The metabolic energy control system of the human organism is designed to be fueled by either glucose (carbohydrates) or fatty acids (lipids).1, pp. 160 In a healthy individual, the fuel of choice is largely determined by diet composition and intake schedule. Because food intake is a batch process for most people, the availability of food in the digestive system cycles daily through full, empty, full, and so forth. Thus, for a diet in which the macronutrients (carbohydrates, proteins, and lipids) are consistent and in reasonable proportion, it is customary for the choice of fuel to switch back and forth seamlessly between glucose and fatty acids during the day in response to the alimentation cycles.
The messenger that tells the body which fuel to use is the blood insulin/glucagon ratio. Immediately after eating, insulin is dominant (in response to glucose intake) and its analogous hormone glucagon is negligible. The high insulin/glucagon ratio signals the use of glucose as fuel. As hours go by, dietary glucose becomes spent and the need to conserve glucose by stopping its use as fuel comes into play. The lowered insulin level makes way for glucagon to come to the fore and preserve blood glucose levels. The drop in insulin/glucagon ratio signals conversion to use of fatty acids.
The insulin/glucagon ratio is the most important determinant of the relative contribution of the two major sources of fuel for the body’s energy needs. When the ratio is large, glucose is the major fuel; when the ratio is small, it is fatty acids. The insulin/glucagon ratio can vary almost a 100-fold depending on nutritional state and/or glucose availability. It can be from as high as 30 after eating to as low as 0.3 after fasting.
In the well-fed state, glucose is the usual and ready source of metabolic energy for humans, with intermittent dependence on fatty acids for energy until the next supply of dietary glucose is forthcoming. Despite the fact that glucose serves as the usual and ready source of energy for metabolic functions, fatty acids are a much more efficient fuel than glucose. For example, palmitic acid (16 carbons) yields about 25 percent more energy than glucose (6 carbons) on a carbon-for-carbon basis.
Fatty acids are also a much more efficient form for storage of fuel. Triglycerides, the storage form of fatty acids, require less space for storage than glycogen, the storage form of glucose. In addition, triglycerides have an almost endless supply of adipose tissue storage depots throughout the human body whereas glycogen has a limited number of depots, the largest and most important of which is in the liver.
Biochemical Overview of Mechanism
Glucose as the energy source: The glycolytic pathway is the biochemical entry point for conversion of glucose to chemical energy. Glucose is metabolized by a series of ten reactions to form pyruvate, the end point of glycolysis. Pyruvate is then oxidatively decarboxylated to form acetyl CoA in preparation for entry into the Krebs cycle (also known as the tricarboxylic acid or citric acid cycle). In the eight reactions of the Krebs cycle, acetyl CoA is oxidized to CO2, H2O, and high energy phosphate bonds in the form of ATP. The energy yield from one molecule of glucose by way of glycolysis and the Krebs cycle is approximately 32 molecules of ATP.
The switch to fatty acids: A brief outline of the metabolic events that occur with conversion of the energy source from glucose to fatty acids is as follows: When blood glucose falls too low or below normal levels, the rate of glycolysis slows; This decreases the amount of pyruvate formed (the end point of glycolysis). The decrease in quantity of pyruvate results in a decrease in amount of acetyl CoA formed for entry into the Krebs cycle. Because pyruvate is also a precursor of oxaloacetic acid, a decrease in the quantity of pyruvate also can result ultimately in a decrease in oxaloacetic acid (the entry point of acetyl CoA into the Krebs cycle) required for operation of the Krebs cycle.
The deficiencies of acetyl CoA and oxaloacetic acid slow the Krebs cycle. The resulting reduction in energy production by the Krebs cycle creates the demand for more energy than is available from glucose alone. This is met by mobilization of fat from storage depots and degradation of fatty acids. The energy produced by b-oxidation of fatty acids replaces that normally provided by glucose.
