The early phase

We have already looked at the pattern of metabolism in very short-term starvation (Section 6.5.1), namely the postabsorptive 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.

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Fig. 8.1 The phases of starvation, assessed from the point of view of glucose metabolism. Reproduced from Ruderman (1975). With permission, from the Annual Review of Medicine 26: 245-258. ©1975 by Annual Reviews www.annualreviews.org.

The postabsorptive state leads into a phase sometimes called the gluconeogenic phase, lasting until the second or third day of absolute starvation. Liver glycogen stores are virtually depleted within 24 hours (Fig. 8.2), 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 decrease in insulin/glucagon ratio. The concentration of another important hormonal stimulator of gluconeogenesis, cortisol, does not change systematically in starvation. In addition, the supply of substrate for gluconeogenesis will increase over this period. The falling insulin concentration will lead to net proteolysis in muscle and release of amino acids, mainly alanine and glutamine. The latter is partially converted to alanine in the intestine (see Section 6.3.2.3), 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 gluconeogenesis.

Gluconeogenesis in this early stage of starvation is therefore proceeding largely at the expense of muscle protein, a situation that is clearly not good for survival. Studies of experimental underfeeding of volunteers have shown that muscle function is impaired with surprisingly small degrees of undernutrition. Not all amino acids can be converted into alanine and glutamine, and some are oxidised, representing an irreversible loss from the body's stores. Around 1.75 g

Fig. 8.2 Liver glycogen concentrations in normal human volunteers, after overnight fast, then during 2-10 days' total starvation, and then following refeeding with a carbohydrate-rich diet. The 'basal' value already includes the effects of 12-14 hours without food (a sample was not taken in the fed state). The samples were obtained with a fine needle inserted through the rib cage. Based on Nilsson & Hultman (1973).

Fig. 8.2 Liver glycogen concentrations in normal human volunteers, after overnight fast, then during 2-10 days' total starvation, and then following refeeding with a carbohydrate-rich diet. The 'basal' value already includes the effects of 12-14 hours without food (a sample was not taken in the fed state). The samples were obtained with a fine needle inserted through the rib cage. Based on Nilsson & Hultman (1973).

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 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 interrelated adaptations to starvation, which are summarised in Table 8.2.

Table 8.2 Metabolic adaptations that lead to sparing of muscle protein in starvation.

1. Ketogenesis increases; brain begins to use significant quantities of ketone bodies; therefore the need for glucose production is decreased

2. Gluconeogenesis is stimulated, so other precursors are used maximally (e.g. lactate is efficiently recycled)

3. As lipolysis increases, glycerol becomes an increasingly important substrate for gluconeogenesis

4. Thyroid hormone concentrations fall (probably via a fall in leptin concentration); metabolic rate is decreased, thus lessening demand for energy generally

5. Ketone bodies may exert a restraining influence on muscle protein breakdown (discussed in text; see Section 8.3.2.3).

Fig. 8.3 Rate of urinary nitrogen excretion in five obese subjects during starvation.

Based on Owen, O.E., Tappy, L., Mozzoli, M.A. & Smalley, K.J. (1990) Acute starvation. In: The Metabolic and Molecular Basis of Acquired Disease Vol. 1 (eds Cohen, R.D., Lewis, B., Alberti, K.G.M.M. & Denman, A.M.), 550-570. With permission of the publisher W.B. Saunders.

Fig. 8.3 Rate of urinary nitrogen excretion in five obese subjects during starvation.

Based on Owen, O.E., Tappy, L., Mozzoli, M.A. & Smalley, K.J. (1990) Acute starvation. In: The Metabolic and Molecular Basis of Acquired Disease Vol. 1 (eds Cohen, R.D., Lewis, B., Alberti, K.G.M.M. & Denman, A.M.), 550-570. With permission of the publisher W.B. Saunders.

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 (Fig. 8.3). 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 level 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.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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