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D J Millward

Publications and source records attributed to D J Millward.

At least 55 records · Page 3Linked to original sources
PubMed1991

The nutritional sensitivity of the diurnal cycling of body protein enables protein deposition to be measured in subjects at nitrogen equilibrium.

In adults in overall protein balance on intakes of protein equal to or greater than minimum requirements, the diurnal pattern of feeding and fasting results in cycling of body protein, with fasted losses and fed state gains of increasing amplitude with increasing habitual protein intake. Measurement of the slope of the fed state gain-intake relationship enables investigation of the ability of various patient groups to utilise dietary protein, without the need to impose negative nitrogen balance due to sub-maintenance protein intakes.

Journal Article↗
PubMed1990

Responses to protein deficiency of plasma and tissue insulin-like growth factor-I levels and proteoglycan synthesis rates in rat skeletal muscle and bone.

The relative biological importance of plasma levels of insulin-like growth factors (IGFs) is uncertain since the IGFs may act through endocrine mechanisms involving circulating IGFs secreted by the liver, or by autocrine/paracrine mechanisms with IGF production in or close to their target cells. We report here studies in rats designed to examine this problem with an investigation of the changes in plasma and tissue concentrations of IGF-I in relation to the inhibition of bone and muscle growth and proteoglycan synthesis, a putative IGF-I-sensitive process, by protein deficiency. Over a 3-week period in young well-fed growing rats, there were marked increases in plasma IGF-I, whereas in the protein-deficient animals in which growth was inhibited concentrations fell markedly. In bone, concentrations of IGF-I were initially 20% of plasma, did not increase with age and were minimally influenced by protein deficiency. In skeletal muscle, concentrations of IGF-I were initially 3% of plasma, did not increase with age, but did fall with protein deficiency. In bone, the inhibition of proteoglycan synthesis by the protein deficiency was not correlated with changes in tissue IGF-I concentrations and was poorly correlated with changes in plasma hormone concentrations, although in the latter case an exponential relationship could be fitted to the data from the initial control and subsequent protein-deficient animals. In muscle, the changes in proteoglycan synthesis were significantly linearly correlated with changes in tissue IGF-I compared with an exponential relationship with plasma concentrations from the initial control and subsequent protein-deficient animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Muscle glutamine concentration and protein turnover in vivo in malnutrition and in endotoxemia.

A comparison of the changes in the concentration of glutamine [Gln] in skeletal muscle in a variety of catabolic states with the attendant changes in rates of protein synthesis and degradation indicates a number of substantial correlations which provide insight into both the way in which [Gln] is regulated in muscle and possible regulatory influences of [Gln] on protein balance. There is a striking direct correlation between [Gln] and the rate of protein synthesis in the whole data set. Further examination of this relationship in protein deficiency shows that the changes in [Gln] correlate mainly with the reductions in ribosomal concentration (RNA/protein) and with the decrease in the rate of protein degradation. Because the fall in [Gln] in protein deficiency is also correlated with the decrease in free T3 concentrations, it is suggested that in this case the correlations of [Gln] with rates of protein turnover may be incidental, reflecting thyroidal influences on both protein turnover and glutamine transport. In contrast, in endotoxemia the changes in [Gln] were highly correlated with the ribosomal activity, kRNA, and in this case [Gln] was inversely correlated with the rate of protein degradation. Similar correlated changes occur in starvation and in response to glucocorticoids, and it is suggested that the reductions in [Gln] in endotoxemia could be causally related to the development of insulin resistance and the inhibition of the translational phase of protein synthesis which occurs in these circumstances. The mechanism of the reduction in [Gln] and any linked inhibition of protein synthesis is unknown, but it is shown to be independent of prostaglandin production.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗
PubMed1989

Effect of the cyclo-oxygenase inhibitor fenbufen on muscle and liver protein metabolism, muscle glutamine and plasma insulin in endotoxaemic rats.

