Role of nutrients in the regulation of in vivo protein metabolism in humans

Nutrients regulate protein metabolism both in an acute fashion and on a long-term basis. The ingestion of meals is associated with a dramatic switch from an overall catabolic state to a state of net protein anabolism. The acute response of protein metabolism to meal ingestion is mediated, in part, by an increase in insulin secretion, itself a consequence of glucose absorption. Whereas insulin may primarily suppress rates of proteolysis, amino acids are responsible for the stimulation of protein synthesis that follows food intake. In the long run, the effects of nutrition on protein metabolism depend on the energy supply, the source of the energy (carbohydrate versus fat) and dietary protein intake. Finally, specific amino acids, such as glutamine, may play an additional role as protein anabolic agents.     

Effect of insulin with oral nutrients on whole-body protein metabolism in growing pubertal children with type 1 diabetes

Insulin treatment of children with insulin-dependent diabetes mellitus improves whole body protein balance. Our recent study, conducted in pubertal children with type 1 diabetes with provision of both insulin and amino acids, indicated a positive effect of insulin on protein balance, primarily through decreased protein degradation. The current study was undertaken to assess the effect of insulin on protein metabolism in adolescents with type 1 diabetes during oral provision of a complete diet. Whole-body protein metabolism in six pubertal children (13-17 y) with type 1 diabetes mellitus was assessed with L-[1-13C]leucine during a basal (insulin-withdrawn) period and during infusion of 0.15 U/kg/h regular insulin with hourly meals to meet protein and energy requirements. Net leucine balance was significantly higher with insulin and nutrients (13.1 +/- 6.3 micromol leucine/kg/h) than in the basal state (-21.4 +/- 2.8, p < 0.01) with protein degradation decreased from 138 +/- 5.6 mumol leucine/kg/h to 108 +/- 5.9 (p < 0.01) and no significant change in protein synthesis. Even with an ample supply of nutrients, insulin does not increase whole-body protein synthesis in pubertal children with type 1 diabetes mellitus and positive protein balance is solely due to a substantial reduction in the rate at which protein is degraded.     

Effect of insulin with concurrent amino acid infusion on protein metabolism in rapidly growing pubertal children with type 1 diabetes

Insulin treatment of prepubertal children with insulin-dependent diabetes improves body protein balance by decreasing the rate of protein degradation without stimulating protein synthesis. However, insulin also causes hypoaminoacidemia, so the inability of insulin to stimulate protein synthesis may have been limited by substrate availability. We investigated the ability of insulin to stimulate protein synthesis in growing pubertal children who were given sufficient amino acids to counter insulin-induced hypoaminoacidemia. Protein metabolism in six pubertal children with type 1 diabetes was assessed from leucine kinetics during a primed, 6-h infusion of L-[1-(13)C]leucine. The children were studied in the postabsorptive state during a basal (insulin withdrawn) period and during the infusion of 0.83 mU * kg(-1) * min(-1) human regular insulin. Amino acids and glucose were given with insulin to prevent hypoaminoacidemia and hypoglycemia. Net leucine balance was significantly higher with insulin than in the basal state, the result of decreased protein degradation but also decreased protein synthesis. The data suggest that insulin alone does not increase protein synthesis in pubertal children with type 1 diabetes.     

De darm: een egoïstisch orgaan

The portal-drained viscera (stomach, intestine, pancreas and spleen) have a much higher rate of both energy expenditure and protein synthesis than can be estimated on the basis of their weight. A high utilization rate of dietary nutrients by the portal-drained viscera could result in a low systemic availability, which determines whole-body growth. In this paper we discuss the energy expenditure by the portal-drained viscera; which substrates are used as a source of energy; the amino acid utilization by the portal-drained viscera under normal feeding conditions; the impact of protein restriction on the portal availability of dietary amino acids; recycling of amino acids by the intestine. We conclude: that the energy expenditure by the portal-drained viscera is three times higher than could be expected on the basis of their weight; that dietary amino acids are the major fuel source, while glucose is oxidized as well; that 65% of the dietary amino acid intake is utilized by the portal-drained viscera; that protein restriction increases the amino acid utilization by the portal-drained viscera to 81% of the dietary intake, while amino acids are not longer the main oxidative substrate and that recycling of endogenous synthesized intestinal proteins contributes significantly to overall systemic amino acid availability, resulting in an overall amino acid availability of 48% of the daily protein intake.     

