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Biomedical subjects

D J Millward

Publications and source records attributed to D J Millward.

At least 19 recordsLinked to original sources
PubMed2003

Physiological mechanisms mediating aspartame-induced satiety.

Aspartame has been previously shown to increase satiety. This study aimed to investigate a possible role for the satiety hormones cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) in this effect. The effects of the constituents of aspartame, phenylalanine and aspartic acid, were also examined. Six subjects consumed an encapsulated preload consisting of either 400 mg aspartame, 176 mg aspartic acid+224 mg phenylalanine, or 400 mg corn flour (control), with 1.5 g paracetamol dissolved in 450 ml water to measure gastric emptying. A 1983-kJ liquid meal was consumed 60 min later. Plasma CCK, GLP-1, glucose-dependent insulinotropic polypeptide (GIP), glucose, and insulin were measured over 0-120 min. Gastric emptying was measured from 0 to 60 min. Plasma GLP-1 concentrations decreased following the liquid meal (60-120 min) after both the aspartame and amino acids preloads (control, 2096.9 pmol/l min; aspartame, 536.6 pmol/l min; amino acids, 861.8 pmol/l min; incremental area under the curve [AUC] 60-120 min, P<.05). Desire to eat was reduced from 60 to 120 min following the amino acids preload (control, -337.1 mm min; aspartame, -505.4 mm min; amino acids, -1497.1 mm min; incremental AUC 60-120 min, P<.05). However, gastric emptying rates, plasma CCK, GIP, insulin, and glucose concentrations were unaffected. There was a correlation between the increase in plasma phenylalanine and decrease in desire to eat after the liquid meal following the constituent amino acids (r=-.9774, P=.004). In conclusion, it is unlikely that aspartame increases satiety via CCK- or GLP-1-mediated mechanisms, but small changes in circulating phenylalanine concentrations may influence appetite.

Adult↗
PubMed2003

Whole-body protein turnover of a carnivore, Felis silvestris catus.

The cat (Felis silvestris catus) has a higher dietary protein requirement than omnivores and herbivores, thought to be due to metabolic inflexibility. An aspect of metabolic flexibility was examined with studies of whole-body protein turnover at two levels of dietary protein energy, moderate protein (MP; 20 %) and high protein (HP; 70 %), in five adult cats in a crossover design. Following a 14 d pre-feed period, a single intravenous dose of [15N]glycine was administered and cumulative excretion of the isotope in urine and faeces determined over 48 h. N flux increased (P<0.005) with dietary protein, being 56 (se 5) mmol N/kg body weight (BW) per d for cats fed the MP diet and 146 (se 8) mmol N/kg BW per d for cats fed the HP diet. Protein synthesis was higher (P<0.05) on the HP diet (75 (se 10) mmol N/kg BW per d; 6.6 (se 1) g protein/kg BW per d) than the MP diet (38 (se 5) mmol N/kg BW per d; 3.4 (se 0.4) g protein/kg BW per d). Protein breakdown was higher (P<0.05) on the HP diet (72 (se 8) mmol N/kg BW per d; 6.3 (se 0.7) g protein/kg BW per d) than the MP diet (44 (se 3) mmol N/kg BW per d; 3.9 (se 0.3) g protein/kg BW per d). Compared with other species the rate of whole-body protein synthesis in the well-nourished cat (9.7 (se 1.3) g protein/kg BW0.75 per d) is at the lower end of the range. These results show that feline protein turnover adapts to dietary protein as has been shown in other species and demonstrates metabolic flexibility. Further work is required to determine exactly why cats have such a high protein requirement.

Adaptation, Physiological↗
PubMed2003

Casein and whey exert different effects on plasma amino acid profiles, gastrointestinal hormone secretion and appetite.

Protein, generally agreed to be the most satiating macronutrient, may differ in its effects on appetite depending on the protein source and variation in digestion and absorption. We investigated the effects of two milk protein types, casein and whey, on food intake and subjective ratings of hunger and fullness, and on postprandial metabolite and gastrointestinal hormone responses. Two studies were undertaken. The first study showed that energy intake from a buffet meal ad libitum was significantly less 90 min after a 1700 kJ liquid preload containing 48 g whey, compared with an equivalent casein preload (P<0.05). In the second study, the same whey preload led to a 28 % increase in postprandial plasma amino acid concentrations over 3 h compared with casein (incremental area under the curve (iAUC), P<0.05). Plasma cholecystokinin (CCK) was increased by 60 % (iAUC, P<0.005), glucagon-like peptide (GLP)-1 by 65 % (iAUC, P<0.05) and glucose-dependent insulinotropic polypeptide by 36 % (iAUC, P<0.01) following the whey preload compared with the casein. Gastric emptying was influenced by protein type as evidenced by differing plasma paracetamol profiles with the two preloads. Greater subjective satiety followed the whey test meal (P<0.05). These results implicate post-absorptive increases in plasma amino acids together with both CCK and GLP-1 as potential mediators of the increased satiety response to whey and emphasise the importance of considering the impact of protein type on the appetite response to a mixed meal.

