.
The plasma levels of fatty acids and ketone bodies increase in starvation, whereas that of glucose decreases.
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We shall now consider the biochemical responses to a series of physiological conditions. Our first example is the starved-fed cycle, which we all experience in the hours after an evening meal and through the night's fast. This nightly starved-fed cycle has three stages: the postabsorptive state after a meal, the early fasting during the night, and the refed state after breakfast. A major goal of the many biochemical alterations in this period is to maintain glucose homeostasis—that is, a constant blood-glucose level.
The well-fed, or postabsorptive, state. After we consume and digest an evening meal, glucose and amino acids are transported from the intestine to the blood. The dietary lipids are packaged into chylomicrons and transported to the blood by the lymphatic system. This fed condition leads to the secretion of insulin, which is one of the two most important regulators of fuel metabolism, the other regulator being glucagon. The secretion of the hormone insulin by the β cells of the pancreas is stimulated by glucose and the parasympathetic nervous system (Figure 30.15). In essence, insulin signals the fed state—it stimulates the storage of fuels and the synthesis of proteins in a variety of ways. For instance, insulin initiates protein kinase cascades—it stimulates glycogen synthesis in both muscle and the liver and suppresses gluconeogenesis by the liver. Insulin also accelerates glycolysis in the liver, which in turn increases the synthesis of fatty acids.
The liver helps to limit the amount of glucose in the blood during times of plenty by storing it as glycogen so as to be able to release glucose in times of scarcity. How is the excess blood glucose present after a meal removed? Insulin accelerates the uptake of blood glucose into the liver by GLUT2. The level of glucose 6-phosphate in the liver rises because only then do the catalytic sites of glucokinase become filled with glucose. Recall that glucokinase is active only when blood-glucose levels are high. Consequently, the liver forms glucose 6-phosphate more rapidly as the blood-glucose level rises. The increase in glucose 6-phosphate coupled with insulin action leads to a buildup of glycogen stores. The hormonal effects on glycogen synthesis and storage are reinforced by a direct action of glucose itself. Phosphorylase a is a glucose sensor in addition to being the enzyme that cleaves glycogen. When the glucose level is high, the binding of glucose to phosphorylase a renders the enzyme susceptible to the action of a phosphatase that converts it into phosphorylase b, which does not readily degrade glycogen. Thus, glucose allosterically shifts the glycogen system from a degradative to a synthetic mode.
The high insulin level in the fed state also promotes the entry of glucose into muscle and adipose tissue. Insulin stimulates the synthesis of glycogen by muscle as well as by the liver. The entry of glucose into adipose tissue provides glycerol 3-phosphate for the synthesis of triacylglycerols. The action of insulin also extends to amino acid and protein metabolism. Insulin promotes the uptake of branched-chain amino acids (valine, leucine, and isoleucine) by muscle. Indeed, insulin has a general stimulating effect on protein synthesis, which favors a building up of muscle protein. In addition, it inhibits the intracellular degradation of proteins.
The early fasting state. The blood-glucose level begins to drop several hours after a meal, leading to a decrease in insulin secretion and a rise in glucagon secretion; glucagon is secreted by the α cells of the pancreas in response to a low blood-sugar level in the fasting state. Just as insulin signals the fed state, glucagon signals the starved state. It serves to mobilize glycogen stores when there is no dietary intake of glucose. The main target organ of glucagon is the liver. Glucagon stimulates glycogen breakdown and inhibits glycogen synthesis by triggering the cyclic AMP cascade leading to the phosphorylation and activation of phosphorylase and the inhibition of glycogen synthase (Section 21.5). Glucagon also inhibits fatty acid synthesis by diminishing the production of pyruvate and by lowering the activity of acetyl CoA carboxylase by maintaining it in an unphosphorylated state. In addition, glucagon stimulates gluconeogenesis in the liver and blocks glycolysis by lowering the level of F-2,6-BP.
All known actions of glucagon are mediated by protein kinases that are activated by cyclic AMP. The activation of the cyclic AMP cascade results in a higher level of phosphorylase a activity and a lower level of glycogen synthase a activity. Glucagon's effect on this cascade is reinforced by the diminished binding of glucose to phosphorylase a, which makes the enzyme less susceptible to the hydrolytic action of the phosphatase. Instead, the phosphatase remains bound to phosphorylase a, and so the synthase stays in the in-active phosphorylated form. Consequently, there is a rapid mobilization of glycogen.
The large amount of glucose formed by the hydrolysis of glucose 6-phosphate derived from glycogen is then released from the liver into the blood. The entry of glucose into muscle and adipose tissue decreases in response to a low insulin level. The diminished utilization of glucose by muscle and adipose tissue also contributes to the maintenance of the bloodglucose level. The net result of these actions of glucagon is to markedly increase the release of glucose by the liver.
Both muscle and liver use fatty acids as fuel when the blood-glucose level drops. Thus, the blood-glucose level is kept at or above 80 mg/dl by three major factors: (1) the mobilization of glycogen and the release of glucose by the liver, (2) the release of fatty acids by adipose tissue, and (3) the shift in the fuel used from glucose to fatty acids by muscle and the liver.