1. The effect of fenbufen (gamma-oxo-[1,1'-biphenyl]-4-butanoic acid), a known cyclo-oxygenase inhibitor, on the changes in muscle and liver protein metabolism in response to Escherichia coli endotoxin has been investigated in the rat. 2. Young male rats were fed a purified diet [18% (w/w) casein], with or without fenbufen (1.2 g/kg of diet). Groups of animals were injected with either endotoxin (LPS; Escherichia coli lipopolysaccharide 0.127 B8; 3 mg/kg body weight) or saline. Rectal temperature and food intake were measured over the following 24 h period, after which time measurements were made of muscle and liver protein content and synthesis in vivo, muscle protein degradation as the difference between protein synthesis and growth rates, muscle glutamine concentration and plasma insulin. 3. Fenbufen treatment alone tended to lower rectal temperature. It also reduced plasma insulin, slightly reduced food intake and slowed growth and muscle protein turnover, although muscle glutamine concentrations were unchanged. The slower protein synthesis mainly reflected reduced translational activity, which was consistent with the reduced insulin concentration. 4. LPS treatment increased rectal temperature by 1.6 degrees C, and this was abolished by fenbufen, indicating that the dose of the drug was sufficient to block prostaglandin production in the hypothalamus. 5. LPS treatment induced similar losses in body weight and muscle protein in both control and fenbufen groups, despite a 50% lower food intake in the LPS plus fenbufen group compared with the LPS-only group. The loss of muscle protein in both groups reflected reduced protein synthesis and increased protein degradation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Whole body protein synthesis: studies with different amino acids in the rat.

These studies were undertaken to determine to what extent constant infusion measurements and plasma sampling could provide sensible answers for rates of whole body protein turnover and also which amino acid would be the most representative probe of whole body protein turnover. Whole body protein synthesis rates were estimated in 70-g rats with L-[U-14C]threonine, L-[U-14C]lysine, L-[U-14C]tyrosine, L-[U-14C]phenylalanine, and L-[1-14C]leucine by either simultaneous tracer infusion of four amino acids or by injections of large quantities of 14C-labeled amino acids. In the infusion experiment, indirect estimates of whole body protein turnover based on free amino acid specific radioactivity and stochastic modeling were compared with direct measurement of the incorporation of the tracer into proteins. These two methods of analysis provided similar results for each amino acid, although in each case fractional synthesis rates were lower (by between 26 and 63%) when calculations were based on plasma rather than tissue specific radioactivity. With the flooding-dose method, whole body fractional protein synthesis rates were 41.4, 25.6, 31.1, and 31.4% with threonine, lysine, phenylalanine, and leucine, respectively. These values were similar to those obtained by the continuous infusion method using tissue specific radioactivity for threonine and lysine. For leucine, however, the flooding-dose method provided an intermediate value between the two estimates derived either from the plasma or the tissue specific radioactivity in the infusion method.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1988

The role of insulin and thyroid hormones in the regulation of muscle growth and protein turnover in response to dietary protein in the rat.

