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hoe ' starvation' in zn werk gaat: misschien interessant voor sommigen hier
In het boek "burn the fat, feed the muscle" kom je vaak de term 'starvation' tegen. Nu is het proces in het algemeen wel bekend bij de meesten hier maar ik heb toevallig afgelopen week een stuk gelezen over hoe het proces wat specifieker in zn werk gaat. Ik dacht, misschien interessant voor sommige mensen hier. Het is wel droge stof, vooral omdat ik de afbeeldingen eruit heb geplukt. Dit stuk gaat overigens wel over complete uithongering die uiteindelijk tot de dood leidt.
Ik plemp het hieronder neer:
The body’s fuel stores.
Carbohydrate
The amount of free glucose in the circulation and extracellular fluid is small, about 12 g in all. If we were able to use all of this without replenishing it, it would support the metabolism of the brain for about 2 h. Clearly, this is not adequate even to keep us alive overnight, and hence have stores of carbohydrate. We looked in Chapter 1 at the osmotic problem that would arise if free glucose were stored in cells, and why we store our carbohydrate in polymeric form as glycogen. Only two tissues, skeletal muscle and liver, have stores of glycogen that are significant in relation to the needs of the whole body, although most tissues have a small store for ' local' use. Approximately 40 %of the human body is skeletal muscle --say 25kg on average. A typical concentration of glycogen in skeletal muscle is around 15g/kg of wet weight, i.e. each kilogram of muscle in its normal, hydrated state contains app. 15 g of glycogen; thus the total muscle glycogen store is 350-400g.(this is very variable and can be expanded considerably under certain conditions, such as high carbohydrate intake after exercise). This is not available directly as glucose to enter the circulation, since muscle lacks glucose-6-phosphatase, although it can be exported to the liver as lactate, pyruvate and/or alanine for formation of glucose. In contrast, the liver glycogen store is more directly available as glucose, and undoubtedly plays the major role of a ' buffer’ for changing hour-to-hour requirements. A typical liver glycogen concentration is app. 50-80 g/kg of wet weight, and varies during the day. The liver weighs app. 1 - 1.5 kg, so the total liver glycogen store is app. 5-120 g. You will see immediately that this is not far from ' 24 hours' worth’ for the brain. Thus our carbohydrate stores are sufficient to enable us to ride out periods of a day or so without food.
Fat
On the other hand, our fat stores are usually larger by one to two orders of magnitude. This should not surprise us. We saw in Chapter 1 the considerable advantage, in weight terms, of storing excess energy in the form of hydrophobic triacylglycerol molecules, in the lipid droplets of adipocytes. A typical figure for body fat content is about 15 - 30 % of body weight. Thus an average fat store is of the order of 10 - 20 kg. The energy content of fat is around 37 kJ/g, so we store the equivalent of around 500 MJ in the form of fat. A typical daily energy expenditure )(to be discussed further in Chapter 10) is around 10 MJ, so we store sufficient energy for about 50 days of life or more; as we shall see, on of the prominent aspects of the metabolic adaptation to starvation is that daily metabolic rate (energy expenditure) is reduced. This accords well with recorded times for survival of starvation victims of up to 60 days for people who were initially normal. A few obese people have starved, voluntarily, for therapeutic reasons for considerably longer periods. (They were closely monitored medically, and given the necessary vitamin and mineral supplements.)
However, storage of most of our energy reserves in the form of fat poses biochemical problems, since some tissues and organs require glucose and cannot oxidize fatty acids. Fatty acids cannot be converted to glucose in mammals because acetyl-CoA formed from fatty acids is oxidized completely to CO2, in the tricarboxylic acid cycle and is therefore unable to contribute to the gluconeogenic pathway. On the glycerol component of triacylglycerol can form glucose, and this is a minor contributor in terms of numbers of carbon atoms. As we shall see, one strategy adopted during starvation is an increased conversion of fatty acids into water-soluble intermediates, the ketone bodies, which can be used by tissues which normally require glucose, particularly the brain.
