AbstractMuch of the research that has examined the interaction between metabolism and

exercise has been conducted in comfortable ambient conditions. It is clear, however,

that environmental temperature, particularly extreme heat, is a major practical issue

one must consider when examining muscle energy metabolism. When exercise is

conducted in very high ambient temperatures, the gradient for heat dissipation is

significantly reduced which results in changes to thermoregulatory mechanisms

designed to promote body heat loss. This can ultimately impact upon hormonal and

metabolic responses to exercise which act to alter substrate utilisation. In general,

the literature examining metabolic responses to exercise and heat stress has

demonstrated a shift towards increased carbohydrate use and decreased fat use.

Although glucose production appears to be augmented during exercise in the heat,

glucose disposal and utilisation appears to be unaltered. In contrast, glycogen use

has been consistently demonstrated to be augmented during exercise in the heat.

This increase in glycogenolysis is observed via both aerobic and anaerobic

pathways. Although several hypotheses have been proposed as mechanisms for the

substrate shift towards greater carbohydrate metabolism during exercise and heat

stress, recent work suggests that an augmented sympatho-adrenal response and

intramuscular temperature may be responsible for such a phenomenon.

http://www.ncbi.nlm.nih.gov/pubmed/11219501

Stress induces a hypermetabolic state of increased urinary nitrogen loss and increased metabolic rate. The principal reason for such a response is the mobilization of amino acids and the production of glucose to provide energy for the cells involved in the host immune response and wound repair. The endocrine hormones, eg, cortisol, the catecholamines, and glucagon, are largely responsible for these effects. Insulin and growth hormone administration can produce anabolic effects to block the loss of body protein. Administration of specific amino acids, such as glutamine, also appears to be beneficial. However, the hypermetabolic state goes beyond derangement of endocrine hormone levels. Although the cytokines are also important mediators, it is not clear how these mediators, in concert with hormonal changes, produce all of the manifestations of the hypermetabolic state seen in stress.

Food Intake and Starvation Induce Metabolic Changes

We shall now consider the biochemical responses to a series of physiological conditions. Our first example is thestarved-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.

1.

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.

2.

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 alow 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 AMPcascade 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 synthasea 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.

3.

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.

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30.3.1. Metabolic Adaptations in Prolonged Starvation Minimize Protein Degradation

 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.

Even under starvation conditions, the blood-glucose level must be maintained above 2.2 mM (40 mg/dl). The first priority of metabolism in starvation is to provide sufficient glucose to the brain and other tissues (such as red blood cells) that are absolutely dependent on this fuel. However, precursors of glucose are not abundant. Most energy is stored in the fatty acyl moieties of triacylglycerols. Recall that fatty acids cannot be converted into glucose, because acetylCoA cannot be transformed into pyruvate (Section 22.3.7). The glycerol moiety of triacylglycerol can be

converted into glucose, but only a limited amount is available. The only other potential source of glucose is amino acids derived from the breakdown of proteins. However, proteins are not stored, and so any breakdown will necessitate a loss of function. Thus, the second priority of metabolism in starvation is to preserve protein, which is accomplished by shifting the fuel being used from glucose to fatty acids and ketone bodies (Figure 30.16).

Figure 30.16

Fuel Choice During Starvation. 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.

How is the loss of muscle curtailed? After about 3 days of starvation, the liver forms large amounts of acetoacetate andD -3-hydroxybutyrate (ketone bodies; Figure 30.17). 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.

Figure 30.17

Synthesis of Ketone Bodies by the Liver.

Table 30.2

Fuel metabolism in starvation.

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.

Figure 30.18

Entry of Ketone Bodies Into the Citric Acid Cycle.

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.

Biochemistry. 5th edition.

Show details

Berg JM, Tymoczko JL, Stryer L.

New York: W H Freeman; 2002.

Energy metabolism in feasting and fasting.Owen OE, Reichard GA Jr, Patel MS, Boden G.