The effect of oral essential amino acids and their ketoanalogues on children receiving regular haemodialysis

The plasma aminogram in uremic children receiving conservative treatment or undergoing hemodialysis demonstrated a similar profile to that first described in adults and children. We were able to demonstrate that dialysis did not correct the abnormal plasma amino acid pattern and that free amino acid losses in the dialysate during hemodialysis could not be compensated for by children receiving an adequate protein intake. Oral supplementation with essential amino acids (EAA) or ketoanalogues (KAA) only partially corrected the amino acid abnormalities and biochemical improvement in protein metabolism was not observed, however, increasing the relative proportions of branch chain amino acids in the supplement might be associated with improvement in metabolism. These data are in contrast to previous studies on the use of EAA or KAA in adults and children in which patients received a reduced protein intake, whereas in the present study protein intake was not restricted. The raised plasma levels of methionine and 3-methyl-histidine were not associated with side effects.     

Control of Protein Synthesis and Its Relationship to the Bioenergetics of Growth

A key goal of nutritional therapies designed to prevent or treat protein energy malnutrition (PEM) is achievement of adequate growth rates and thus positive balances of protein and energy. Positive protein balance is the net result of protein turnover, i.e., of recycling protein through energy-requiring anabolic and catabolic pathways. Thus, protein turnover is inexorably linked to energy metabolism and to energy balance. A long-standing hypothesis is that new tissue synthesis is predominantly a postprandial event. Thus, postprandial rates of protein turnover may regulate the bioenergetics of growth. Traditional methods to evaluate nutritional therapies for diarrhea and PEM, i.e., metabolic balance, ¹⁵N-labeled amino acids, fecal output, illness duration, or change in body weight, are not specific to studies of the regulation of acute protein turnover and growth by nutritional intervention. Newer techniques based on ¹³C-labeled amino acids should be applied to evaluate nutritional interventions such as dietary substrate ratios, protein quality, feeding frequencies, or ratios of dietary protein to energy in terms of their abilities to optimize postprandial protein turnover and thus nutritional management of diarrhea or PEM.     

Studies on requirements for amino acids in infants with disorders of amino acid metabolism. I. Effect of alanine

Two infants with disorders of propionate metabolism were studied at 7 months of age to determine optimum levels of intake of protein and calories to meet the requirements for essential amino acid for growth in infancy, and at the same time minimize the accumulation of toxic intermediates. An effect of alanine was found that permitted growth at otherwise limiting levels of protein intake. This was not simply an effect of nonessential nitrogen as neither glycine nor glutamic acid could substitute for alanine in this protein-sparing effect. This appears to represent further evidence of the relationship between alanine and the branched-chain amino acids and of the importance of the alanine-glucose cycle in human physiology.     

Maple syrup urine disease: Treatment of the acutely ill newborn

Three patients with maple syrup urine disease were treated during the acute neonatal stage. Multiple exchange transfusions proved to be a satisfactory means of achieving rapid clinical and biochemical improvement during this phase. On the other hand, evidence is provided suggesting that in addition to exchange transfusions, a high calorie intake above 150 Cal/kg body weight/day is necessary to lower the plasma concentration of the branched chain amino acids to near-normal levels. As long as this calorie intake was not provided, further exchange transfusions failed to lower the plasma leucine concentration to below 17 mg/100 ml in one patient. It is assumed that this high calorie intake is necessary to prevent the breakdown of endogenous protein. Treatment of acute episodes in maple syrup urine disease should therefore not only eliminate the elevated alpha-keto acids and branched chain amino acids quickly (i.e. by multiple exchange transfusions or peritoneal dialysis), but in addition should provide a high calorie intake.Dedicated to Prof. Dr. F. Linneweh on the occasion of his 70th birthday     

Dietary Intake, Trace Elements and Serum Protein Status in Young Diabetics

ABSTRACT. Dietary intake of energy and nutrients and its relation to trace element and protein status, as observed in 27 diabetic children and 13 healthy controls are discussed. The diabetic children had consistently higher intakes than the healthy controls in nearly all respects, except for carbohydrate and ascorbic acid. In spite of this, the diabetic children had a significantly lower mean serum magnesium than the healthy controls. It is suggested that hypomagnesemia in diabetic children may be the result of increased urinary loss or diversion of magnesium from normal metabolic pathways in this disease. This review also revealed a significantly higher mean serum selenium level in the diabetic children than in the healthy controls. However, no significant correlation WBS observed between serum selenium concentrations and protein intake, suggesting that a factor other than protein intake underlay the elevated levels of serum selenium. The diabetic children as a group had significantly lower levels of selected serum proteins than the controls, in spite of a significantly higher intake of protein by the diabetic group. It is suggested that both reduced serum proteins and elevated levels of serum selenium in the diabetic children are an expression of altered metabolism in combination with the effects of current modes of insulin treatment in this disease.     

