The nutritional phenotype in the age of metabolomics.

The concept of the nutritional phenotype is proposed as a defined and integrated set of genetic, proteomic, metabolomic, functional, and behavioral factors that, when measured, form the basis for assessment of human nutritional status. The nutritional phenotype integrates the effects of diet on disease/wellness and is the quantitative indication of the paths by which genes and environment exert their effects on health. Advances in technology and in fundamental biological knowledge make it possible to define and measure the nutritional phenotype accurately in a cross section of individuals with various states of health and disease. This growing base of data and knowledge could serve as a resource for all scientific disciplines involved in human health. Nutritional sciences should be a prime mover in making key decisions that include: what environmental inputs (in addition to diet) are needed; what genes/proteins/metabolites should be measured; what end-point phenotypes should be included; and what informatics tools are available to ask nutritionally relevant questions. Nutrition should be the major discipline establishing how the elements of the nutritional phenotype vary as a function of diet. Nutritional sciences should also be instrumental in linking the elements that are responsive to diet with the functional outcomes in organisms that derive from them. As the first step in this initiative, a prioritized list of genomic, proteomic, and metabolomic as well as functional and behavioral measures that defines a practically useful subset of the nutritional phenotype for use in clinical and epidemiological investigations must be developed. From this list, analytic platforms must then be identified that are capable of delivering highly quantitative data on these endpoints. This conceptualization of a nutritional phenotype provides a concrete form and substance to the recognized future of nutritional sciences as a field addressing diet, integrated metabolism, and health.

Maternal and infant factors associated with failure to thrive in children with vertically transmitted human immunodeficiency virus-1 infection: the prospective, P2C2 human immunodeficiency virus multicenter study.

OBJECTIVE: Many children with human immunodeficiency virus-1 (HIV-1) have chronic problems with growth and nutrition, yet limited information is available to identify infected children at high risk for growth abnormalities. Using data from the prospective, multicenter P2C2 HIV study, we evaluated the relationships between maternal and infant clinical and laboratory factors and impaired growth in this cohort. METHODS: Children of HIV-1-infected women were enrolled prenatally or within the first 28 days of life. Failure to thrive (FTT) was defined as an age- and sex-adjusted weight z score < or =-2.0 SD. Maternal baseline covariates included age, race, illicit drug use, zidovudine use, CD4+ T-cell count, and smoking. Infant baseline predictors included sex, race, CD4+ T-cell count, Centers for Disease Control stage, HIV-1 RNA, antiretroviral therapy, pneumonia, heart rate, cytomegalovirus, and Epstein-Barr virus infection status. RESULTS: The study cohort included 92 HIV-1-infected and 439 uninfected children. Infected children had a lower mean gestational age, but birth weights, lengths, and head circumferences in the 2 groups were similar. Mothers of growth-delayed infants were more likely to have smoked tobacco and used illicit drugs during pregnancy. In repeated-measures analyses of weight and length or height z scores, the means of the HIV-1-infected group were significantly lower at 6 months of age (P <.001) and remained lower throughout the first 5 years of life. In a multivariable Cox regression analysis, FTT was associated with a history of pneumonia (relative risk [RR] = 8.78; 95% confidence interval [CI]: 3.59-21.44), maternal use of cocaine, crack, or heroin during pregnancy (RR = 3.17; 95% CI: 1.51-6.66), infant CD4+ T-cell count z score (RR = 2.13 per 1 SD decrease; 95% CI: 1.25-3.57), and any antiretroviral therapy by 3 months of age (RR = 2.77; 95% CI: 1.16-6.65). After adjustment for pneumonia and antiretroviral therapy, HIV-1 RNA load remained associated with FTT in the subset of children whose serum was available for viral load analysis. CONCLUSIONS: Clinical and laboratory factors associated with FTT among HIV-1-infected children include history of pneumonia, maternal illicit drug use during pregnancy, lower infant CD4+ T-cell count, exposure to antiretroviral therapy by 3 months of age (non-protease inhibitor), and HIV-1 RNA viral load.

Glucose production, gluconeogenesis, and insulin sensitivity in children and adolescents: an evaluation of their reproducibility.

