Major source of energy for most tissues, including ketones for brain
High use of protein to supply glucose to the brain
Less need for glucose, conservation of protein, utilization of fat reserved
Figures 47.1 and 47.2 describe these stages and their metabolic significance. First, however, a summary of energy production and utilization is useful.
Energy production and utilization
Glucose, fatty acids, and L-amino acids are the major fuels of the body. Although a complete description of their metabolism is beyond the scope of this chapter (a good resource is Biochemistry: a case-oriented approach ), their use for energy production can be simplified as follows:
Fatty acid catabolism occurs in the mitochondria of virtually all tissues except the brain and red blood cells. In the energy-producing process of beta-oxidation, two-carbon fragments are successively removed from the fatty acid to form acetyl CoA and ATP. The acetyl CoA enters the Krebs cycle for conversion to more ATP.
Energy production from glucose metabolism is primarily through the formation of pyruvate (glycolysis), which is converted to acetyl CoA for entry into the Krebs cycle.
When used for energy production, the L-amino acids are, in general, converted to pyruvate, alpha-ketoglutarate, and oxaloacetate, again for entry into the Krebs cycle.
Figure 47-2Mechanisms of glucose production during fasting
The major form of utilizable energy in all cells is ATP, which is produced by oxidative catabolism of D-glucose, alpha-ketones, fatty acids, and/or L-amino acids.
The energy for resting heart and skeletal muscle is met primarily by oxidation of acetoacetate (produced by the liver from acetyl CoA) and fatty acids, and secondarily by glucose oxidation. Muscle contraction requires a continuous supply of ATP, large amounts of which may be almost instantaneously produced by massive conversion of glycogen to lactate (the primary purpose of muscle glycogen). During extreme muscle activity, other short-term energy sources, such as phosphocreatine, are also used. Neither of these is utilized, however, to maintain energy levels during fasting. Exercise also greatly increases glucose utilization by heart and skeletal muscle, which, as discussed below, is probably why resting is important in fasting, since the major source of glucose during fasting is protein catabolism.
Under the fed condition, the energy requirement of the mature brain is met almost entirely by glucose. Since the glycogen content of the brain is very low (0.1%), there is essentially no brain-glucose reserve. After a few days of fasting, the brain switches to oxidation of beta-hydroxybutyrate (produced by the liver from acetyl CoA) as its primary energy source.
The initial physiological response to the lack of food is the increased synthesis of the glucose by the liver for release into the bloodstream. Glucose is especially needed by the brain, which consumes about 65% of the total circulating glucose (400–600 kcal/day), and the red blood cells. Together they consume 100–180 g of glucose per day. Early on in fasting, the liver is the sole source of glucose for the bloodstream. The liver initially synthesizes glucose from glycogen through glycogenolysis. However, liver glycogen stores can only supply enough glucose for a few hours (see Tables 47.1 and 47.2 ), and glucose production from gluconeogenesis soon becomes necessary. Although muscle actually contains more glycogen than liver, it lacks the enzyme D-glucose-6-phosphatase and therefore cannot convert glycogen to glucose for release into the bloodstream. Later in fasting, the glycogen reserves are restored.
Gluconeogenesis utilizes primarily L-amino acids for glucose synthesis, although glycerol from triglyceride catabolism is also used. Since liver glycogenic amino acid stores are quickly depleted, substrate from other tissues, primarily the muscles, is required. As the fast proceeds, the kidneys become progressively more important in the maintenance of blood glucose levels, and eventually the renal cortex synthesizes more glucose from amino acids than does the liver. If the body continued to require its normal 100–180 g/day of glucose, gluconeogenesis during fasting would quickly use up much body protein, and death would ensue within 3–4 weeks. Early on in fasting, the body catabolizes 60–84 g/day of protein.
Initially, sodium, potassium, and water diuresis occurs and hypovolemia develops. Calcium and magnesium are also lost. Plasma ketones rise, and ketones appear in the urine by the third day.
Research using respiratory quotient and urinary nitrogen studies has repeatedly shown that triglycerides are the major fuel during fasting. To leave the adipocyte, triglycerides must first be hydrolyzed (lypolysis) to fatty acids and glycerol. The fatty acids are transported in the blood, in a physical complex with albumin, to the liver, muscle, and other tissues.