AbstractDuring feasting on a balanced carbohydrate, fat, and protein meal resting metabolic

rate, body temperature and respiratory quotient all increase. The dietary components

are utilized to replenish and augment glycogen and fat stores in the body. Excessive

carbohydrate is also converted to lipid in the liver and stored along with the

excessive lipids of dietary origin as triglycerides in adipose tissue, the major fuel

storage depot. Amino acids in excess of those needed for protein synthesis are

preferentially catabolized over glucose and fat for energy production. This occurs

because there are no significant storage sites for amino acids or proteins, and the

accumulation of nitrogenous compounds is ill tolerated. During fasting, adipose

tissue, muscle, liver, and kidneys work in concert to supply, to convert, and to

conserve fuels for the body. During the brief postabsorptive period, blood fuel

homeostasis is maintained primarily by hepatic glycogenolysis and adipose tissue

lipolysis. As fasting progresses, muscle proteolysis supplies glycogenic amino acids

for heightened hepatic gluconeogenesis for a short period of time. After about three

days of starvation, the metabolic profile is set to conserve protein and to supply

greater quantities of alternate fuels. In particular, free fatty acids and ketone bodies

are utilized to maintain energy needs. The ability of the kidney to conserve ketone

bodies prevents the loss of large quantities of these valuable fuels in the urine. This

delicate interplay among liver, muscle, kidney, and adipose tissue maintains blood

fuel homeostasis and allows humans to survive caloric deprivation for extended

periods.

Normal Body Composition:

   A 70-kg human is composed of approximately 55 percent water, 40 percent organic materials, and 5 percent minerals. The actual water content is inversely related to the amount of body fat and diminishes progressively with age.1 Itemization of the body's

organic materials and caloric equivalents indicates that approximately 166,000 total calories are present (Table).2 Of the 6 kg of body protein, muscle protein accounts for approximately 4 kg and hemoglobin for approximately 1 kg. The remaining 1 kg is located in various body organs, with serum protein representing a very small fraction.

Metabolic Effects of Starvation:

Short-Term Starvation: When dietary intake is interrupted, the body turns to endogenous "stored" calories to provide energy for essential functions. Initially, the central nervous system remains dependent on glucose as its primary energy substrate, metabolizing 100 to 150 g/day completely to carbon dioxide and water.3 If an adequate amount of glucose is not continuously available, a rapid alteration of neuronal activity occurs, characterized by personality changes, confusion, lethargy, and coma. Irreversible neurological damage occurs if carbohydrate deprivation is prolonged for as few as 10 to 20 minutes. The renal medulla, bone marrow, red blood cells, and peripheral nerves are also glucose-dependent, metabolizing a total of 30 to 40 g/day glucose to lactate and pyruvate.4,5,6 Lactate can be recycled back to glucose through the Cori cycle in the liver and kidney, a process that utilizes energy derived from oxidation of fatty acids. Pyruvate can undergo oxidation with formation of ATP or can serve as a substrate for gluconeogenesis in the liver. Fibroblasts and phagocytes derive much of their energy from the anaerobic metabolism of glucose to lactate. The liver derives much of its energy from the oxidation of free fatty acids to acetoacetate, acetone, and ß-hydroxybutyrate (the ketone bodies). The heart, skeletal muscle, and renal cortex, although utilizing glucose for a major share of their energy during normal nutrition, can and do utilize free fatty acids and ketone bodies during starvation. The skeletal muscle also oxidizes the branched-chain amino acids for energy. The gastrointestinal tract utilizes glutamine, oxidizing it to carbon dioxide and water.

   Since liver glycogen and extracellular glucose reserves are small (Table), and since muscle glycogen cannot be converted to blood glucose owing to a lack of glucose-6-phosphatase in muscle, humans depend mainly on gluconeogenesis to meet obligatory glucose requirements. The normal glycolysis pathway is shown in (Figure). Although most steps are reversible, three enzymes are necessary for gluconeogenesis to occur. The first is

a specific phosphatase capable of converting fructose diphosphate to fructose 6-phosphate. This enzyme is highly active during conditions of fasting, diabetes, and glucocorticoid excess. The increased activity aids in conversion of glycerol from hydrolysis of triglycerides into glucose. Phosphoenolpyruvate carboxykinase catalyzes the conversion of oxaloacetate to phosphoenolpyruvate. This step permits oxaloacetate, and any substance that can be transformed into oxaloacetate, such as aspartate, to serve as substrates for gluconeogenesis. Finally, pyruvate carboxylase catalyzes conversion of pyruvate to oxaloacetate, thereby allowing lactate, alanine, serine, and similar substances to enter gluconeogenesis upon their conversion into pyruvate. It is apparent from Figure 8-12 that such substrates as lactate, pyruvate, glycerol, dicarboxylic acids, and amino acids all can be utilized for gluconeogenesis.