Increased urinary excretion of inorganic sulfate in premature infants fed bovine milk protein

We report measurements of urinary inorganic sulfate (iSO4) in 38 very low birth weight (VLBW) premature infants receiving various protein intakes in the first 2 months of life. The primary source of urinary iSO4 is the metabolism of amino acids containing sulfur (methionine, cysteine, taurine). It was hypothesized that urinary iSO4 excretion would be increased in VLBW infants fed the relatively high concentrations of protein in mother's own milk (HM), mother's own milk fortified with 0.85 gm/dl bovine whey (fortified HM), and a special formula for premature infants (Similac Special Care, 20 cal/oz), and that urinary iSO4 excretion would correlate with calcium excretion. VLBW premature infants fed HM (protein intake 3.3 gm/kg day) excreted very small amounts of urinary iSO4 compared with infants fed fortified HM (4.5 gm/kg/day protein), Similac SC (2.9 gm/kg/day protein), or Similac (2.7 gm/kg/day protein), all three of which contain bovine whey. Unlike the case in adults, there was no correlation between either total protein intake and urinary calcium excretion or urinary iSO4 excretion. There was, however, a significant correlation between methionine intake and urinary iSO4 excretion (r = 0.48). We speculate that increased urinary iSO4 excretion is indicative of an overload of sulfur-containing amino acids, namely methionine, present in bovine whey protein. The data also support the ability of premature infants to catabolize relatively large quantities of sulfur-containing amino acids after 2 weeks of age.     

Normal and abnormal maternal metabolism during pregnancy

Metabolic adaptations during pregnancy are essential to meet the physiological demands of pregnancy as well as adequate growth and development of the fetus. There has been considerable interest in carbohydrate metabolism during pregnancy, with diabetes, the main disorder of glucose metabolism, a considerable focus for research. Whereas disorders of protein and lipid metabolism are recognised during pregnancy, their influence has received less attention. Fasting glucose values fall in early pregnancy with a rise in plasma free fatty acids, enhanced ketogenesis and a fall in plasma amino acids. Decreased hepatic insulin sensitivity in later pregnancy plays a key role in bringing about the appropriate changes in carbohydrate, lipid and amino acid metabolism which are essential for normal fetal development and survival.     

The effect of graded intake of glycyl-L-tyrosine on phenylalanine and tyrosine metabolism in parenterally fed neonates with an estimation of tyrosine requirement

Although tyrosine is considered indispensable during the neonatal period, its poor solubility has limited its inclusion in parenteral amino acid solutions to less than 1% of total amino acids. Dipeptides of tyrosine are highly soluble, have been shown to be well used and safe in animal models and humans, and, therefore, may be used as an effective means of providing tyrosine in the parenterally fed neonate. The goal of the present study was to determine the tyrosine requirement of the parenterally fed neonate receiving graded intakes of glycyl-L-tyrosine as a source of tyrosine. Thirteen infants receiving adequate energy (340 +/- 38 kJ. kg(-1).d(-1)) and protein (2.4 +/- 0.4 g.kg(-1).d(-1)) were randomized to receive parenteral nutrition with one of five graded levels of glycyl-L-tyrosine. The mean requirement and safe level of intake were estimated using a 1-(13)C-phenylalanine tracer and linear regression cross-over analysis that identified a break point in the response of label appearance in breath CO(2) (F(13)CO(2)) and phenylalanine oxidation to graded tyrosine intake. Based on the mean estimates of whole-body phenylalanine oxidation, the tyrosine mean requirement and safe level of intake were found to be 74 mg.kg(-1). d(-1) and 94 mg.kg(-1).d(-1), respectively. This represents 3.1 and 3.9% of total amino acids, respectively, considerably higher than levels found in present commercially available pediatric amino acid solutions. These data raise concern regarding the adequacy of aromatic amino acid intake in the parenterally fed neonate.     