Although the brain converts to oxidation of beta-hydroxybutyrate after 4–7 days, there is still an obligatory need for approximately 80 g/day of glucose for the brain, red cells, muscles, and other tissues. This requirement increases significantly during exercise. Although much of the lactate produced by anaerobic metabolism of glucose and glycogen is resynthesized to glucose by the liver via the Cori cycle, the need for glucose is increased, since there is a net loss due to urinary excretion of lactic acid and metabolic inefficiency. Approximately 16 g of glucose is synthesized from triglyceride glycerol, with the rest of the glucose requirement (and the other metabolic processes requiring amino acids, e.g. enzyme turnover) being met by the catabolism of 18–24 g/day of protein. In experimental animals, as much as 14% of the energy needed by muscle may come from the oxidation of branched-chain amino acids. Glucose is also recycled by the breakdown of blood cells in the liver. The mechanisms of glucose production during fasting are summarized in Figure 47.2 .
Research has determined that an average 70 kg male has the fat stores to maintain basic caloric requirements for 2–3 months of fasting.
Starvation occurs when the body’s fat reserves are depleted and significant protein catabolism again becomes necessary for energy production. As noted above, unless fat reserves are being utilized for energy production and glucose sparing, the body protein stores are adequate for only a few weeks of gluconeogenesis, after which essential proteins are utilized and death occurs.
Mechanism of ketosis
During fasting, when excessive amounts of fatty acids are being oxidized and inadequate glucose is available, large quantities of ketones are secreted into the bloodstream. Ketone bodies are made in the liver from acetyl CoA.
During adequate energy input, the conversion of fatty acids to acetyl CoA is regulated by the availability of L-glycerol 3-phosphate (derived from glucose through the glycolytic pathway). As the concentration of acetyl CoA rises, it is resynthesized into triglycerides, with L-glycerol 3-phosphate serving as the accepter to which three acyl CoA groups are attached (through esterification). During fasting, there is inadequate glucose to provide the needed glycerol for triglyceride synthesis, resulting in acetyl CoA levels in excess of the oxidative capacity of the Krebs cycle. The excess is then shunted into the synthesis of ketone bodies. These ketone bodies (acetoacetic acid, acetone, and beta-hydroxybutyric acid) are utilized by the heart, and, later in fasting, by the brain for energy production.
Mechanism of acidosis
Since the ketone bodies are acids, their entry into the plasma results in an increase in hydrogen ions. This is buffered by the conversion of bicarbonate into carbonic acid and then to CO2 , which is exhaled. Eventually the buffering capacity is exceeded, and the plasma pH decreases, resulting in mild metabolic acidosis. The body compensates for this by increasing the respiratory rate to promote further elimination of CO2 and by excreting ketone bodies in the urine. These adaptations may result in some electrolyte imbalance.
With the exception of leucine, which appears to be a regulator of protein turnover in muscle, all amino acids are glucogenic. However, alanine plays a prominent role in a cycle analogous to the Cori cycle for lactate. The alanine cycle provides the mechanism for the recycling of a fixed supply of glucose and the effective transportation to the liver of amino acid nitrogen derived from muscle breakdown. Because muscle, unlike liver, is incapable of synthesizing urea, most of the amino nitrogen from protein breakdown is transferred to pyruvate to form alanine. The alanine enters the blood and is taken up by the liver. The amino groups are removed to form urea, and the resulting pyruvate is converted to glucose. The newly synthesized glucose is secreted into the blood, taken up by the muscle, and catabolized to pyruvate to reseed the alanine cycle.
Serum electrolyte levels usually do not change significantly during fasting and are not good indicators of tissue stores but are considered the most important blood values during fasting. During early fasting the body loses 150–250 mEq (3.5–5.8 g) of sodium and 40–45 mEq (1.6–1.8 g) of potassium a day. Later, these drop to 1–15 mEq (0.02–0.35 g) and 10–15 mEq (0.4–0.6 g), respectively. The total body stores of sodium are 83–97 g (of which 65% is exchangeable) and of potassium are 115–131 g (of which 98% is exchangeable). The typical daily dietary intake of sodium is 3–7 g and of potassium is 3–5 g. Serum potassium usually decreases but may be elevated. Results below 3 mEq/L or above 6 mEq/L may necessitate breaking the fast. Total calcium is usually stable, but ionic calcium often decreases, especially if vomiting is present.
Physical changes during fasting
Physical changes during the fast generally include a decrease in weight, pulse, and blood pressure. EKG changes may include sinus bradycardia, decreased QRS complex and T-wave amplitude, elongation of the QT interval, and shifts to the right of the QRS and T-wave axes. These changes return to normal after fasting.