Amino Acids
The body contains around 20% by weight of protein --around 10- 15 kg. Amino acids can be oxidized to provide energy, or converted to glucose and fatty acids, which can then be oxidized. Amino acids, when completely oxidized in a calorimeter, liberate around 24 kJ/g. This is not a realistic figure for metabolic oxidation, since urea is formed, which itself has a certain energy content; amino acid catabolism to CO2 and urea liberates about 17 kJ/g/ Thus about 200 MJ of biological energy is present in the body in the form of protein; however, we must be careful in interpreting this as an energy store. Animals do not produce any specific protein purely for storage of amino acids; all proteins have some other function -- as structural components, enzymes. etc. Thus the body’s content of protein is only available as an energy store at the expense of loss of some functional protein. In fact, in the metabolic adaptation to starvation, the body protein is conserved so far as is consistent with the body’s metabolic requirements; protein is not utilized as an energy reserve in the same way that carbohydrate and fat are.
Of the 10 - 15 kg of protein in the body, about 5 kg is in skeletal muscle. This appears to be the main source of supply when amino acids are required. There is some loss from other organs and tissues, but presumably they are relatively ' spared' because of their vital functions. It appears that the body can only tolerate a loss of about half of its muscle protein. After this, the respiratory muscles become so weakened that chest infection and pneumonia may set in (probably assisted by impaired immune function as a result of malnutrition) and death follows.
Starvation.
The response to absolute deprivation of food proceeds in a number of stages, leading ultimately to death; but the manner in which metabolism adapts, to postpone that final end-point as long as possible, illustrates a number of important points about the integration of metabolic regulation in the whole body. Starvation has, undoubtedly, always been a threat to humans and other animals, and the metabolic responses which minimize its impact have evolved throughout the development of all living things. Because this response has evolved so directly to counteract the threat posted by lack of food, it is tempting to look on it as ' purposeful' and indeed it helps considerably in understanding it if we think in terms of the body’s' strategy'. Nevertheless, bear in mind that the use of a term such as strategy does not imply anything other than a response that has evolved because it is beneficial.
There are distinctions between absolute starvation and partial starvation or under nutrition. We will consider absolute starvation as this provides the clearest illustration of metabolic adaptation.
The early phase
We have already looked at the pattern of metabolism in very-short-term starvation, namely the post-absorptive state after overnight fast. A gentle decrease in the concentration of glucose in the plasma led to a small decrease in the ratio of insulin/glucagon, stimulation of hepatic glycogenolysis and liberation of fatty acids from adipose depots. The availability of fatty acids in the plasma leads tissues such as muscle to use fat --and spare glucose -- as their major metabolic fuel.
The post-absorptive state leads into the gluconeogenic phase, which lasts until the second or third day of absolute starvation. Liver glycogen stores are virtually depleted within 24 h, and, therefore, gluconeogenesis must come into operation to supply the requirements of the brain and other glucose-requiring tissues (e.g. erythrocytes). The main signal for this will again be the change in insulin/glucagon ratio. The concentration of another important hormonal stimulator of glyconeogenesis, cortisol, does not change systematically in starvation. In addition, the supply of substrate for glyconeogenesis will increase over this period, as net proteolysis in muscle -- resulting from the falling insulin concentration -- leads to release of amino acids, mainly alanine and glutamine; the latter is partially converted to alanine in the intestine, and thus the liver receives an increased supply of this amino acid. Increasing lipolysis in adipose tissue releases glycerol, which is also a substrate for glyconeogensis.
Gluconeogenesis in this early stage of starvation is, therefore, proceeding largely at the expense of muscle protein, a situation which is clearly not good for survival. Studies of experimental underfeeding of volunteers have shown that muscle function is impaired with surprisingly small degrees of under nutrition. Not all amino acid carbons can be converted into alanine and glutamine, and some are oxidized, representing an irreversible loss from the body’s stores. Around 1.7 g of muscle protein must be broken down to provide each gram of glucose, since not all amino acids can be converted to glucose, and, with the brain requiring around 100 - 120 g of glucose per day, the rate of muscle protein breakdown could be rapid. If no other adaptations took place, this would require the breakdown of around 150 g of protein per day. (some glucose is, of course, provided from glycerol.) The body’s store of protein in muscle would be rapidly depleted. This is avoided by a series of inter-related adaptations to starvation, which are summarized in table 7.2 (not included)
The sparing of the body’s protein stores is brought about gradually. The excretion of nitrogen in the urine, a measure of the irreversible loss of amino acids, decreases steadily from the start of starvation. At first sight this seems to contradict the idea of increased gluconeogenesis from amino acids in the early phase of starvation; however, this is not a fair picture. We should think in terms of nitrogen balance. Nitrogen balance is the difference between total nitrogen intake, and total nitrogen loss. Some nitrogen is lost in faeces and shed skin cells, but most is lost in the urine in the form of urea and ammonia, and represents the catabolism of amino acids. During normal life, we are approximately in nitrogen balance on a day-to-day basis; the amount of nitrogen we take in is equal to the amount we lose, and the body store of nitrogen (mainly in amino acids and protein) stays roughly constant. At the start of starvation, nitrogen intake falls suddenly to zero, but nitrogen excretion continues at about the same lever as before. Suddenly, therefore, there is a net loss of the body’s protein stores. Nitrogen excretion then declines steadily, representing the sparing that is necessary for starvation to be prolonged beyond a week or two.