The drop in acetyl CoA from pyruvate is more than made up by acetyl CoA from degradation of fatty acids (acetyl CoA is the end point of b-oxidation). If the low-blood-glucose interval is relatively brief, as in the case of the normal individual described above, deficiency of oxaloacetic acid may not have time to occur. In this event, acetyl CoA will continue to be processed by the Krebs cycle.
Fatty acids as the energy source: Part 1: The catabolic pathway known as b-oxidation is the biochemical entry point for conversion of fatty acids to chemical energy. Fatty acids are dismantled two carbons at a time starting at the carboxyl end of the fatty acid chain. The first two carbons after the carboxyl carbon are labeled alpha and beta. Thus, in b-oxidation, the beta carbon is oxidized to a carboxyl group and the original carboxyl and alpha carbons are split off from the carbon chain. The original carboxyl and alpha carbons form an acetyl group, which becomes acetyl CoA, and the balance of the carbon chain becomes a two-carbon-shorter fatty acid.
b-oxidation reaction is repeated sequentially along the chain until the entire fatty acid has produced the appropriate number of acetyl CoA molecules. The energy yield from formation of one molecule of acetyl CoA by b-oxidation is approximately 10 molecules of ATP. However, b-oxidation is only half the story of fatty acid use as fuel for metabolic energy. The acetyl CoA produced by b-oxidation has as much energy left in it as was liberated in its formation. It produces the same energy through the Krebs cycle as does the acetyl CoA produced by glucose.
Fatty acids as the energy source: Part 2: Prolonged insufficiency of glucose as the energy source can deplete the store of oxaloacetic acid in the Krebs cycle, as described above. This moves the use of fatty acid as fuel into a second phase.
In the second phase, the Krebs cycle will slow to such an extent that the acetyl CoA from b-oxidation accumulates and cannot be converted adequately to CO2, H2O, and energy. In this case, an oxidative pathway other than the Krebs cycle must be used for continued energy production. This alternate pathway diverts acetyl CoA from the Krebs cycle via HMG CoA (b-hydroxy-b-methylglutaryl-butyrate CoA) to the pathway that leads to ketone body synthesis. This pathway is called ketogenesis.
A rough sketch of the biochemistry of ketogenesis is as follows: Acetyl CoA condenses with itself to form acetoacetate; Acetoacetate is either reduced to b-hydroxybutyrate or decarboxylated to acetone (depending on body’s need at the moment); b-hydroxybutyrate is thought to be the ketone body responsible for energy production and acetone is considered a waste product to be excreted in the urine and breath. Ketone bodies can restore activity of the Krebs cycle by entering the cycle at a point earlier than the blocked oxaloacetic acid step (e.g. the succinate step). This may be a key mechanism by which ketone bodies are oxidized to provide metabolic energy.
What is acetoacetate’s true role in ketogenesis? It has been described as being like an old maid waiting for a proposal; does it go to b-hydroxybutyrate? or acetone? or does it go back home to acetyl CoA? What it does is follow the most immediate need of the body at the moment. The synthesis of acetoacetate has been mentioned as one of biochemistry’s futile cycles (energy cost with no yield). Apparently if acetoacetate is not used fairly quickly, the reaction reverses back to acetyl CoA.
Effect of Diet on Metabolic Energy Control
There are many biochemical pathways in the human organism that are not in constant use but are available for use when the need for them arises. Like stand-by activities that figuratively march in time until their substrates are presented to them, the metabolic control switching mechanisms wait for orders. The ease with which the body switches back and forth between glucose and fatty acids for energy depends on how often the switch is called into play.
In the case of routine operation, as described above, the switch is frequent and essentially effortless. However, significant deviations from a nutritional pattern of moderate (controlled) carbohydrates, proper balance between omega-6 and omega-3 essential fatty acids, and adequate micronutrients can send confusing (inflammatory) signals to the switching mechanism.