   Gluconeogenesis occurs mainly in the liver early in starvation, with the kidney providing up to half of the total glucose produced as starvation continues.7 The main amino acid substrate for gluconeogenesis in the liver is alanine.8 Felig9 and Mallette et al.10 proposed a glucose-alanine cycle between skeletal muscle and the liver (see Figure). In muscle, pyruvate is generated from the anaerobic metabolism of glucose. The nitrogen moiety of branched-chain amino acids (valine, leucine, and isoleucine) is transaminated to pyruvate, forming alanine, which is released into the blood. The branched-chain amino acid carbon skeleton is completely oxidized in the muscle to carbon dioxide and water, providing additional ATP for local use. The alanine released from muscle is taken up by the liver, where the nitrogen is split off. The resultant pyruvate is recycled to glucose by gluconeogenesis. Most of the nitrogen is excreted in the urine as urea; however, some is reutilized in protein synthesis. The main substrate for gluconeogenesis in the kidney is glutamine, with other amino acids being converted into it by transamination (Figure). The main nitrogenous by-product is ammonia, which is partly excreted in the urine and partly reutilized in protein synthesis.

    Early in starvation, approximately 75 g of body protein and 160 g of adipose tissue are metabolized each day for every 1800 kcal utilized.5,6 All endogenous proteins are utilized, including those that play important metabolic roles, such as plasma and organ proteins and digestive enzymes.11,12,13Serum albumin is used in the ratio of 1 g albumin to 30 g tissue protein lost. The most clinically evident protein loss is from skeletal muscles.

    Lipolysis, which increases as serum insulin concentrations fall with starvation, releases free fatty acids and glycerol. Although free fatty acids cannot participate directly in gluconeogenesis,

they can serve as an energy source in the liver for the Cori cycle and generate acetyl-CoA, which enhances the conversion of pyruvate to oxaloacetate.14,15 Glycerol is readily converted to glucose but provides only about 18 g glucose per 24 hours.5 The increased rate of metabolism of triglycerides is associated with a slight elevation of free fatty acids in the serum and a gradual rise in serum ketone bodies.

Prolonged Starvation: With prolonged starvation there is a gradual decrease in total body energy expenditure (Figure). This decreased metabolic activity is manifested by diminished muscle activity, increased sleep, and decreased core temperature. In addition to a decrease in metabolic rate, the need for gluconeogenesis diminishes, mainly as the result of the conversion of the central nervous system to utilization of ketone bodies for energy rather than glucose. The stimulus for this adaptation is unknown, although it may be in part caused by the rise in serum alanine or ketone body concentrations or by the lowered serum molar ratio of insulin to glucagon. Protein catabolism falls from 75 to 20 g/day, with a marked decrease in excretion of urea nitrogen to 3 to 5 g/day (Figure).6,16 In fully adapted starvation, protein catabolism provides as little as 5 percent of the total daily calories. With decrease in gluconeogenesis, adipose tissue becomes even more important as an energy substrate, with 60 percent of the total caloric expenditure derived from metabolism of fat to carbon dioxide, 10 percent from conversion of free fatty acids to ketone bodies, and 25 percent from metabolism of ketone bodies by peripheral tissues. Serum ketone body concentrations increase with the increased fat metabolism and eventually exceed the renal threshold. Metabolic acidosis is not present. The appearance of ketone bodies in the urine is the hallmark of the physiological response to prolonged starvation. It is in this adapted state that humans can best tolerate prolonged fasting, perhaps for 60 to 70 days.

   Survival from prolonged starvation is dependent on body reserves and the severity of the caloric deficit. Click HERE for a program to calculate days to survival during inadequate nutrition support.

    The provision of fluid requirements as 5 percent dextrose solutions, long advocated to decrease proteolysis and starvation ketosis, has recently come under question.17,18,19 The actual effect of administration of 100 to 150 g dextrose a day intravenously is a combination of (l) reduced requirements for gluconeogenesis

from amino acids and glycerol, and (2) an increased endogenous insulin release which reduces lipolysis, increases protein synthesis, and increases requirements for gluconeogenesis. Indeed, nitrogen-sparing has been demonstrated to be better with use of glucose-free salt or water solutions, allowing complete adaptation to starvation. Use of 3 to 4 percent amino acid solutions, whether with isotonic carbohydrate solutions or sterile water, has shown further nitrogen-sparing in non-stressed patients (see Peripheral Protein Sparing).

Endocrine Response to Starvation:

    Endocrine responses to starvation are often complex (Table). To simplify this discussion, the endocrine response is divided into substances enhancing catabolism, those stimulating anabolism, and those influencing fluid and electrolyte balance. The degree of stimulation and the relative potency of each hormone determine the overall host response. An in-depth review of endocrine responses can be obtained from references 20 and 21.