The period of adaptation to starvation.
The changes listed in table 7.2 (not included) come into place gradually over the first three weeks or so of total starvation; this is the period of adaptation. Beyond three weeks, the body has adapted as far as it can, and a kind of steady state is reached.
Hormonal changes.
The onset of starvation is marked by a decrease in the level of the active thyroid hormone tri-iodothyronine (T3) in the blood. It is not clear what causes this, although the mechanism is in part a shift towards production of an inactive form, reverse-T3. The effect of the fall in T3 concentration is to reduce overall metabolic rate, and to reduce the rate of proteolysis in the muscle. The reduction in overall metabolic rate leads to a decrease in the rate of depletion of the body’s fuels stores. However, it is unlikely that the metabolism of the brain, usually the largest glucose consumer is reduced significantly, so the need for glucose is still present; it is reduced, however, by the mechanisms described below.
Both the sympathetic nervous system and the adrenal medulla play some role during starvation. However, although starvation is a state in which fuel mobilization is required, the adrenergic systems play a much lesser role than in other, more stress-driven states (such as exercise). There is some activation of both sympathetic nervous system and adrenaline secretion during the first week or so of starvation. These changes would normally cause an elevation in overall metabolic rate; this is not seen, since it is outweighed by the reduction in T3 concentration.
On the other hand, the adrenergic stems are probably important in stimulation of lipolysis in adipose tissue. This latter will be reinforced by the continuing reduction in insulin concentration. Therefore, the plasma non-esterified fatty acid concentration rises during the adaptation period.
Adaptation of fatty acid, ketone body and glucose metabolism.
The elevation in plasma non-esterified fatty acid concentration leads to a number of adaptations. Skeletal muscle will use non-esterified fatty acids almost entirely in preference to glucose for its energy production. In the liver, the rate of fatty acid esterification, usually stimulated by insulin, will decrease; fatty acids will be diverted into oxidation (glucagon stimulates this pathway). This diversion is mediated in part by a decrease in hepatic malonyl-CoA concentration, a result of the decrease in insulin concentration. Increased oxidation of fatty acids leads to increased production of the ketone bodies, 3-hydroxybutyrate and acetoacetate. These can be used as an oxidative fuel by many tissues, at a rate which simply depends on their concentration in the blood. Most importantly, they can be used by the brain, which begins to use a fuel derived from the fat stores in preference to glucose. By the end of the third week of starvation, blood ketone body concentrations may reach 6-7 mmol/l, compared with < 0.2 mmol/l normally. At this stage, ketone body oxidation can account for approximately two-thirds of the oxygen consumption of the brain. Thus about 70-80 g of glucose per day is spared oxidation.
The body’s need to form new glucose from amino acids is also reduced by the stimulation of gluconeogenesis in the liver, which enables glucose to be efficiently recycled. Glycolytic cells and tissues such as erythrocytes and the renal medulla will still need to use glucose. (they cannot use ketone bodies since they do not have the oxidative capacity.) Glycolyisis in these tissues, however, leads to the release of lactate which is returned to the liver and avidly reconverted into glucose. Thus the glucose which must be used by these tissues is recycled. Energy for this process comes form the increased oxidation of fatty acids in the liver, forming the NADH necessary to drive gluconeogenesis (so that, in effect, the glycolytic tissues ' run' on energy derived from the fat stores).
Sparing of muscle protein.
By these mechanism, the need to produce glucose from muscle protein is reduced, and the loss of nitrogen in the urine decreases. However, with the insulin concentration decreasing, the net stimulus would seem to be for increasing muscle protein breakdown. How is the sparing of muscle protein brought about?