The major disruptive force in the normal interconversion between fuel sources is the dietary indiscretion of excessive consumption of sugars and starches. Diets that are low or lacking in sugars or starches do not appear to disrupt the switching mechanism but rather alter the relative contribution of each fuel to the organism’s metabolic energy production.
High-Carbohydrate Diet: The sequence of events from normal weight through obesity to diabetes starts with a customary dietary pattern of high carbohydrate intake. The usual chain of events is hypoglycemia (unstable blood glucose), hypoglycemia-hyperglycemia rollercoaster effect, insulin resistance, obesity, and ultimately type-2 diabetes. Normal switching from glucose to fatty acid fuel is impeded by constant dietary replenishment with glucose that prevents the insulin/glucagon ratio from falling into a range that would signal a switch to fatty acids. The glycolytic pathway is overwhelmed with an excess of dietary glucose; fatty acid oxidation is inhibited by high insulin/glucagon ratios.
This apparent disturbance of fuel selection at the cellular level is not a defect of the cell’s mechanism of energy production; rather it is the result of the cell’s energy production being dictated by its host’s diet. The failure to switch from glucose to fatty acids is not a cause of obesity but a co-symptom with obesity as the consequence of an unhealthful diet.
The Controlled Carbohydrate Diet: The overview of the metabolic fuel switching pattern discussed above describes that of nutritional plans that permit regular daily full-range excursions of the insulin/glucagon ratio. It can be imagined that because the potential number of different dietary combinations of carbohydrates, proteins, and fats is large, so too is the number of individual fuel switching patterns that occur in response.
It is quite probable that in the range of controlled carbohydrate nutritional patterns, depending on the dietary contribution of glucose, the second step of fatty acid utilization (ketogenesis) for metabolic energy may seldom or never be invoked.
The Low- or No-Carbohydrate Diet: A nutritional plan that contains little or no dietary carbohydrates is referred to as a ketogenic diet. It provides little or no glucose for use as an energy source. Any glucose that is gleaned from the diet or made anew from glycerol and/or nonessential amino acids is spared primarily to serve the blood glucose pool. The major fuel for metabolic energy in ketogenic diets is fatty acids with the acetyl CA from b-oxidation diverted to HMG CoA.
The difficulty or ease of transition to a ketogenic diet can vary greatly depending on the nutritional plan that it is replacing. The greatest difficulty occurs in people who have a long history of high-carbohydrate intake, disturbed insulin/glucagon ratios, and possible insulin resistance. The only fuel these bodies have been offered is glucose; they do not have the familiarity of using fatty acids for energy. It has been estimated that conversion to a metabolic energy control system normal for a ketogenic diet takes a minimum of two to three weeks.
The period of transition to a ketogenic diet, although difficult, is not dangerous. It will relieve inflammation and ultimately support healing. Once the new dietary pattern is established and the energy control system is stabilized, fuel use will be dictated by the insulin/glucagon ratio, with glucose serving only when in excess of needs for blood glucose and fatty acids serving at all other times. A routine lack of glucose for fuel does not seem to impair the ease of switching between glucose and fatty acids as necessary. However, it is at this point that the quality and quantity of fatty acids selected for use as fuel becomes critical (see Ketopia post The Importance of Dietary Animal Fat).
Ketone Bodies and Ketosis
Because the public has been so misinformed about the significance of ketone body production, it is important to explain more fully what ketone bodies are and how and why they are formed.
Ketones are organic chemicals in which an interior carbon in a molecule forms a double bond with an oxygen molecule. Acetone, a familiar chemical, is the smallest ketone possible. It is composed of three carbons, with the double bond to oxygen on the middle carbon. Biological ketone bodies include acetone, larger ketones, and biochemicals that can become ketones. The most important of the ketone bodies for human biochemistry are b-hydroxybutyrate and acetoacetate, both of which are formed from condensation of two acetyl CoA molecules. Acetone is formed from a nonenzymatic decarboxylation of acetoacetate.