What is the result of depletion of the liver's glycogen stores? Gluconeogenesis from lactate and alanine continues, but this process merely replaces glucose that had already been converted into lactate and alanine by the peripheral tissues. Moreover, the brain oxidizes glucose completely to CO2 and H2O. Thus, for the net synthesis of glucose to occur, another source of carbons is required. Glycerol released from adipose tissue on lipolysis provides some of the carbons, with the remaining carbons coming from the hydrolysis of muscle proteins.
The refed state. What are the biochemical responses to a hearty breakfast? Fat is processed exactly as it is processed in the normal fed state. However, this is not the case for glucose. The liver does not initially absorb glucose from the blood, but rather leaves it for the peripheral tissues. Moreover, the liver remains in a gluconeogenic mode. Now, however, the newly synthesized glucose is used to replenish the liver's glycogen stores. As the blood-glucose levels continue to rise, the liver completes the replenishment of its glycogen stores and begins to process the remaining excess glucose for fatty acid synthesis.
What are the adaptations if fasting is prolonged to the point of starvation? A typical well-nourished 70-kg man has fuel reserves totaling about 161,000 kcal (670,000 kJ; see Table 30.1). The energy need for a 24-hour period ranges from about 1600 kcal (6700 kJ) to 6000 kcal (25,000 kJ), depending on the extent of activity. Thus, stored fuels suffice to meet caloric needs in starvation for 1 to 3 months. However, the carbohydrate reserves are exhausted in only a day.
The plasma levels of fatty acids and ketone bodies increase in starvation, whereas that of glucose decreases.
).
The metabolic changes on the first day of starvation are like those after an overnight fast. The low blood-sugar level leads to decreased secretion of insulin and increased secretion of glucagon. The dominant metabolic processes are the mobilization of triacylglycerols in adipose tissue and gluconeogenesis by the liver. The liver obtains energy for its own needs by oxidizing fatty acids released from adipose tissue. The concentrations of acetyl CoA and citrate consequently increase, which switches off glycolysis. The uptake of glucose by muscle is markedly diminished because of the low insulin level, whereas fatty acids enter freely. Consequently, muscle shifts almost entirely from glucose to fatty acids for fuel. The β-oxidation of fatty acids by muscle halts the conversion of pyruvate into acetyl CoA, because acetyl CoA stimulates the phosphorylation of the pyruvate dehydrogenase complex, which renders it inactive (Section 17.2.1). Hence, pyruvate, lactate, and alanine are exported to the liver for conversion into glucose. Glycerol derived from the cleavage of triacylglycerols is another raw material for the synthesis of glucose by the liver.
Proteolysis also provides carbon skeletons for gluconeogenesis. During starvation, degraded proteins are not replenished and serve as carbon sources for glucose synthesis. Initial sources of protein are those that turn over rapidly, such as proteins of the intestinal epithelium and the secretions of the pancreas. Proteolysis of muscle protein provides some of three-carbon precursors of glucose. However, survival for most animals depends on being able to move rapidly, which requires a large muscle mass, and so muscle loss must be minimized.
| Amount formed or consumed in 24 hours (grams) | ||
|---|---|---|
| Fuel exchanges and consumption | 3d day | 40th day |
| Fuel use by the brain | ||
 Glucose | 100 | 40 |
| Ketone bodies | 50 | 100 |
| All other use of glucose | 50 | 40 |
| Fuel mobilization | ||
| Adipose-tissue lipolysis | 180 | 180 |
| Muscle-protein degradation | 75 | 20 |
| Fuel output of the liver | ||
| Glucose | 150 | 80 |
| Ketone bodies | 150 | 150 |
). Their synthesis from acetyl CoA increases markedly because the citric acid cycle is unable to oxidize all the acetyl units generated by the degradation of fatty acids. Gluconeogenesis depletes the supply of oxaloacetate, which is essential for the entry of acetyl CoA into the citric acid cycle. Consequently, the liver produces large quantities of ketone bodies, which are released into the blood. At this time, the brain begins to consume appreciable amounts of acetoacetate in place of glucose. After 3 days of starvation, about a third of the energy needs of the brain are met by ketone bodies (Table 30.2). The heart also uses ketone bodies as fuel.
After several weeks of starvation, ketone bodies become the major fuel of the brain. Acetoacetate is activated by the transfer of CoA from succinyl CoA to give acetoacetyl CoA (Figure 30.18
). Cleavage by thiolase then yields two molecules of acetyl CoA, which enter the citric acid cycle. In essence, ketone bodies are equivalents of fatty acids that can pass through the blood-brain barrier. Only 40 g of glucose is then needed per day for the brain, compared with about 120 g in the first day of starvation. The effective conversion of fatty acids into ketone bodies by the liver and their use by the brain markedly diminishes the need for glucose. Hence, less muscle is degraded than in the first days of starvation. The breakdown of 20 g of muscle daily compared with 75 g early in starvation is most important for survival. A person's survival time is mainly determined by the size of the triacylglycerol depot.
