyond the scope of this book. The primary role that the catecholamines have in terms of the ketogenic diet is to stimulate free fatty acid release from fat cells.
When insulin levels are low, epinephrine and norepinephrine are both involved in fat mobilization. In humans, only insulin and the catecholamines have any real effect on fat mobilization with insulin inhibiting fat breakdown and the catecholamines stimulating fat breakdown.
The liver is one of the most metabolically active organs in the entire body. All foods coming through the digestive tract are processed initially in the liver. To a great degree, the level of liver glycogen is the key determinant of the body’s overall trend to store or breakdown nutrients.
Additionally, high levels of liver glycogen tends to be associated with higher bodyfat levels.
The liver is basically a short term storehouse for glycogen which is used to maintain blood glucose. The breakdown of liver glycogen to glucose, to be released into the bloodstream, is stimulated by an increase in glucagon as discussed previously.
When liver glycogen is full, blood glucose is maintained and the body is generally anabolic, which means that incoming glucose, amino acids and free fatty acids are stored as glycogen, proteins, and triglycerides respectively. This is sometimes called the ‘fed’ state.
When liver glycogen becomes depleted, via intensive exercise or the absence of dietary carbohydrates, the liver shifts roles and becomes catabolic. Glycogen is broken into glucose, proteins are broken down into amino acids, and triglycerides are broken down to free fatty acids.
This is sometimes called the ‘fasted’ state.
If liver glycogen is depleted sufficiently, blood glucose drops and the shift in insulin and glucagon occurs. This induces ketone body formation, called ketogenesis.
The final regulator of fuel use in the body is enzyme activity. Ultimately enzyme levels are determined by the nutrients being ingested in the diet and the hormonal levels which result.
For example, when carbohydrates are consumed and insulin is high, the enzymes involved in glucose use and glycogen storage are stimulated and the enzymes involved in fat breakdown are inhibited. By the same token, if insulin drops the enzymes involved in glucose use are inhibited and the enzymes involved in fat breakdown will increase.
Long term adaptation to a high carbohydrate or low carbohydrate diet can cause longer term changes in the enzymes involved in fat and carbohydrate use as well. If an individual consumes no carbohydrates for several weeks, there is a down regulation of enzymes in the liver and muscle which store and burn carbohydrates. The end result of this is an inability to use carbohydrates for fuel for a short period of time after they are reintroduced to the diet.
Although there are four major fuels which the body can use, for our purposes only the interactions between glucose and free fatty acids need to be considered. As a general rule, assuming that the body’s total energy requirements stay the same, an increase in glucose use by the body will result in a decrease in the use of fatty acids and vice versa.
There are four major factors that regulate fuel use by the body. Ultimately they are all determined by the intake of dietary carbohydrates. When carbohydrate availability is high, carbohydrate use and storage is high and fat use is low. When carbohydrate availability is low, carbohydrate use and storage is low and fat use is high.
The most basic premise of the ketogenic diet is that the body can be forced to burn greater amounts of fat by decreasing its use of glucose.
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