Catabolic Hormones

Catecholamines: The adrenalin response to stress and injury was first described by Cannon in 1939.22 The two catecholamines, epinephrine and norepinephrine, are secreted following a large variety of stimuli, including excitement, fear, anger, tissue injury, and fractures. Epinephrine, which is secreted only by the adrenal medulla, stimulates hepatic glycogenolysis and gluconeogenesis, inhibits secretion of insulin, inhibits uptake of glucose by peripheral tissues, favors release of amino acids from muscle, and directly stimulates hydrolysis of fat. Norepinephrine, produced throughout the body at nerve synapses and also by the adrenal medulla, has less marked metabolic activity but does stimulate hydrolysis of fat. As the result of their extremely short biological half-lives, the metabolic effects of catecholamines are transient, lasting only 24 to 48 hours.

    During starvation, secretion of catecholamines is decreased, reducing their impact on metabolic activity. In addition, there is reduced catecholamine-stimulated glucagon release from the pancreas and adrenocorticotropic hormone from the pituitary gland, resulting in lowered glucocorticoid and aldosterone secretion.23

Glucocorticoids: Corticoid production decreases during starvation. The reduced corticoid production favors lipogenesis and results in less inhibition of protein synthesis, less stimulus for the mobilization of amino acids from skeletal muscle, and increased renal tubular reabsorption of amino acids. In addition, there is less induction of transaminating enzymes for gluconeogenesis, less suppression of insulin secretion, and less release of glucagon. The stimulus for conversion of lactic acid to glycogen and protection of the lysosomal membrane against pH changes is also reduced.

Anabolic Hormones:

Growth Hormone: During starvation or hyperglycemia, blood levels of human growth hormone may be elevated two to three times above normal. Human growth hormone is produced by the acidophilic cells of the anterior pituitary gland. It stimulates nitrogen, phosphorus, and potassium retention, and also lipolysis, fatty acid oxidation, and ketogenesis. Growth hormone antagonizes the actions of insulin, depressing glucose uptake by muscle and elevating blood glucose levels. It also stimulates synthesis of chondroitin sulfate and collagen. Infusion of amino acids (especially arginine) strongly stimulates growth hormone secretion even in the absence of fasting.

Androgens: Little change is seen in androgen production during starvation. Testosterone is considered the major androgen. The normal female produces 0.34 mg/day, and the male 7 mg/day. This hormone has potent anabolic activity, stimulating retention of nitrogen, potassium, phosphorus, and calcium and increasing lean body and visceral protein masses. It may also function to decrease amino acid catabolism.

Insulin and Glucagon: Secretions of the pancreatic islet cells play a major role in the regulation of body fuel metabolism. Insulin, secreted by the beta cell, functions as a potent anabolic hormone. It promotes storage of exogenous glucose, inhibits gluconeogenesis and glycogenolysis, strongly inhibits lipolysis, and favors protein synthesis. In contrast, glucagon, secreted by the pancreatic alpha cell, is a potent catabolic hormone. It acts to prevent hypoglycemia by stimulating gluconeogenesis, glycogenolysis, proteolysis, and lipolysis.24,25 The pancreatic delta islet cells are interposed between the alpha and beta cells and regulate both by secretion of the inhibitory hormone somatostatin. The interreactions between the pancreatic islets

cells result in very precise glucose homeostasis. The absolute concentrations of insulin and glucagon appear not to be as important in glucose homeostasis as the insulin:glucagon molar ratio.26,27 Following an overnight fast, the insulin:glucagon molar ratio is only slightly depressed from its normal level of about 4.0, slightly favoring gluconeogenesis.28,29,30 Further starvation, up to 6 to 8 days, is associated with a marked depression of the ratio to as low as 0.4, strongly favoring catabolism.28,29,30,31,32 The increased glucagon secretion is felt to play a prominent role in stimulating the glucose-alanine cycle as discussed above.33 With prolonged starvation there is an increased production of ketone bodies which in turn stimulate the release of insulin. As insulin inhibits lipolysis, there is a feedback control preventing severe ketosis. In addition, the increased insulin secretion raises the insulin:glucagon molar ratio, limiting the rate of catabolism.