Ketone bodies are fuel molecules that can be used for energy by all organs of the body except the liver. The production of ketone bodies is a normal, natural, and important biochemical pathway in animal biochemistry. Small quantities of ketone bodies are always present in the blood, with the quantity increasing as hours without food increase. During fasting or carbohydrate deprivation, larger amounts of ketone bodies are produced to provide the energy that is normally provided by glucose.
Excessive levels of circulating ketone bodies can result in ketosis, a condition in which the quantity of circulating ketone bodies is greater than the quantity the organs and tissues of the body need for energy. People who go on extremely low-carbohydrate diets to lose a large excess of body fat usually go into a mild ketosis that moderates as weight is lost. There is no scientific evidence that a low-carbohydrate diet is capable of producing sufficient ketone bodies to be harmful.
Excess ketone bodies are excreted by the kidneys and lungs. Exhaled acetone gives the breath a characteristic, sweetish odor. If ketosis is maintained for prolonged periods, as can occur in untreated type-1 diabetes (insulin-dependent diabetes), the blood can become very acidic. This life-threatening disorder is known as ketoacidosis.
Ketone bodies that are excreted in the urine and the breath carry with them the calories they contain. These are calories that were counted in the diet but were made unavailable to the body by being excreted before being used. In effect, the body actually receives fewer calories than the amount calculated. Thus, for individuals with normal pancreatic function, a ketogenic (low-carbohydrate) diet containing a given number of calories will result in greater weight loss than a nonketogenic diet (high-carbohydrate) containing the same number of calories. This difference in apparent caloric content between low-carbohydrate and high-carbohydrate diet plans has given rise to the observation that ketogenic diets have a metabolic advantage over nonketogenic diets with regard to weight loss. The difference is also relevant to the argument about whether a calorie is a calorie.
Dietetic versus Diabetic Ketosis
The nutrition community has fostered the popular misconception that ketone-body production, per se, is an undesirable metabolic circumstance. It has warned that the formation of ketone bodies is a dangerous consequence of low-carbohydrate diets in an effort to discredit any recommendations that deviate from official dietary recommendations. As a result, the public has come to view formation of ketone bodies as a symptom of a pathological condition rather than a normal move by the body to satisfy its demands for energy when glucose supplies are short. This unfortunate misunderstanding stems from allegations that brief periods of dietary ketosis from diets low in carbohydrates have the same medical significance as diabetic ketosis. These allegations are grossly in error.
Diabetic Ketosis: There is no question that the ketosis of type-1 diabetes is undesirable and dangerous. In type-1 diabetes, the ability of the pancreas to make insulin is either diminished or absent. The mechanism by which ketone bodies are formed in type-1 diabetes is similar to that which occurs with a low-carbohydrate diet. In the absence of insulin, fatty acids are mobilized and degraded, excess acetyl CoA is produced, and the excess is directed to HMG CoA and ketone bodies and potentially to ketoacidosis.
Dietary Ketosis: Dietary ketosis is an entirely different condition because it usually occurs in people with sound pancreatic function with an ample supply of insulin. If glucose is not supplied by the diet, blood glucose levels drop. As a result of low blood glucose, insulin drops to a low level and its counterpart hormone, glucagon, assumes control. To spare glucose by providing a substitute energy source, glucagon stimulates the degradation of fatty acids and the conversion of surplus acetyl CoA to ketone bodies. It is only when glucose sources are severely restricted that excess ketone bodies are produced and the acetone odor in the breath becomes noticeable.
In summary: Diabetic ketosis is the body’s demanding call for insulin. It is a warning signal that insulin levels have been permitted to fall too low and blood sugar levels are too high and out of control. On the contrary, dietary ketosis is the body’s demanding call for glucose. It is a warning signal that the glucose supply is insufficient and, as a result, the body is burning fatty acids mobilized from fat storage sites for energy.
- Adapted from Ottoboni A, Ottoboni F. The Modern Nutritional Diseases and How to Prevent Them, Second Edition. Fernley, NV: Vincente Books, 2013.