The possible role of the decreasing T3 concentration has been mentioned: T3 usually has the effect of stimulation muscle porteolysis. Another possibility is that the increase in plasma adrenaline concentration may be involved. Adrenergic drugs have an anabolic effect on muscle, although this effect is not clearly understood and the receptors by which it is mediated have not been delineated.
The other possible mediator is the increase in blood ketone body concentration. Some experimental studies show that this leads to a reduction in the net breakdown of muscle protein. There is a possible mechanism. The branched-chain amino acids are catabolized in muscle by transamination, followed by the action of the branched-chain 2-oxo-acid dehydrogenate complex. This enzyme complex has many similarities with pyruvate dehydrogenase. Like pyruvate dehydrogenase, its activity is inhited by phospohorylation in response to a high acetyl-CoA/CoASH ratio. In other words, if the muscle is plentifully supplied with other substrates for oxidation (such as fatty acids and ketone bodies, in starvation) the oxidation of the branched chain amino acids will be suppressed.
However, the fall in nitrogen loss in starvation may be another facet of the general slowing down of metabolism. In this case no specific mechanism need be postulated. This has been discussed by Henry et al. (1988), who argued that conventional understanding of the response to starvation is heavily biased, since it is based largely on obese subjects undergoing starvation for the purpose of weight reduction.
Kidney metabolism
During this period of starvation, there are marked changes in the metabolic pattern of the kidney which will be briefly discussed. The concentrations of lipid-derived fuels -- non-esterified fatty acids and ketone bodies -- are high in the plasma. These are biological acids. Therefore, the production of hydrogen ions increases and the pH of the blood tends to fall. To counter this, the body must excrete excess hydrogen ions. In section 5.3.2.3 one means for achieving this was mentioned: the kidney can excrete ammonia, which carries with it one hydrogen ion, since it will be in the form of NH4+/ The ammonia may be derived from the action of glutaminase on glutamine, and glutamate dehydrogenase on glutamate, in the kidney. The renal uptake of glutamine increases in starvation to provide a means for excretion of excess hydrogen ions. Glutamine metabolism in the kidney can lead to glucose production, especially during starvation when the kidney can become an important gluconeogenic tissue. Thus again we see the efficiency of metabolism: a metabolic process (ammonia excretion) necessary to regulate blood pH is coupled with the conversion of a muscle-derived amino acid to glucose.
The period of adapted starvation.
Form about three weeks of total starvation onwards the body appears to be fully adapted to starvation and there is a kind of steady state, in which there is gradual depletion of the body’s protein mass (minimized by the mechanisms discussed earlier), and steady depletion of the fat stores. Ketone body concentrations in the blood reach about 6-8 mmol/l, and ketone bodies provide about two-thirds of the metabolic requirement of the brain. Other tissues that require glucose (e.g. erythrocytes, renal medulla) produce lactate which is effienctly recycled, using energy derived from fatty acid oxidation. Thus the rate of irreversible loss of glucose is minimized. The major fuel flows in this state are summarized in figure 7.6
The pattern of metabolism is governed by the physico-chemical features of fat and carbohydrate outlined in Chapter 1, so that fat --the most energy dense fuel store -- constitutes the major long -term fuel reserve, and metabolism is geared to derive the maximum proportion of energy from fat oxidation. The changes which bring about this metabolic adaptation are mediated in a gradual way by changing concentrations of substrates in the blood and by the almost automatic responses of the endocrine system: insulin secretion decreases as the plasma glucose concentration falls, while glucagon secretion increases. The central nervous system is involved in these responses, with a change in thyroid hormone secretion (via the hypothalamic- pituitary system) and mild activation of the adrenal medulla and sympathetic nervous system. However, the involvement of the central nervous system is very much less than in situations such as exercise and trauma.
The adapted state may come to an end with re-feeding. Otherwise it will continue, usually until weakness of the respiratory muscles leads to inability to clean the lungs properly, and pneumonia sets in and leads to death. There is some evidence that survival is determined by the size of the fat stores: when the fat stores are depleted as far as they can be, there is a sudden additional loss of protein and death follows quickly.