The prevalence of overweight and obese children has doubled, and the incidence of type 2 diabetes in children (0-19 y) has increased 4-fold during the past several decades. As a result we can anticipate an increased number of metabolic studies in children. There are few data on measures of glucose metabolism in normal children, and virtually none relating to their reproducibility. The aims of this study were 1) to provide new data on energy expenditure and glucose, lipid, and protein metabolism in nonobese, healthy children and adolescents; 2) to evaluate their reproducibility; and 3) on the basis of these data, to perform power calculations for metabolic studies. Eight nonobese subjects (8-16 y) were studied on two occasions, preceded by 7 d of a diet with identical energy content and macronutrient distribution. Gluconeogenesis, measured by deuterium oxide, accounted for 50% of glucose production. Insulin sensitivity, measured by the labeled minimal model, averaged 4.9 x 10(-4) mL(mU x min)(-1). Glucose appearance rate was significantly higher (p < 0.01) in the children than in the adolescents. Furthermore, we demonstrated that for energy intake and expenditure, plasma concentrations of glucose and C-peptide, and rates of appearance of glucose and leucine, a 10% difference can be detected in fewer than five subjects with a power of 80% and a type I error of 5%. Insulin concentration, gluconeogenesis, insulin secretory indices, insulin sensitivity, and glucose effectiveness were more variable, but with the above power a difference of 25% could be detected in 7-11 subjects using a paired study design.

Undermodeling affects minimal model indexes: insights from a two-compartment model.

The classic (hereafter cold) and the labeled (hereafter hot) minimal models are powerful tools to investigate glucose metabolism. The cold model provides, from intravenous glucose tolerance test (IVGTT) data, indexes of glucose effectiveness (SG) and insulin sensitivity (SI) that measure the effect of glucose and insulin, respectively, to enhance glucose disappearance and inhibit endogenous glucose production. The hot model provides, from hot IVGTT data, indexes of glucose effectiveness (SG*) and insulin sensitivity (SI*) that, respectively, measure the effects of glucose and insulin on glucose disappearance only. Recent reports call for a reexamination of some of the assumptions of the minimal models. We have previously pointed out the criticality of the single-compartment description of glucose kinetics on which both the minimal models are founded. In this paper we evaluate the impact of single-compartment undermodeling on SG, SI*, and by using a two-compartment model to describe the glucose system. The relationships of the minimal model indexes to the analogous indexes measured with the glucose clamp technique are also examined. Theoretical analysis and simulation studies indicate that cold indexes are more affected than hot indexes by undermodeling. In particular, care must be exercised in the physiological interpretation of SG, because this index is a local descriptor of events taking place in the initial portion of the IVGTT. As a consequence, SG not only reflects glucose effect on glucose uptake and production but also the rapid exchange of glucose between the accessible and nonaccessible glucose pools that occurs in the early part of the test.

Gluconeogenesis in very low birth weight infants receiving total parenteral nutrition.

Very low birth weight (VLBW) infants are dependent on total parenteral nutrition (TPN) to prevent hypoglycemia and provide a sufficient energy intake. However, diminished tolerance for parenteral glucose delivered at high rates frequently provokes hyperglycemia. We hypothesized that when their glucose supply is reduced to prevent hyperglycemia, VLBW infants can maintain normoglycemia via gluconeogenesis from glycerol and amino acids. Twenty infants born at 27 +/- 0.2 (mean +/- SE) gestational weeks and having a birth weight of 996 +/- 28 g, received lipids (1.6 +/- 0.1 mg x kg(-1) x min(-1)), protein (2.2 +/- 0.1 mg x kg(-1) x min(-1)), and glucose (3.1 +/- 0.1 mg x kg(-1) x min(-1) [17.1 +/- 0.2 micromol x kg(-1) x min(-1)]) parenterally over a period of 8-12 h on day 5.0 +/- 0.2 of life. Gluconeogenesis was estimated using [U-13C]glucose (n = 8) or [2-(13)C] glycerol (n = 6) and mass isotopomer distribution analysis (MIDA), or 2H2O (n = 6) and the rate of deuterium incorporation in carbon 6 of glucose. Blood glucose averaged 3.0 +/- 0.1 mmol/l; plasma glucose appearance rate (glucose Ra), 28.8 +/- 1.1 micromol x kg(-1) x min(-1); and glucose production rate (GPR), 10.7 +/- 1.0 micromol x kg(-1) x min(-1). The [U-13C]glucose and [2-(13)C]glycerol tracers provided similar estimates of gluconeogenesis, averaging 28 +/- 2 and 26 +/- 2% of glucose Ra and 72 +/- 5 and 73 +/- 9% of GPR, respectively. Glycerol contributed 64 +/- 5% of total gluconeogenesis. Gluconeogenesis measured by 2H2O, which does not include the contribution from glycerol, was comparable to the nonglycerol fraction of gluconeogenesis derived by the [2-(13)C]glycerol MIDA. We conclude that in VLBW infants receiving TPN, normoglycemia was maintained during reduced glucose infusion by glucose production primarily derived from gluconeogenesis, and that glycerol was the principal gluconeogenic substrate.