What happens after depletion of the triacylglycerol stores? The only source of fuel that remains is proteins. Protein degradation accelerates, and death inevitably results from a loss of heart, liver, or kidney function.
We now consider diabetes mellitus, a complex disease characterized by grossly abnormal fuel usage: glucose is overproduced by the liver and underutilized by other organs. The incidence of diabetes mellitus (usually referred to simply as diabetes) is about 5% of the population. Indeed, diabetes is the most common serious metabolic disease in the world; it affects hundreds of millions. Type I diabetes, or insulin-dependent diabetes mellitus (IDDM), is caused by autoimmune destruction of the insulinsecreting β cells in the pancreas and usually begins before age 20. The term insulin-dependent means that the individual requires insulin to live. Most diabetics, in contrast, have a normal or even higher level of insulin in their blood, but they are quite unresponsive to the hormone. This form of the disease—known as type II, or non-insulin-dependent, diabetes mellitus (NIDDM)—typically arises later in life than does the insulin-dependent form.
Named for the excessive urination in the disease. Aretaeus, a Cappadocian physician of the second century a.d., wrote: “The epithet diabetes has been assigned to the disorder, being something like passing of water by a siphon.” He perceptively characterized diabetes as “being a melting-down of the flesh and limbs into urine.”
Mellitus-
From Latin, meaning “sweetened with honey.” Refers to the presence of sugar in the urine of patients having the disease.
Mellitus distinguishes this disease from diabetes insipidus, which is caused by impaired renal reabsorption of water.
In type I diabetes, insulin is absent and consequently glucagon is present at higher-than-normal levels. In essence, the diabetic person is in biochemical starvation mode despite a high concentration of blood glucose. Because insulin is deficient, the entry of glucose into cells is impaired. The liver becomes stuck in a gluconeogenic and ketogenic state. The excessive level of glucagon relative to insulin leads to a decrease in the amount of F-2,6-BP in the liver. Hence, glycolysis is inhibited and gluconeogenesis is stimulated because of the opposite effects of F-2,6-BP on phosphofructokinase and fructose-1,6-bisphosphatase (Section 16.4; see also Figures 30.4 and 30.6). The high glucagon/insulin ratio in diabetes also promotes glycogen breakdown. Hence, an excessive amount of glucose is produced by the liver and released into the blood. Glucose is excreted in the urine (hence the name mellitus) when its concentration in the blood exceeds the reabsorptive capacity of the renal tubules. Water accompanies the excreted glucose, and so an untreated diabetic in the acute phase of the disease is hungry and thirsty.
Because carbohydrate utilization is impaired, a lack of insulin leads to the uncontrolled breakdown of lipids and proteins. Large amounts of acetyl CoA are then produced by β-oxidation. However, much of the acetyl CoA cannot enter the citric acid cycle, because there is insufficient oxaloacetate for the condensation step. Recall that mammals can synthesize oxaloacetate from pyruvate, a product of glycolysis, but not from acetyl CoA; instead, they generate ketone bodies. A striking feature of diabetes is the shift in fuel usage from carbohydrates to fats; glucose, more abundant than ever, is spurned. In high concentrations, ketone bodies overwhelm the kidney's capacity to maintain acid-base balance. The untreated diabetic can go into a coma because of a lowered blood pH level and dehydration.
Type II, or non-insulin-dependent, diabetes accounts for more than 90% of the cases and usually develops in middle-aged, obese people. The exact cause of type II diabetes remains to be elucidated, although a genetic basis seems likely.
In the United States, obesity has become an epidemic, with nearly 20% of adults classified as obese. Obesity is identified as a risk factor in a host of pathological conditions including diabetes mellitus, hypertension, and cardiovascular disease. The cause of obesity is quite simple in the vast majority of cases—more food is consumed than is needed, and the excess calories are stored as fat.
Although the proximal cause of obesity is simple, the biochemical means by which caloric homeostasis and apetite control are usually maintained is enormously complex, but two important signal molecules are insulin and leptin. A protein consisting of 146 amino acids, leptin is a hormone secreted by adipocytes in direct proportion to fat mass. Leptin acts through a membrane receptor (related in structure and mechanism of action to the growth-hormone receptor; Section 15.4) in the hypothalamus to generate satiation signals. During periods when more energy is expended than ingested (the starved state), adipose tissue loses mass. Under these conditions, the secretion of both leptin and insulin declines, fuel utilization is increased, and energy stores are used. The converse is true when calories are consumed in excess.
The importance of leptin to obesity is dramatically illustrated in mice. Mice lacking leptin are obese and will lose weight if given leptin. Mice that lack the leptin receptor are insensitive to leptin administration. Preliminary evidence indicates that leptin and its receptor play a role in human obesity, but the results are not as clear-cut as in the mouse. The interplay of genes and their products to control caloric homeostasis will be an exciting area of research for some time to come.