[Bron: the body`s fuel stores. In: Metabolic regulation. A human perspective. London: Portland Press, 1996, p 163175]
In het boek "burn the fat, feed the muscle" kom je vaak de term 'starvation' tegen. Nu is het proces in het algemeen wel bekend bij de meesten hier maar ik heb toevallig afgelopen week een stuk gelezen over hoe het proces wat specifieker in zn werk gaat. Ik dacht, misschien interessant voor sommige mensen hier. Het is wel droge stof, vooral omdat ik de afbeeldingen eruit heb geplukt. Dit stuk gaat overigens wel over complete uithongering die uiteindelijk tot de dood leidt.
Ik plemp het hieronder neer:
The body’s fuel stores.
Carbohydrate
The amount of free glucose in the circulation and extracellular fluid is small, about 12 g in all. If we were able to use all of this without replenishing it, it would support the metabolism of the brain for about 2 h. Clearly, this is not adequate even to keep us alive overnight, and hence have stores of carbohydrate. We looked in Chapter 1 at the osmotic problem that would arise if free glucose were stored in cells, and why we store our carbohydrate in polymeric form as glycogen. Only two tissues, skeletal muscle and liver, have stores of glycogen that are significant in relation to the needs of the whole body, although most tissues have a small store for ' local' use. Approximately 40 %of the human body is skeletal muscle --say 25kg on average. A typical concentration of glycogen in skeletal muscle is around 15g/kg of wet weight, i.e. each kilogram of muscle in its normal, hydrated state contains app. 15 g of glycogen; thus the total muscle glycogen store is 350-400g.(this is very variable and can be expanded considerably under certain conditions, such as high carbohydrate intake after exercise). This is not available directly as glucose to enter the circulation, since muscle lacks glucose-6-phosphatase, although it can be exported to the liver as lactate, pyruvate and/or alanine for formation of glucose. In contrast, the liver glycogen store is more directly available as glucose, and undoubtedly plays the major role of a ' buffer’ for changing hour-to-hour requirements. A typical liver glycogen concentration is app. 50-80 g/kg of wet weight, and varies during the day. The liver weighs app. 1 - 1.5 kg, so the total liver glycogen store is app. 5-120 g. You will see immediately that this is not far from ' 24 hours' worth’ for the brain. Thus our carbohydrate stores are sufficient to enable us to ride out periods of a day or so without food.
Fat
On the other hand, our fat stores are usually larger by one to two orders of magnitude. This should not surprise us. We saw in Chapter 1 the considerable advantage, in weight terms, of storing excess energy in the form of hydrophobic triacylglycerol molecules, in the lipid droplets of adipocytes. A typical figure for body fat content is about 15 - 30 % of body weight. Thus an average fat store is of the order of 10 - 20 kg. The energy content of fat is around 37 kJ/g, so we store the equivalent of around 500 MJ in the form of fat. A typical daily energy expenditure )(to be discussed further in Chapter 10) is around 10 MJ, so we store sufficient energy for about 50 days of life or more; as we shall see, on of the prominent aspects of the metabolic adaptation to starvation is that daily metabolic rate (energy expenditure) is reduced. This accords well with recorded times for survival of starvation victims of up to 60 days for people who were initially normal. A few obese people have starved, voluntarily, for therapeutic reasons for considerably longer periods. (They were closely monitored medically, and given the necessary vitamin and mineral supplements.)
However, storage of most of our energy reserves in the form of fat poses biochemical problems, since some tissues and organs require glucose and cannot oxidize fatty acids. Fatty acids cannot be converted to glucose in mammals because acetyl-CoA formed from fatty acids is oxidized completely to CO2, in the tricarboxylic acid cycle and is therefore unable to contribute to the gluconeogenic pathway. On the glycerol component of triacylglycerol can form glucose, and this is a minor contributor in terms of numbers of carbon atoms. As we shall see, one strategy adopted during starvation is an increased conversion of fatty acids into water-soluble intermediates, the ketone bodies, which can be used by tissues which normally require glucose, particularly the brain.