Glucose production during an IVGTT by deconvolution: validation with the tracer-to-tracee clamp technique.

Recently, a new method, based on a two-compartment minimal model and deconvolution [A. Caumo and C. Cobelli. Am. J. Physiol 264 (Endocrinol. Metab. 37): E829-E841, 1993; P. Vicini, G. Sparacino, A. Caumo, and C. Cobelli. Comput. Meth. Prog. Biomed. 52: 147-156, 1997], has been proposed to estimate endogenous glucose production (EGP) from labeled intravenous glucose tolerance test (IVGTT) data. Our aim here is to compare this EGP profile with that independently obtained with the reference method, based on the tracer-to-tracee ratio (TTR) clamp. An insulin-modified (0.03 U/kg body wt infused over 5 min) [6,6-2H2]glucose-labeled IVGTT (0.33 g/kg of glucose) was performed in 10 normal subjects. A second tracer ([U-13C]glucose) was also infused during the test in a variable fashion to clamp endogenous glucose TTR. The TTR clamp was quite successful. As a result, the EGP profile, reconstructed from [U-13C]glucose data with the models of Steele and Radziuk, were almost superimposable. The deconvolution-obtained EGP profile, calculated from [6,6-2H2]glucose data, showed remarkable agreement with that obtained from the TTR clamp. Some differences between the two profiles were noted in the estimated basal EGP and in the initial modalities of EGP inhibition. A high interindividual variability was also observed with both methods in the resumption of EGP to baseline; variability was high in both the timing and the extent of resumption. In conclusion, the use of the two-compartment minimal model of the IVGTT and deconvolution allows the estimation of a profile of EGP that is in very good agreement with that independently obtained with a TTR clamp.

Stable isotopes in biosciences, their measurement and models for amino acid metabolism.

In order to follow the movement and quantify the metabolic fates of biologically important molecules in vivo, both tracers and kinetic modeling are required. For the study of intermediary metabolism in children, stable isotopically labeled substrates satisfy both the analytical and ethical requirements for tracer use in children. Stable isotope tracers have been proven safe over more than a half-century of use in humans. In addition, mass spectrometric analysis of stable nuclide molecular position and isotopic enrichment in biological molecules is both highly specific and extraordinarily precise. Using stable isotope data to develop models of biological system dynamics in vivo is an essential element of estimating substrate events that take place in cells or organs otherwise inaccessible for ethical sampling in children. Further, modeling is also a critical component in the development and the testing of hypotheses about the structure of the biological system in question and the mechanisms which control its operational parameters.

Regulation of gluconeogenesis by glutamine in normal postabsorptive humans.