    In non-diabetic subjects, infusion of carbohydrate results in an increased insulin:glucagon ratio to as high as 70, whereas infusion of amino acids decreases it.28 The simultaneous infusion of hypertonic dextrose and amino acids, as in total parenteral nutrition, results in an overall increase in the insulin:glucagon ratio, favoring anabolism.24,34,35

   Certain diseases may be associated with hyperglucagonemia, which makes the establishment of anabolism during parenteral nutrition more difficult. Glucagon is cleared from the plasma by the liver and the kidneys.33,34,35,36,37,38 In either hepatic or renal failure, decreased glucagon clearance can become significant. Further, diabetic patients often demonstrate baseline hyperglucagonemia, an exaggerated release of glucagon with protein meals, and a paradoxical increase in glucagon with carbohydrate infusion.28

Fluid and Electrolyte Balance:

Aldosterone: Uncomplicated starvation is associated with only small increases in aldosterone secretion, whereas the major fluid shifts of trauma may result in marked increases. Aldosterone decreases renal excretion of sodium and bicarbonate, while increasing potassium losses. By increasing sodium ion concentrations in the serum and thus serum osmolarity, the extracellular fluid volume is increased. Aldosterone secretion is increased by catecholamines and hyponatremia. In addition, isotonic hypovolemia stimulates renin release by the renal

juxtaglomerular apparatus. This promotes angiotensin formation, which in turn stimulates aldosterone release.39,40

Antidiuretic Hormone: Antidiuretic hormone inhibits free-water clearance by the kidneys. Clinical situations associated with hypovolemia or hyperosmolality stimulate the release of antidiuretic hormone, which results in an increase in intravascular volume and decrease in osmolality.

   As discussed previously, the two hormones of fluid and electrolyte balance respond primarily to decreased intravascular volume and decreased serum osmolality. After prolonged malnutrition, patients often are markedly dehydrated, with depleted intravascular volumes. Initiation of parenteral nutrition in these patients may be associated with marked initial fluid retention until the intravascular volume is replenished. Solution formulas reflecting normal serum electrolyte content are most effective in replacing the intravascular volume; hypotonic electrolyte solutions are contraindicated and can lead to the syndrome of inappropriate antidiuretic hormone secretion with excessive shifting of fluid into extravascular spaces.

Recovery from Starvation:

    Normal total body protein synthesis occurs at a rate of approximately 18 to 30 g/day. It is, therefore, possible to predict the approximate time required for metabolic recovery by dividing the estimated total deficit by the average daily gain. The actual time required to replace all protein losses is somewhat longer than calculated, since maximum anabolism is not immediately obtained or always maintained. During recovery, essential amino acid, total protein, and caloric requirements all are greater than normal. After nitrogen losses have been restored, fat is gained almost exclusively for several weeks or months until the normal body fat stores are regained.41 In this phase, nitrogen balance is zero, although carbon balance is positive.

    This section has dealt with the metabolic effects of short- and long-term starvation. An understanding of these metabolic processes, as well as needs for vitamins, electrolytes, and minerals, is critical for effective administration of nutritional support. Every effort should be made to recognize losses of body mass caused by starvation and to avoid significant nutritional depletion by providing adequate nutritive support. If nutritional

support is provided before marked wasting occurs, an anabolic state is more easily obtained and maintained.

Some hormonal influences on glucose and ketone body metabolism in normal human subjects.Johnston DG, Pernet A, McCulloch A, Blesa-Malpica G, Burrin JM, Alberti KG.

AbstractControl of glucose and ketone body metabolism is integrated by a variety of

hormones. Insulin is the major anabolic hormone, and its actions are antagonized by

rapidly acting catabolic hormones, such as glucagon and the catecholamines, and by

others such as cortisol, growth hormone and the thyroid hormones, which generally

have more delayed effects. In the normal human subject, the effects of catabolic

hormones to raise blood glucose are limited by a compensatory increase in insulin

secretion, and these effects are enhanced in insulin deficiency. Hyperketonaemic

actions of the catabolic hormones may result from increased supply of non-esterified

fatty acids from lipolysis, although glucagon has a major direct action to increase

ketogenesis at the liver. As expected, these actions are also restricted in normal

humans by the compensatory rise in insulin secretion. Hyperketonaemia does,

however, occur with adrenaline (epinephrine) and noradrenaline (norepinephrine),

even in the presence of mildly elevated insulin concentrations. These

catecholamines may assume particular importance in mobilization of lipid fuels in

milder forms of stress, when insulin secretion is normal or mildly increased. In severe

stress, when there is catecholamine-induced suppression in insulin secretion,

lipolytic and hyperketonaemic effects of all the catabolic hormones may be manifest.

Starvation in humans also results in diminished insulin secretion and increased

catabolic hormone secretion. The relative importance of individual hormones in lipid

mobilization during starvation is uncertain, although glucagon, growth hormone,

noradrenaline and, possibly, dopamine may all play a part.