Adult↗
PubMed2003

An adaptive metabolic demand model for protein and amino acid requirements.

The shortcomings of the metabolic implications of the current protein requirements model are reviewed, and an alternative model, validated with [1-(13)C]leucine balance results in human adults, is presented and evaluated in the context of defining protein requirements. The model identifies metabolic demands for amino acids as comprising a small fixed component and a variable adaptive component that is relatively insensitive to acute food or protein intake, but which changes slowly with a sustained change in intake, enabling N equilibrium to be achieved. The model accounts for the apparent low efficiency of utilisation of animal proteins in N balance studies and enables more realistic efficiency values to be measured within an experimental framework that takes account of the adaptive metabolic demand. However, the complex relationship between the adaptive metabolic demand and habitual level and quality of protein intake prevents prediction of protein quality by amino acid scoring, which can markedly underestimate actual values. In contrast to the current model, for fully adapted individuals risk of deficiency (i.e. negative N balance after complete adaptation) will only start to increase when intakes fall below the range of the true minimum requirements, i.e. a value that is currently unknown, but likely to be between 0.40 and 0.50 g/kg per d at the lower end of the reported distribution of requirements. At intakes greater than this with additional metabolic demands varying directly with intake, deficiency is only likely as a short-term response to a change to a lower intake within the adaptive range. Thus, for adults satisfying energy needs on most mixed human diets, intakes will be within the adaptive range, and N equilibrium ceases to be a useful indicator of nutritional adequacy of protein. In the context of prescriptive dietary guidelines it may be expedient to retain current values until the benefits (and any risks) of protein intakes within the adaptive range can be quantified. However, from a diagnostic perspective, indicators other than N balance need to be identified, since maintenance of N balance can no longer be used as a surrogate of adequate protein-related health.

Adult↗
PubMed2001

The use of P-aminobenzoic acid and chromic oxide to confirm complete excreta collection in a carnivore, Felis silvestris catus.

Complete excreta collection is a pre-requisite for several protocols in protein metabolism, and lack of confidence in achieving this may be increased when working with carnivores. Recovery of p-aminobenzoic acid (PABA) as a check for complete urine collection and chromic oxide for complete faeces collection were assessed in the cat. A single oral dose of PABA (4 mg/kg BW) was excreted more slowly than has been reported in the human (82% recovery at 6 h). A daily dose of PABA proved a useful method for confirming complete urine collection in the cat, and was 99% excreted in 72 h. Chromic oxide (500 mg/cat) was administered orally and recovery of chromium in the faeces was 90% after 96 h. A HPLC method for the analysis of PABA in cat urine was developed, and from the application of the techniques to a nitrogen balance study, it was concluded that PABA and chromic oxide are useful checks for complete excreta collection in the cat.

4-Aminobenzoic Acid↗
PubMed2001

Protein and amino acid requirements of adults: current controversies.

Protein intakes vary widely but costs and benefits of such variation is a long standing unresolved issue. The wide range of reported values for the minimum protein intake for N equilibrium in adults, i.e. 0.39 to 1.09 g/kg is best explained by an Adaptive Metabolic Demands model in which metabolic demands include amino acid oxidation at a rate varying with habitual protein intake and which changes slowly with dietary change. Thus within the reported data the true minimum requirement intake, the lowest values in the range at intakes approaching the Obligatory Nitrogen Loss, allows only fully adapted subjects to achieve N equilibrium. The higher values reflect incomplete adaptation. (13)C-1 leucine tracer balance studies of this model show (a) a fall with age in apparent protein requirements, (b) better than predicted efficiency of wheat protein utilization, and (c) controversially, lower lysine requirements than other workers, consistent with new evidence of de novo synthesis of lysine from urea salvaged by large bowel microflora. The main implication of the requirements model for athletes on high protein diets is increased exercise induced amino acid oxidation and risk of loss of body N when such high intakes are not maintained.

Adult↗
PubMed2000

Effect of habitual dietary-protein intake on appetite and satiety.