Protein intake and metabolism in formula-fed infants given Swedish or Italian weaning foods

The aim of the study was to compare protein intake and metabolism between infants from two countries given similar infant formulae but different weaning foods. Healthy Swedish and Italian infants were studied between 3 and 12 mo. Infants in both populations were assigned to 1 of 3 infant formulae, containing 13, 15 or 18/20 g l^-1 of protein, given in addition to Swedish or Italian weaning foods. Protein intake from weaning foods was higher in Italian than in Swedish infants at 6 and 12 mo, whereas protein intake from formula at 6 mo and from formula/milk at 12 mo was similar in both populations. Plasma isoleucine, leucine, lysine, histidine and valine at 6 mo were lower in Italian than in Swedish infants fed formula with 13 g l^-1 of protein. All essential plasma amino acids were similar in Italian and Swedish groups at 12 mo. Serum urea was similar at 6 mo in corresponding formula groups, but was higher at 12 mo in the Italian than in the Swedish formula group. Serum albumin and growth were normal in both populations throughout infancy. In conclusion, formula with protein content of 13 g l^-1 seems to provide sufficient protein intake when combined with Swedish or Italian weaning foods during the second half of infancy, as indicated by normal serum albumin and normal growth. However, the bioavailability of protein and amino acids from weaning foods, in addition to their protein content, should be considered, as indicated by some indices of protein metabolism in the Italian infants.     

Insulin signaling in skeletal muscle and liver of neonatal pigs during endotoxemia

Sepsis has been associated with tumor necrosis factor alpha (TNF-alpha) and nitric oxide (NO) overproduction, insulin resistance, and a profound suppression of muscle protein synthesis. However, lesser suppression of muscle protein synthesis in neonatal pigs occurs in response to endotoxin (LPS) when glucose and amino acids are provided. We hypothesize that the LPS-induced TNF-alpha and NO overproduction down-regulates insulin signaling pathway activation in neonatal pigs in the presence of fed levels of insulin, glucose, and amino acids. In skeletal muscle, inducible NOS activity was increased in response to LPS infusion, but phosphorylation of the insulin receptor, insulin receptor substrate-1 (IRS-1), p42/p44 mitogen-activated protein kinase (MAPK), and protein kinase B, the association of IRS-1 with phosphatidylinositol 3-kinase (PI 3-kinase), and constitutive NOS activity were not altered. In liver, activation of the insulin receptor, IRS-1, and PI 3-kinase were not affected by LPS, but p42 MAPK phosphorylation was increased. The absence of a down-regulation in the insulin signaling cascade in muscle despite the LPS-induced increase in TNF-alpha and muscle iNOS, may contribute to the near-maintenance of muscle protein synthesis rates in the presence of glucose and amino acids in LPS-infused neonatal pigs.     

Effect of fasting on uteroplacental amino acid metabolism in the pregnant sheep.

In the fed state, the net utilization of most amino acids by the ovine uteroplacental unit (defined as uterine uptake minus umbilical uptake) is zero. This study was to determine if this is true for the fasted pregnant ewe also, when uteroplacental glucose uptake is diminished. Glucose and amino acid concentrations were determined in 9 pregnant ewes across the uterine and umbilical circulations. Uterine and umbilical blood flows were determined by the steady state antipyrine diffusion method, and net uptakes across each circulation calculated by application of the Fick principle. Five amino acids were found to have a consistently greater uterine uptake than umbilical uptake. In addition, glutamate had a negative net umbilical uptake coupled with no net uterine uptake. Fasting resulted in an increase in the differences between the respective uptakes for all five amino acids. No additional amino acids were found to have disparate uptakes than were seen in the fed state. Umbilical glutamate uptake became less negative during fasting, but the difference between the uterine and umbilical circulations remained unchanged, as the uterine circulation took up glutamate during fasting. The umbilical circulation took up alpha-ketoisocaproate 0.626 +/- 0.18, fed), and the uptake was increased during fasting (1.8 +/- 0.6). These findings suggest that the branched chain amino acids and glutamine are utilized by the ovine uteroplacenta to a greater degree than are most other amino acids, and at increased rates during fasting of the ewe. These amino acids, through deamination, may be the source of uteroplacental ammonia production, as well as serving as an energy substrate when glucose supply is limited.     

Influence of diabetes on metabolism of vascular smooth muscle.

Glucose utilization and the conversion of glucose to lactate, CO2, glycogen and lipids are decreased in the aorta from diabetic rats and rabbits. In addition the incorporation of amino acid into protein is reduced in diabetic rat aorta. The metabolic changes produced by diabetes are counteracted by insulin treatment, but there is a time lag of about 2 days before the effect of insulin treatment appears. The membrane transport of glucose in smooth muscle is carried out by a specific transport system of the facilitated diffusion type. A rate limiting influence of membrane transport on glucose metabolism is found in bovine mesenteric arteries and rabbit colon smooth muscle. In these preparations the influence of glucose concentrations on glucose metabolism is most pronounced in the range 0-11.1 mmol exhibiting saturation at higher glucose concentrations. Insulin in a high concentration (0.1 U/ml) has acute (less than or equal to 3 h) metabolic effects in vitro on smooth muscle which are qualitatively similar to those in skeletal muscle, but are weaker and appear later. The threshold concentration for the acute metabolic effects of insulin on smooth muscle in vitro is 10-100 times above the physiological levels, indicating a low acute sensitivity to insulin.     