1. We have investigated the relations between changes in plasma insulin and 3,5,3'-triiodothyronine (T3), and muscle growth and protein turnover in the rat in response to diets of varying protein concentrations. 2. Young rats were fed ad lib. on a control (180 g casein/kg) diet or low-protein diets containing 80, 45 and 0 g casein/kg in four separate experiments. Measurements were made of food intakes, muscle and body-weight growth rates, muscle protein turnover in vivo, plasma insulin, and plasma free and total T3. 3. The food intakes of the 80 and 45 g casein/kg diet groups were variable, with the 80 g casein/kg diet group consuming either the same or more than the controls, and the 45 g casein/kg diet group consuming less or more than the controls. Body-weight and skeletal-muscle growth rates varied with the protein but not energy intakes, which in turn reflected both dietary composition and the food intake, with the hyperphagic 80 g casein/kg diet group of rats growing almost normally and the 0 g casein/kg diet group losing body-weight and muscle mass. 4. Changes in rates of muscle growth were accompanied by parallel changes in rates of protein synthesis and degradation, as well as parallel changes in concentrations of plasma insulin and free T3, to the extent that all these variables were highly correlated with each other. 5. Partial correlation analysis was used to separate interactions between variables. This indicated that dietary energy had no identifiable influence on muscle growth. In contrast dietary protein appeared to stimulate muscle growth directly by increasing muscle RNA content and inhibiting proteolysis, as well as increasing insulin and free T3 levels. Insulin and free T3 stimulated each other as well as muscle protein turnover; insulin stimulating the RNA activity particularly at low insulin levels, free T3 stimulating the RNA content and both hormones stimulating proteolysis. 6. These apparent relations are shown to be consistent in the main part with previous studies of the mechanism of action of insulin and T3, but the possibility cannot be discounted that other anabolic hormones not measured in these studies are involved, particularly in the apparent direct influence of dietary protein on muscle.

Animals↗
PubMed1988

Relationship between glutamine concentration and protein synthesis in rat skeletal muscle.

Muscle glutamine concentration ([GLN]) and protein synthesis rate (Ks) have been examined in vivo in well-fed, protein-deficient, starved, and endotoxemic rats. With protein deficiency (8 or 5% casein diet), [GLN] fell from 7.70 to 5.58 and 3.56 mmol/kg in the 8 and 5% diet groups, with Ks falling from 15.42 to 9.1 and 6.84%/day. Three-day starvation reduced [GLN] and Ks to 2.38 mmol/kg and 5.6%/day, respectively. In all these groups food intakes and insulin were generally well maintained (except in the starved group), whereas free 3,5,3'-triiodothyronine (T3) was depressed in the starved and 5% protein group. The E. coli lipopolysaccharide endotoxin (3 mg/kg) reduced [GLN] to 5.85 and 4.72 mmol/kg and Ks to 10.5 and 9.10%/day in two well-fed groups. Insulin levels were increased, and free T3 levels fell. Combined protein deficiency and endotoxemia further reduced [GLN] and Ks to 1.88 mmol/kg and 4.01%/day, respectively, in the 5% protein rats. Changes in both ribosomal activity (KRNA) and concentration (RNA/protein) contributed to the fall in Ks in malnutrition and endotoxemia, although reductions in the RNA concentration were most marked with protein deficiency and reductions in the KRNA dominated the response to the endotoxin. The changes in [GLN] and Ks were highly correlated as were [GLN] and both KRNA and the RNA concentration, and these relationships were unique to glutamine. These relationships could reflect sensitivity of glutamine transport and protein synthesis to the same regulatory influences, and the particular roles of insulin and T3 are discussed, as well as any direct influence of glutamine on protein synthesis.

Animals↗
PubMed1988

Involvement of sympathetic nervous system and brown fat in endotoxin-induced fever in rats.

The object of this study was to assess the role of brown adipose tissue (BAT) and the sympathetic nervous system in the rise in heat production associated with endotoxin-induced fever. Oxygen consumption (VO2) was found to be significantly increased (28%) over a 4-h period after two doses of endotoxin (Escherichia coli lipopolysaccharide, 0.3 mg/100 g body wt) given 24 h apart. Injection of a mixed beta-adrenoceptor antagonist (propranolol) reduced VO2 by 14% in endotoxin-treated rats, whereas the selective beta 1- (atenolol) or beta 2- (ICI 118551) antagonists suppressed VO2 by 10%. These drugs did not affect VO2 in control animals. BAT thermogenic activity assessed from measurements of in vitro mitochondrial guanosine 5'-diphosphate (GDP) binding was elevated by 54% in interscapular BAT and by 171% in other BAT depots. Surgical denervation of one lobe of the interscapular depot prevented these responses. Endotoxin failed to stimulate GDP binding in rats fed protein-deficient diets. This may have been because BAT thermogenic activity was already elevated in control rats fed these diets or because endotoxin caused a marked suppression of food intake in the protein-deficient animals. The results indicate that sympathetic activation of BAT is involved in the thermogenic responses to endotoxin and that these can be modified by dietary manipulation.