Amino Acids
The body contains around 20% by weight of protein --around 10- 15 kg. Amino acids can be oxidized to provide energy, or converted to glucose and fatty acids, which can then be oxidized. Amino acids, when completely oxidized in a calorimeter, liberate around 24 kJ/g. This is not a realistic figure for metabolic oxidation, since urea is formed, which itself has a certain energy content; amino acid catabolism to CO2 and urea liberates about 17 kJ/g/ Thus about 200 MJ of biological energy is present in the body in the form of protein; however, we must be careful in interpreting this as an energy store. Animals do not produce any specific protein purely for storage of amino acids; all proteins have some other function -- as structural components, enzymes. etc. Thus the body’s content of protein is only available as an energy store at the expense of loss of some functional protein. In fact, in the metabolic adaptation to starvation, the body protein is conserved so far as is consistent with the body’s metabolic requirements; protein is not utilized as an energy reserve in the same way that carbohydrate and fat are.
Of the 10 - 15 kg of protein in the body, about 5 kg is in skeletal muscle. This appears to be the main source of supply when amino acids are required. There is some loss from other organs and tissues, but presumably they are relatively ' spared' because of their vital functions. It appears that the body can only tolerate a loss of about half of its muscle protein. After this, the respiratory muscles become so weakened that chest infection and pneumonia may set in (probably assisted by impaired immune function as a result of malnutrition) and death follows.
Starvation.
The response to absolute deprivation of food proceeds in a number of stages, leading ultimately to death; but the manner in which metabolism adapts, to postpone that final end-point as long as possible, illustrates a number of important points about the integration of metabolic regulation in the whole body. Starvation has, undoubtedly, always been a threat to humans and other animals, and the metabolic responses which minimize its impact have evolved throughout the development of all living things. Because this response has evolved so directly to counteract the threat posted by lack of food, it is tempting to look on it as ' purposeful' and indeed it helps considerably in understanding it if we think in terms of the body’s' strategy'. Nevertheless, bear in mind that the use of a term such as strategy does not imply anything other than a response that has evolved because it is beneficial.
There are distinctions between absolute starvation and partial starvation or under nutrition. We will consider absolute starvation as this provides the clearest illustration of metabolic adaptation.
The early phase
We have already looked at the pattern of metabolism in very-short-term starvation, namely the post-absorptive state after overnight fast. A gentle decrease in the concentration of glucose in the plasma led to a small decrease in the ratio of insulin/glucagon, stimulation of hepatic glycogenolysis and liberation of fatty acids from adipose depots. The availability of fatty acids in the plasma leads tissues such as muscle to use fat --and spare glucose -- as their major metabolic fuel.
The post-absorptive state leads into the gluconeogenic phase, which lasts until the second or third day of absolute starvation. Liver glycogen stores are virtually depleted within 24 h, and, therefore, gluconeogenesis must come into operation to supply the requirements of the brain and other glucose-requiring tissues (e.g. erythrocytes). The main signal for this will again be the change in insulin/glucagon ratio. The concentration of another important hormonal stimulator of glyconeogenesis, cortisol, does not change systematically in starvation. In addition, the supply of substrate for glyconeogenesis will increase over this period, as net proteolysis in muscle -- resulting from the falling insulin concentration -- leads to release of amino acids, mainly alanine and glutamine; the latter is partially converted to alanine in the intestine, and thus the liver receives an increased supply of this amino acid. Increasing lipolysis in adipose tissue releases glycerol, which is also a substrate for glyconeogensis.
Gluconeogenesis in this early stage of starvation is, therefore, proceeding largely at the expense of muscle protein, a situation which is clearly not good for survival. Studies of experimental underfeeding of volunteers have shown that muscle function is impaired with surprisingly small degrees of under nutrition. Not all amino acid carbons can be converted into alanine and glutamine, and some are oxidized, representing an irreversible loss from the body’s stores. Around 1.7 g of muscle protein must be broken down to provide each gram of glucose, since not all amino acids can be converted to glucose, and, with the brain requiring around 100 - 120 g of glucose per day, the rate of muscle protein breakdown could be rapid. If no other adaptations took place, this would require the breakdown of around 150 g of protein per day. (some glucose is, of course, provided from glycerol.) The body’s store of protein in muscle would be rapidly depleted. This is avoided by a series of inter-related adaptations to starvation, which are summarized in table 7.2 (not included)
The sparing of the body’s protein stores is brought about gradually. The excretion of nitrogen in the urine, a measure of the irreversible loss of amino acids, decreases steadily from the start of starvation. At first sight this seems to contradict the idea of increased gluconeogenesis from amino acids in the early phase of starvation; however, this is not a fair picture. We should think in terms of nitrogen balance. Nitrogen balance is the difference between total nitrogen intake, and total nitrogen loss. Some nitrogen is lost in faeces and shed skin cells, but most is lost in the urine in the form of urea and ammonia, and represents the catabolism of amino acids. During normal life, we are approximately in nitrogen balance on a day-to-day basis; the amount of nitrogen we take in is equal to the amount we lose, and the body store of nitrogen (mainly in amino acids and protein) stays roughly constant. At the start of starvation, nitrogen intake falls suddenly to zero, but nitrogen excretion continues at about the same lever as before. Suddenly, therefore, there is a net loss of the body’s protein stores. Nitrogen excretion then declines steadily, representing the sparing that is necessary for starvation to be prolonged beyond a week or two.