Experimental approach to nutritional problems in chronic renal insufficiency

The many published studies of experimental chronic renal failure (CRF) include a few findings which are similar to those reported in children with the naturally occurring disease. Experimental CRF has proved a useful model for investigating changes in eating behaviors: lack of appetite for sweet foods and selection of foods with high protein contents was comparable to behaviors exhibited by children. Optimal protein intake was found to be close to the minimum recommended intake for "optimal" growth (different from maximum growth in rats). Excessive protein intake had detrimental effects on renal function and growth with conventional dehydrated feeds, but water intake may have a greater impact than blood urea nitrogen and acidosis. A 50% reduction in protein intake with adequate amounts of essential amino acids ensured normal growth and slowed progression of renal lesions. Replacement of protein by mixtures of ketoanalogs was more likely to be responsible for growth failure; where similar growth rates were achieved, there was no evidence of a beneficial effect on renal lesions. Diets with high sucrose contents were poorly tolerated by CRF rats and were associated with fructose "intolerance" and reduced liver energy stores.     

Metabolic aspects of fetal and neonatal growth.

This review covers the transplacental transport of amino acids to the fetus and the role of placental metabolism and fetal metabolism in the utilization of amino acids. Particular attention is paid to the non-essential amino acids and to their rates of production within the fetus or placenta. The supply of amino acids is compared with their requirements for accretion in protein and for their use as metabolic fuels. Recent studies of protein synthesis in relation to gestational age are also reviewed.     

Total parenteral nutrition in the newborn: energy substrates and plasma total fatty acids

Carbohydrate and lipid intakes have both been found to modulate the metabolism of long-chain fatty acids. To define the respective influence of these two energy substrates on plasma fatty acid concentrations, 32 studies were performed in 16 parenterally fed newborn infants (mean +/- SEM, birth wt: 2.15 +/- 0.1 kg, age: 10 +/- 1 d). In a paired cross-over design, the infants received for a given level of energy (60 versus 80 kcal/kg/d) two 6-d isonitrogenous and isocaloric regimens constructed so that the level of fat intake, 1 or 3 g/kg/d varied inversely with that of glucose. Total plasma fatty acid levels did not reflect the composition of the emulsion and varied with energy substrates. Plasma levels of three fatty acids rose inversely to the lipid intake, during the high glucose regimen: 16:1w7, 20:3w9 biologic markers of essential fatty acid deficiency, and 20:3w6 a derivative of 18:2w6. Glucose intake could exert its influence on 20:3w9 and 20:3w6 via insulin, an activator of delta 6 desaturase. Both glucose and fat should be taken into account when evaluating plasma fatty acid profile.     

早期蛋白质和能量摄入对早产儿生长影响的研究

目的：探讨出生后早期蛋白质和能量摄入对早产儿早期生长速率的影响。方法：采用回顾性研究的方法,收集出生体重小于1800 g并治愈出院的164例早产儿的临床资料,记录早产儿一般情况、肠内外营养支持及体格增长情况。按氨基酸应用起始日的不同分为24 h内应用氨基酸组（EAA组,n=112）和24 h后应用氨基酸组（LAA组,n=52）,比较两组早产儿在住院期间的蛋白质和能量摄入、蛋白/能量比及体格增长速率,并对两组早产儿的蛋白质和能量摄入及蛋白/能量比与体格增长速率的关系进行相关分析。结果：EAA组的早产儿体重下降幅度比LAA组低（6.3% vs 8.8%）,恢复至出生体重时间比LAA组早（7 d vs 9 d）;每周头围增长速率比 LAA组快（0.79±0.25 cm vs 0.55±0.25 cm）;每日平均体重增长速率比LAA组快（20±3 g/kg vs 17±3 g/kg)。相关分析表明,早产儿第3天及第7天的蛋白质和能量摄入及蛋白/能量比与住院期间平均体重增长速率均呈正相关。恢复出生体重后每周的蛋白质和能量摄入与每周体重增长速率呈多元线性相关（r=0.709,P<0.01）。早产儿第3天及第7天的蛋白质摄入与早产儿头围增长速率及身长增长速率呈正相关。结论：早期应用氨基酸能够降低早产儿出生早期的体重下降幅度,更早恢复至出生体重,加速住院期间的体重及头围增长速度。在适宜能量摄入相对固定的情况下,在一定范围内提高蛋白质摄入量能够增加早产儿的体重、头围及身长的增长速率。