Starvation in the midst of plenty

The development, growth and application of arti®cial nutrition in the last 40 years has encompassed major scienti®c, technical and thankfully, clinical advances. Nevertheless, some problems have remained particularly intractable. Whereas it is all too easy to turn a bedridden patient into the human equivalent of a Strasbourg goose by feeding glucose and simply increasing the availability of amino acids is a poor way of stimulating the accretion of lean tissue mass, the full re-gaining of which may take months after discharge. There seems to be something peculiar about the responses of tissue protein metabolism in sick patients to the provision of nutrients. In many circumstances, supplying extra amino acids, even in the presence of suf®cient fuel, fat or glucose, to meet the energy needs of the patient simply results in a stimulation of amino acid oxidation, with the production of urea, and acetate used for more fat synthesis. It is as though the lean tissues were resistant to amino acids, which in normal circumstances promote lean tissue anabolism. Our understanding of the physiology and pathophysiology of protein turnover, particularly the effects of food upon it, has advanced much less quickly than that of fat or carbohydrate metabolism, partly because they have been so dif®cult to study [1]. Certainly, the use of the nitrogen balance technique has allowed us to describe the phenomenology of the net effects of feeding, fasting, injury and infection, but the mechanisms involved and their possible effects on protein synthesis and breakdown have been more dif®cult to disentangle. Nevertheless, over the past 20 years, the use of kinetic techniques, using radioactive and stable isotope tracers, both in animal models and in human beings has allowed us to describe what seem to be common responses of skeletal muscle, the biggest respository of protein in the body, to stimuli that cause cachexia. It appears likely that phenomenologically, muscle wasting is either slow and gradual (and often inexorable until disease related processes have abated) or is ̄orid and rapid, with up to a kilogram of muscle being lost in a week. The former responses are associated with among other conditions, immobilization, cardiac failure, hypothyroidism, some slow growing cancers, chronic renal failure, respiratory failure, and a number of other conditions. All these are also associated with a loss of muscle ribosomes (the machinery which makes protein) and of muscle protein synthesis, but with no evidence of an acceleration of muscle protein breakdown, indeed rather an adaptive fall. On the other hand, some conditions, such as sepsis, rapidly growing cancer, major injury, and burns, both synthesis and breakdown seem to be elevated, with breakdown running ahead, out of control. The behaviour in the second group appears likely to be related to actions of in ̄ammatory agents and cortisol, but in any case neither set of behaviours appears to be particularly amenable to the normally anabolic effects of an elevated supply of amino acids. This effect of amino acids is now well established, although for some reason it took some years before the idea really gained acceptance, partly because of the argument that the charging enzymes of aminoacyl-tRNA were always fully saturated so the amino acids could not be having a mass action like effect. In fact, the effect in normal healthy animals and people is likely to involve no such mechanism. Rather, amino acids appear to switch on the translational arm of protein synthesis and particularly initiation of translation via the so-called eukaryotic initiation factors. The responses of the protein synthetic machinery to feeding in animals were recognized nearly 20 years ago as being too rapid to be a result of the effects of new messages produced by the nucleus, and indeed it was possible to recover, by centrifugation, beads of ribosomes threaded onto the strings of mRNAs from muscle treated with amino acids and insulin. Oddly, the effect of insulin on protein synthesis, so easily demonstrated in animal muscle, was somewhat harder to show in human muscle, partly for technical reasons but now it is clear that both insulin and amino acids, in both animal and human muscle [2,3] stimulate protein synthesis and do so probably by stimulating the initiation step of protein synthesis. But in sick patients it is very hard to see such effects. In burned patients for example, provision of very high concentrations of amino acids does nothing to increase protein anabolism unless very high concentrations of insulin are given. When recombinant human growth hormone became available it seemed as though this might be the answer.