The period of adaptation to starvation.
The changes listed in table 7.2 (not included) come into place gradually over the first three weeks or so of total starvation; this is the period of adaptation. Beyond three weeks, the body has adapted as far as it can, and a kind of steady state is reached.
Hormonal changes.
The onset of starvation is marked by a decrease in the level of the active thyroid hormone tri-iodothyronine (T3) in the blood. It is not clear what causes this, although the mechanism is in part a shift towards production of an inactive form, reverse-T3. The effect of the fall in T3 concentration is to reduce overall metabolic rate, and to reduce the rate of proteolysis in the muscle. The reduction in overall metabolic rate leads to a decrease in the rate of depletion of the body’s fuels stores. However, it is unlikely that the metabolism of the brain, usually the largest glucose consumer is reduced significantly, so the need for glucose is still present; it is reduced, however, by the mechanisms described below.
Both the sympathetic nervous system and the adrenal medulla play some role during starvation. However, although starvation is a state in which fuel mobilization is required, the adrenergic systems play a much lesser role than in other, more stress-driven states (such as exercise). There is some activation of both sympathetic nervous system and adrenaline secretion during the first week or so of starvation. These changes would normally cause an elevation in overall metabolic rate; this is not seen, since it is outweighed by the reduction in T3 concentration.
On the other hand, the adrenergic stems are probably important in stimulation of lipolysis in adipose tissue. This latter will be reinforced by the continuing reduction in insulin concentration. Therefore, the plasma non-esterified fatty acid concentration rises during the adaptation period.
Adaptation of fatty acid, ketone body and glucose metabolism.
The elevation in plasma non-esterified fatty acid concentration leads to a number of adaptations. Skeletal muscle will use non-esterified fatty acids almost entirely in preference to glucose for its energy production. In the liver, the rate of fatty acid esterification, usually stimulated by insulin, will decrease; fatty acids will be diverted into oxidation (glucagon stimulates this pathway). This diversion is mediated in part by a decrease in hepatic malonyl-CoA concentration, a result of the decrease in insulin concentration. Increased oxidation of fatty acids leads to increased production of the ketone bodies, 3-hydroxybutyrate and acetoacetate. These can be used as an oxidative fuel by many tissues, at a rate which simply depends on their concentration in the blood. Most importantly, they can be used by the brain, which begins to use a fuel derived from the fat stores in preference to glucose. By the end of the third week of starvation, blood ketone body concentrations may reach 6-7 mmol/l, compared with < 0.2 mmol/l normally. At this stage, ketone body oxidation can account for approximately two-thirds of the oxygen consumption of the brain. Thus about 70-80 g of glucose per day is spared oxidation.
The body’s need to form new glucose from amino acids is also reduced by the stimulation of gluconeogenesis in the liver, which enables glucose to be efficiently recycled. Glycolytic cells and tissues such as erythrocytes and the renal medulla will still need to use glucose. (they cannot use ketone bodies since they do not have the oxidative capacity.) Glycolyisis in these tissues, however, leads to the release of lactate which is returned to the liver and avidly reconverted into glucose. Thus the glucose which must be used by these tissues is recycled. Energy for this process comes form the increased oxidation of fatty acids in the liver, forming the NADH necessary to drive gluconeogenesis (so that, in effect, the glycolytic tissues ' run' on energy derived from the fat stores).
Sparing of muscle protein.
By these mechanism, the need to produce glucose from muscle protein is reduced, and the loss of nitrogen in the urine decreases. However, with the insulin concentration decreasing, the net stimulus would seem to be for increasing muscle protein breakdown. How is the sparing of muscle protein brought about?