To investigate whether appetite response to a high-protein test meal varies inversely with habitual protein intake, the satiating influence of dietary protein was investigated in 14 subjects. Subjects were divided into two groups on the basis of habitual protein intake: means of 1.0 g/kg/day (LP) and 1.4 g/kg/day (HP). Appetite was assessed in each group following high protein meals (test a). A 13-day period of dietary manipulation increased differences in protein intake between groups to a mean of 0.75 g/kg/day (LP) and 1.96 g/kg/day (HP) and a second satiety test (b) was performed. A third test (c) was performed in the HP group after protein intakes were reduced for 2 days to a mean of 0.85 g/kg/day. Differences in satiety were most marked, with significant correlations between satiety after the three meals and daily protein intake (r=-0.36). LP satiety was significantly greater than HP after test b (p=0.025), and approached significance when satiety response during LPb was compared with HPc (p=0.07). Results support the hypothesis that the satiating effect of dietary protein varies inversely with habitual protein intake.

Adult↗
PubMed2000

Human adult amino acid requirements: [1-13C]leucine balance evaluation of the efficiency of utilization and apparent requirements for wheat protein and lysine compared with those for milk protein in healthy adults.

BACKGROUND: There is considerable debate about the human lysine requirement and the consequent nutritional value of wheat protein. OBJECTIVE: We used a novel [1-(13)C]leucine balance protocol to examine whether adaptive mechanisms to conserve lysine allow wheat to be utilized more efficiently than expected according to current estimates of lysine requirements and wheat utilization. DESIGN: Wheat and milk proteins were compared in 6 adults infused for 9 h with L-[1-(13)C]leucine in the postabsorptive state (0-3 h), who were fed half-hourly with low-protein (2% of energy, 3-6 h) and isoenergetic higher-protein (12-13% of energy, 6-9 h) meals providing maintenance energy intakes. From acute measurements of [1-(13)C]leucine balance, we predicted nitrogen balance, the metabolic demand for protein, the efficiency of postprandial protein utilization (PPU), and the requirements for wheat protein and lysine. RESULTS: Leucine balance was higher after the milk than after the wheat feeding because of the greater inhibition of proteolysis by milk. PPU, calculated as the ratio of Deltanitrogen balance to Deltanitrogen intake between the low-protein and higher-protein periods, was 0.68 +/- 0.06 for wheat and 1.00 +/- 0.09 for milk (P </= 0.001). The estimated average wheat protein requirement (0. 6/PPU) was 0.89 +/- 0.08 g*kg(-)(1)*d(-)(1), indicating a lysine requirement of 23.2 +/- 2.0 mg*kg(-)(1)*d(-)(1). The measured PPU for wheat, 0.68 +/- 0.06, was higher than the value calculated from wheat lysine intake and milk protein lysine deposition, 0.26 +/- 0. 02, and higher than predicted by most published estimates of lysine requirements, apart from a value of 19 mg/kg indicated by nitrogen balance studies. CONCLUSIONS: The results show that adaptive mechanisms of lysine conservation allow wheat protein to be utilized more efficiently than expected.

Adult↗
PubMed2000

The transfer of 15N from urea to lysine in the human infant.

To explore the nutritional significance of urea hydrolysis for human subjects, male infants being treated for severe undernutrition were given oral doses of 10 mg [15N15N]urea every 3 h for 36 h, on admission, during rapid growth and after repletion with either moderate or generous intakes of protein. Urea hydrolysis was calculated from the 15N enrichment of urinary urea, and where possible, lysine, alanine, glycine and histidine were isolated from urine by preparative ion-exchange chromatography for measurement of 15N enrichment. Sufficient N was obtained for 15N enrichment of lysine to be measured on fifteen occasions from six children. Urea hydrolysis accounted for half of all urea production with 130 (SD 85) mg N/kg hydrolysed per d, most of which appeared to be utilized in synthetic pathways. Of the samples analysed successfully, nine samples of lysine were enriched with 15N (mean atom percent excess 0.0102, range 0.0017-0.0208) with relative enrichment ratios with respect to lysine of 1.63 (range 0.18-3.15), 1.96 (range 0.7-3.73) and 0.9 (range 0.4-1.8) for glycine, alanine and histidine respectively. Enriched samples were identified at each treatment phase and 68% of the variation in lysine enrichment was explained by the variation in urea enrichment with 54% explained by the overall rate of delivery of 15N to the lower gastrointestinal tract. The results indicate a minimum of 4.7 mg lysine per kg body weight made available by de novo synthesis with the more likely value an order of magnitude higher. Thus, urea hydrolysis can improve the quality of the dietary protein supply by enabling an increased supply of lysine and other indispensable amino acids.

