5.Diurnal cycling: the Millward-Rivers model

As mentioned in section 2, Millward starts from the position that there are three levels of requirement: optimal, operational and minimal. No attempt is made to put numbers to the optimal requirement, and little more can be said about it, except to emphasize that the minimal requirement, which has engaged so much attention, is not the be-all and end-all.

The operational requirement is the amount needed to secure balance at a range of intakes above the minimal. That such a range exists has long been recognized. The contribution of the new model (Millward & Rivers, 1988; Millward et al, 1989) is to suggest that the oxidative losses of amino acids can be divided into two parts, obligatory losses, L_O and regulatory losses, L_R. The important point is that the regulatory losses are no longer regarded simply as wasted amino acids; rather they have a beneficial and indeed necessary role. This role is the 'anabolic drive', which includes all the effects of amino acids in stimulating the production of hormones such as insulin and in promoting the deposition of protein after a meal (Millward, 1989, 1990). The fact that the replacement of the obligatory losses (50-60 mg N/kg) requires an intake that is almost twice as great (100 mg N/kg) has previously been taken as an effect of inefficiency, the nature and causes of which have never been defined. For Millward, L_R makes a necessary contribution to the control of protein metabolism although he now (personal communication) considers it not very important in adults. Nevertheless a state in which oxidative losses were reduced to a level that exactly compensated for the obligatory loss would not be a desirable one. Thus 'a scoring pattern based on minimal obligatory needs is of little practical use' (Millward, 1992).

The consequence of different patterns for growth and maintenance (section 4) is that in the fed state, even at minimal levels of protein intake, some IAAs may be provided in excess of needs. Millward et al (1990, 1991) have pointed out that the branched chain and aromatic IAAs are potentially toxic; their concentrations cannot be allowed to rise and any excess has to be disposed of by oxidation, through high capacity highly regulated oxidative pathways. One might suppose that although the oxidative enzymes are readily inducible, teleologically it would be inadvisable for the expression of them ever to be reduced to zero. This could be regarded as a further reason for the so-called inefficiency of amino acid utilization.

A second contribution of the Millward-Rivers model is that it emphasizes the importance of the diurnal cycle of fasting and feeding. Clugston & Garlick (1982) originally showed that deposition of protein during feeding is balanced by loss in the fasted state. Millward predicted from his model that the amplitude of the fasted-fed swings would increase with increasing protein intake, and his recent studies have shown that this is indeed the case, as shown in Figure 2 (Pacy et al, 1994). As Millward (1992) has said 'The increasing fasting loss with increasing protein intake generates an increasing demand for fed-state protein deposition to balance these losses'. Thus it is impossible to define any particular figure for the operational requirement. However, his dictum 'the more you eat the more you need' seems to imply that the intake can never catch up with the need, which is the logic of Achilles and the tortoise. This must be regarded as artistic license - the intake certainly can overtake the need. Millward's own 24 h balances are positive at high intakes; the same problem that has always plagued conventional nitrogen balance studies (Hegsted, 1976).

Although the mechanism is not understood by which the balance of body protein is maintained over the cycle of feeding and fasting, a good deal is known about the kinetic changes that characterize the cycle. In the original studies of Clugston & Garlick (1982) feeding appeared to cause an increase in whole body synthesis, but it was later suggested that this was an artefact resulting from recycling of amino acids during a prolonged 24 h infusion. The subject has been reviewed by Pacy et al (1994) and by McNurlan & Garlick (1989), and is discussed further in section 12. Most workers (e.g. Nissen & Haymond, 1986) now believe that the main effect of food is to decrease the rate of protein degradation through the combined influences of amino acids, insulin and perhaps other hormones (Millward et al, 1990).

The other component of the diurnal cycle is amino acid oxidation. The fasting oxidation rate is influenced by the preceding diet, as shown in Figure 3, from Price et al (1994). It increased almost 2-fold when the intake rose from 0.36 to 2.3 g/kg/d. There has been some disagreement over fasting oxidation. The MIT group, in their early studies, took the view that it remained constant when the habitual amino acid intake varied. It is apparent from Figure 3 that the change in fasting oxidation rate is only about 7.5 mmol/kg/h when the change in protein intake is 1 g/kg/d. The MIT group were working over a narrower range of leucine intakes than Price et al (section 8) so that, given the variability, the relation to habitual intake was not apparent. The difference between fed and fasted oxidation rates in Figure 3 represents the effect of food. As Millward predicted from his model, the difference increases with increasing intake.

Figure 2 Diurnal changes in nitrogen balance in subjects habituated to four levels of protein intake.

Figure 3 Leucine oxidation in the fed and fasted states in subjects habituated to four levels of protein intake. Data from Table 8.

This work on the diurnal cycle is important and relevant It firmly implicates the processes of protein synthesis and breakdown in the regulation of protein balance. Previously it would have been possible to regard the twin cycles (synthesis-breakdown and input output) as operating to a large extent independently (Waterlow, 1994), but not any more.