The possible role of the decreasing T3 concentration has been mentioned: T3 usually has the effect of stimulation muscle porteolysis. Another possibility is that the increase in plasma adrenaline concentration may be involved. Adrenergic drugs have an anabolic effect on muscle, although this effect is not clearly understood and the receptors by which it is mediated have not been delineated.
The other possible mediator is the increase in blood ketone body concentration. Some experimental studies show that this leads to a reduction in the net breakdown of muscle protein. There is a possible mechanism. The branched-chain amino acids are catabolized in muscle by transamination, followed by the action of the branched-chain 2-oxo-acid dehydrogenate complex. This enzyme complex has many similarities with pyruvate dehydrogenase. Like pyruvate dehydrogenase, its activity is inhited by phospohorylation in response to a high acetyl-CoA/CoASH ratio. In other words, if the muscle is plentifully supplied with other substrates for oxidation (such as fatty acids and ketone bodies, in starvation) the oxidation of the branched chain amino acids will be suppressed.
However, the fall in nitrogen loss in starvation may be another facet of the general slowing down of metabolism. In this case no specific mechanism need be postulated. This has been discussed by Henry et al. (1988), who argued that conventional understanding of the response to starvation is heavily biased, since it is based largely on obese subjects undergoing starvation for the purpose of weight reduction.
Kidney metabolism
During this period of starvation, there are marked changes in the metabolic pattern of the kidney which will be briefly discussed. The concentrations of lipid-derived fuels -- non-esterified fatty acids and ketone bodies -- are high in the plasma. These are biological acids. Therefore, the production of hydrogen ions increases and the pH of the blood tends to fall. To counter this, the body must excrete excess hydrogen ions. In section 5.3.2.3 one means for achieving this was mentioned: the kidney can excrete ammonia, which carries with it one hydrogen ion, since it will be in the form of NH4+/ The ammonia may be derived from the action of glutaminase on glutamine, and glutamate dehydrogenase on glutamate, in the kidney. The renal uptake of glutamine increases in starvation to provide a means for excretion of excess hydrogen ions. Glutamine metabolism in the kidney can lead to glucose production, especially during starvation when the kidney can become an important gluconeogenic tissue. Thus again we see the efficiency of metabolism: a metabolic process (ammonia excretion) necessary to regulate blood pH is coupled with the conversion of a muscle-derived amino acid to glucose.
The period of adapted starvation.
Form about three weeks of total starvation onwards the body appears to be fully adapted to starvation and there is a kind of steady state, in which there is gradual depletion of the body’s protein mass (minimized by the mechanisms discussed earlier), and steady depletion of the fat stores. Ketone body concentrations in the blood reach about 6-8 mmol/l, and ketone bodies provide about two-thirds of the metabolic requirement of the brain. Other tissues that require glucose (e.g. erythrocytes, renal medulla) produce lactate which is effienctly recycled, using energy derived from fatty acid oxidation. Thus the rate of irreversible loss of glucose is minimized. The major fuel flows in this state are summarized in figure 7.6
The pattern of metabolism is governed by the physico-chemical features of fat and carbohydrate outlined in Chapter 1, so that fat --the most energy dense fuel store -- constitutes the major long -term fuel reserve, and metabolism is geared to derive the maximum proportion of energy from fat oxidation. The changes which bring about this metabolic adaptation are mediated in a gradual way by changing concentrations of substrates in the blood and by the almost automatic responses of the endocrine system: insulin secretion decreases as the plasma glucose concentration falls, while glucagon secretion increases. The central nervous system is involved in these responses, with a change in thyroid hormone secretion (via the hypothalamic- pituitary system) and mild activation of the adrenal medulla and sympathetic nervous system. However, the involvement of the central nervous system is very much less than in situations such as exercise and trauma.
The adapted state may come to an end with re-feeding. Otherwise it will continue, usually until weakness of the respiratory muscles leads to inability to clean the lungs properly, and pneumonia sets in and leads to death. There is some evidence that survival is determined by the size of the fat stores: when the fat stores are depleted as far as they can be, there is a sudden additional loss of protein and death follows quickly.
[Bron: the body`s fuel stores. In: Metabolic regulation. A human perspective. London: Portland Press, 1996, p 163175]
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