Alanine↗
PubMed2000

Urea kinetics of a carnivore, Felis silvestris catus.

The effect of two levels of dietary protein energy, moderate (20%; MP) and high (70%; HP), on urea kinetics in eleven domestic cats was studied. After a 3-week prefeed, a single dose of [(15)N(15)N]urea was administered, and urine and faeces collected over the subsequent 5 d. For each 24 h period, total urea and enrichment of [(15)N(15)N]- and [(15)N(14)N]urea in urine were determined, and a model applied to calculate urea production, entry into the gastrointestinal tract, recycling to urine or faeces and, by difference, retention by the body and potentially available for anabolism. Urea production and excretion increased with dietary protein level Most of the urea produced was excreted, with only a small proportion entering the gut, and with the pattern of urea disposal not significantly different between the HP and MP diets. Thus, the percentages of urea production available to the gut were 15% (MP) and 12% (HP), of which 57% (MP) and 59% (HP) was recycled in the ornithine cycle, 40% (MP and HP) was potentially available for anabolism and the rest lost as faecal N. As a percentage of urea produced the amount potentially available for anabolism was very low at 6.41% (MP diet) and 4.79% (HP diet). In absolute terms urea entering the gut, being recycled in the ornithine cycle and potentially available for anabolism was significantly higher on the HP diet These results show that cats operate urea turnover, but at a lower rate, and with less nutritional sensitivity than has been reported for other species.

Animals↗
PubMed1999

The nutritional value of plant-based diets in relation to human amino acid and protein requirements.

The adequacy of plant-based diets in developed and developing countries as sources of protein and amino acids for human subjects of all ages is examined. Protein quantity is shown not to be an issue. Digestibility is identified as a problem for some cereals (millet (Panicum miliaceum) and sorghum (Sorghum sp.)) and generally is poorly understood. Direct measurements of biological value in children are reviewed and scoring is considered. Various existing requirement values for amino acids and especially lysine are reviewed, and it is concluded that stable-isotope studies do not yet provide adequate alternative values of N balance data, which for lysine are robust after recalculation and adjustment. A new maintenance requirement pattern is developed, with higher values than those of Food and Agriculture Organization/World Health Organization/United Nations University (1985) but lower values than the Massachusetts Institute of Technology pattern (Young et al. 1989). Calculations of age-related amino acid requirements are based on most recent estimates of human growth and maintenance protein requirements, a tissue amino acid pattern and the new maintenance amino acid pattern. These values appear valid when used to score plant proteins, since they indicate values similar to or less than the biological value measured directly in young children. When used to score plant-based diets in India, no marked deficiencies are identified. All regions score > 1 for adults, whilst for children scores range from > 1, (Tamil Nadhu) from 6 months of age to 0.78 (West Bengal), rising to 0.9 in the 2-5 year old, consistent with reports that high-lysine maize supports similar weight and height growth to that of casein. Inadequate amino acid supply is not an issue with most cereal-based diets.

Adult↗
PubMed1999

Optimal intakes of protein in the human diet.

For protein, progress is slow in defining quantifiable indicators of adequacy other than balance and growth. As far as current requirements are concerned, only in the case of infants and children is there any case for revision, and this change is to lower values. Such intakes would appear to be safe when consumed as milk formula. In pregnancy, notwithstanding the concern that deficiency may influence programming of disease in later life, there is little evidence of any increased need, and some evidence that increased intakes would pose a risk. For the elderly there is no evidence of an increased requirement or of benefit from increased intakes, except possibly for bone health. For adults, while we now know much more about metabolic adaptation to varying intakes, there would appear to be no case for a change in current recommendations. As far as risks and benefits of high intakes are concerned, there is now only a weak case for risk for renal function. For bone health the established views of risk of high protein intakes are not supported by newly-emerging data, with benefit indicated in the elderly. There is also circumstantial evidence for benefit on blood pressure and stroke mortality. With athletes there is little evidence of benefit of increased intakes in terms of performance, with older literature suggesting an adverse influence. Thus, given that a safe upper limit is currently defined as twice the reference nutrient intake, and that for individuals with high energy requirements this value (1.5 g/kg per d) is easily exceeded, there is a case for revising the definition of a safe upper limit.

Adult↗
PubMed1999

Dietary protein, growth and urea kinetics in severely malnourished children and during recovery.