Adipose Tissue, Brown↗
PubMed1988

The influence of plasma concentrations of tri-iodothyronine on the acute increases in insulin and muscle protein synthesis in the refed fasted rat.

To examine whether the low plasma levels of triiodothyronine (T3) in fasted rats might limit the recovery of muscle protein synthesis on refeeding, rats were fasted for either 3 or 4 days and refed with or without pretreatment with thyroid hormones. Fasting suppressed T3 levels, plasma insulin and the rate of the translational phase of muscle protein synthesis (KRNA; the rate per unit RNA), especially after the 4-day fast. On refeeding, plasma T3 levels remained low for more than 3 h after the 3-day fast and for more than 8 h after the 4-day fast. Insulin concentrations increased within the first hour of refeeding, eventually achieving supranormal concentrations after the 3-day fast. The KRNA increased within the first hour of refeeding, achieving well-fed control values by 3 h after the 3-day fast or 24 h after the 4-day fast. The increases in KRNA were significantly correlated with the increases in insulin at low insulin concentrations, achieving a plateau value at 150 pmol/l, so that further increases in insulin were not associated with any further increases in protein synthesis. Pretreatment with thyroid hormone induced increased T3 levels which were maintained for up to 8 h of refeeding. This had no effect on the responses of either insulin or protein synthesis to refeeding after the 3-day fast, but did result in an acceleration of the recovery in the KRNA and plasma insulin levels in the rats fasted for 4 days. Analysis of the insulin-KRNA relationship showed no evidence for any increase in the insulin sensitivity of muscle protein synthesis with thyroid pretreatment, the initial stimulation of protein synthesis on refeeding the rats fasted for 4 days reflecting increased insulin secretion. Since in the untreated animals, insulin secretion on refeeding was also correlated with T3 levels, these results are consistent with the previously reported thyroidal dependence of insulin secretion.

Animals↗
PubMed1988

The nutritional role of indispensable amino acids and the metabolic basis for their requirements.

Short-term balances and metabolic studies suggest that current estimates of adult indispensable amino acid (IAA) requirements are too low. In addition, the observed biological value of protein is less than that predicted from its amino acid score. We propose that these discrepancies reflect the fact that IAA requirements are complex, and can only be defined under specific artificial conditions. This is because consumption of protein usually results in oxidative losses of IAA and nitrogen, which are important to the organism and variable according to dietary composition. It is likely that the age-related fall in the current values for IAA requirement primarily reflects different dietary designs in the original balance studies, which induced different rates of oxidative losses. A new model for amino acid utilization is proposed which takes account of such losses, and factors that influence them are reviewed. We propose that dietary IAAs serve an important transient function prior to their oxidation, exerting a regulatory influence on maintenance and growth which we call the anabolic drive. The model also allows for diurnal cycling of body protein, in which oxidative losses of amino acids occurring during the postabsorptive phase must be balanced by net protein deposition during feeding if overall balance is to be attained. Diurnal cycling is likely to be nutritionally sensitive, influenced by the anabolic drive and could affect the relationship between total protein and IAA requirements. We argue that oxidative losses should be included in the requirement; this will account for apparent discrepancies in the observed efficiency of protein utilization. We propose that IAA requirements (R) can only be unambiguously defined in terms of Rmin, a value obtainable under artificial conditions when oxidative losses, Lr, are minimal (Lr min); current estimates of adult requirements may be close to this level. An operative requirement of practical value, Rop, will only be defineable when the value to the organism of the oxidative losses induced by usual diets, (Lr op), can be evaluated.

Adult↗