The case mortality for severe malnutrition in childhood remains high, but established best approaches to treatment are not used in practice. The energy and protein content of the diet at different stages of treatment appears important, but remains controversial. The effect on growth, urea kinetics and the urinary excretion of 5-L-oxoproline was compared between a standard infant formula (HP group) provided in different quantities at each stage of treatment and a recommended dietary regimen, which differentiates the requirements of protein and energy during the acute phase of resuscitation (maintenance intake of energy and protein, relatively low protein to energy ratio, LP group) from those during the restoration of a weight deficit (energy and nutrient dense). The energy required to maintain weight was less in the HP than the LP group, but the HP group was not able to achieve as high an energy intake during repletion of wasting because of the high volume which would have had to be consumed. Compared to the LP group, in the HP group during catch-up growth there was significantly greater deposition of lean tissue and higher rates of urea production, hydrolysis and salvage of urea-nitrogen. These, together with higher rates of 5-L-oxoprolinuria, suggest a greater constraint of the formation of adequate amounts of nonessential amino acids, especially glycine, in the face of enhanced demands. Although more effective rehabilitation might be achieved using a standard formula, there is the need to determine the extent to which it might impose metabolic stress compared with the modified formulation.

Diet↗
PubMed1998

Variation in the apparent sensitivity of the insulin-mediated inhibition of proteolysis to amino acid supply determines the efficiency of protein utilization.

1. The variability between normal individuals in the efficiency of postprandial protein utilization (PPU), a determinant of the apparent protein requirement, was examined in relation to the relative responses of protein synthesis and proteolysis to protein feeding by means of [1-13C]leucine turnover and balance studies.2. Twenty-five healthy adults were infused intravenously with L-[1-13C]leucine continuously for 9 h. This was started in the postabsorptive state (PA, 3 h) and followed by low-protein feeding (LP, 3 h), and then by isoenergetic high-protein feeding (HP, 3 h). This allowed protein intake to be varied against a constant postprandial insulin level so that the extent of any amino-acid-mediated responses which were additional to those exerted by insulin could be investigated. Leucine oxidation, O, and balance (intake-oxidation), protein synthesis, S, and degradation, D, were calculated from plasma [1-13C]alpha-ketoisocaproic acid enrichment and 13CO2 excretion.3.PPUprotein, calculated as change in leucine balance/change in intake (HP-LP), varied from 0.58 to 0.99 (mean=0. 81+/-0.10), independently of age or sex. PPUprotein varied directly with the inhibition of D and inversely with the increase in leucine concentration and stimulation of O and S.4. Efficient PPU, as demonstrated by the top quintile of individuals categorized in terms of PPUprotein, involves maximal inhibition of D by protein feeding with minimal increases in free amino acid concentrations, O and S. Lesser inhibition of D and greater stimulation of S and O characterized the lower, less efficient quintile. This indicates that the efficiency of protein utilization in individuals, and a component of their apparent protein requirement, is determined by the sensitivity of the insulin-mediated inhibition of proteolysis to amino acid supply.

Adult↗
PubMed1998

Metabolic demands for amino acids and the human dietary requirement: Millward and rRvers (1988) revisited.

In 1988, Millward and Rivers reappraised existing metabolic models for amino acid requirements. The metabolic demand for amino acids was reviewed in relation to both obligatory metabolic consumption and adaptive pathways of amino acid oxidation. The obligatory demand pattern was deemed unknowable from first principles except that the level of one amino acid would be similar to its concentration in an amount of tissue protein equivalent to the obligatory nitrogen loss. The adaptive demand pattern was predicted to vary in relation to the amount and the periodicity of food protein intake that influenced the amplitude of the diurnal cycle of gains and losses. A regulatory influence of protein intake on anabolism, the anabolic drive, was identified in animal studies; benefit appeared to derive from intakes in excess of the minimum for balance, which could facilitate definition of an optimal requirement. The inherent and design-related limitations of both nitrogen and stable isotope balance studies of requirement were recognized as a major problem in identifying secure values for indispensable amino acid requirements. A decade of research of increasing methodological sophistication has generated much new information, confirming the adaptive diurnal model of balance regulation and allowing development of the anabolic drive into a general protein-stat theory for coordinated control of growth and maintenance of the lean body mass. However, notwithstanding several new estimates of amino acid requirement values, definition of a widely accepted human amino acid requirement pattern remains unresolved. Although a case can be made for an adjusted 1985 FAO adult requirement pattern being a reasonable estimate of the obligatory indispensable amino acid requirements for human maintenance, the problems posed by adaptation, methodological inadequacies and lack of independent measures of adequacy mean that assessment of the adequacy of the human diet to satisfy amino acid needs remains inherently difficult.

Adult↗