There is evidence that glutamine may act as a regulator of protein, free fatty acid, and glycogen metabolism. To test the hypothesis that glutamine may act as a physiological regulator of gluconeogenesis, we infused 16 normal postabsorptive volunteers with glutamine at a rate (11.4 micromol kg(-1) x min(-1)) estimated to approximate its appearance in plasma after a protein meal and assessed changes in production of glucose from glutamine, systemic glucose appearance and disposal, and uptake and release of glucose, glutamine, and alanine by forearm skeletal muscle. Although infusion of glutamine increased plasma glutamine concentration and turnover only threefold (from 0.63 +/- 0.03 to 1.95 +/- 0.10 mmol/l and from 5.43 +/- 0.24 to 14.85 +/- 0.66 micromol x kg(-1) x min(-1), respectively; P < 0.001), formation of glucose from glutamine increased sevenfold from 0.55 +/- 0.03 to 3.74 +/- 0.28 micromol x kg(-1) x min(-1) (P < 0.001). Formation of glucose from alanine was also stimulated (0.52 +/- 0.05 vs. 0.75 +/- 0.04 micromol x kg(-1) x min(-1); P < 0.001) in the absence of a change in plasma alanine concentration. Furthermore, glutamine infusion decreased its own de novo synthesis (4.55 +/- 0.22 vs. 2.81 +/- 0.62 micromol x kg(-1) x min(-1);P < 0.02) while increasing that of alanine (2.82 +/- 0.32 vs. 3.56 +/- 0.32 micromol x kg(-1) x min(-1); P < 0.002). Systemic glucose appearance, systemic glucose disposal, and forearm balance of glucose and alanine were not altered. Because the stimulatory effects of glutamine on gluconeogenesis occurred in the absence of changes in plasma insulin and glucagon levels, these results provide evidence that, in humans, glutamine may act both as a substrate and as a regulator of gluconeogenesis as well as a modulator of its own metabolism.

Anabolic effect of biosynthetic growth hormone in cystic fibrosis patients.

The purpose of this study was to determine whether GH treatment of cystic fibrosis (CF) patients can result in an anabolic effect, i.e., increased weight gain, improved growth rate, nitrogen retention, and improved pulmonary function. Nine prepubertal endocrinologically normal CF patients (3 girls, 6 boys; chronological age (CA) 5.5-9.8 years, and bone age (BA) 4.5-9.0 years), received recombinant human growth hormone (rhGH) 0.3 mg/kg/week subcutaneously for a period of 12 months (N = 8) or 9 months (N = 1). Normal glucose tolerance was determined before treatment. Pulmonary function studies and anthropometric measurements were done every 3 months. Thyroid status, somatomedin C (SmC), BA, and routine chemistries were evaluated every 6 months. The pretreatment growth velocity averaged 5.7 +/- 0.3 (SE) cm/year and significantly increased to 7.8 +/- 0.4 (SE) cm/year during therapy, (P < 0.01). Standard deviation scores (SDS) for height significantly increased during rhGH therapy as compared with pretreatment, (P < 0.05). Weight of the patients during rhGH therapy did not significantly change during or after rhGH therapy. After therapy, all patients showed a significant increase in arm muscle area (AMA) and a significant decrement in arm fat area (AFA) (P < 0.01). Net nitrogen anabolism was negative in all subjects before therapy but became more positive in five patients during rhGH therapy. Three patients achieved positive nitrogen retention. SmC values significantly increased from a mean value of 0.62 +/- 0.1 (SE) U/ml to 1.6 +/- 0.6 (SE) U/ml after therapy. BA advanced 1.0 +/- 0.1 SE per year after treatment. Of the seven patients able to perform adequate pulmonary function testing, improvement occurred in FVC, FEV1.0, and PEFR in 5, 5, and 4 patients, respectively, but these changes did not reach statistical significance. We conclude that biosynthetic rhGH therapy had a significant anabolic effect in CF patients as shown by increased growth velocity, SmC values, increased protein and decreased fet stores, and a positive or less negative net nitrogen retention in five of the patients.

Resistance exercise and growth hormone administration in older men: effects on insulin sensitivity and secretion during a stable-label intravenous glucose tolerance test.

To assess the effects of 16 weeks of heavy resistance exercise training (RE) on insulin sensitivity and secretion in healthy older men aged 64 to 75 years (N = 15), stable-label ([6,6,2H2]glucose) intravenous glucose tolerance tests (IVGTTs) were performed before and 7 days after the last bout of exercise. Glucose disappearance rate (Rd) and an index of insulin sensitivity (Si*) were derived using the minimal model of labeled glucose disappearance, and insulin secretion parameters were derived from C-peptide and glucose concentrations measured during the IVGTT, using a minimal model of C-peptide secretion and kinetics. Each subject trained at an intensity of 70% to 95% maximum strength 4 d/wk for 16 weeks on Nautilus (DeLand, FL) weight-training equipment. In conjunction with exercise, six men received daily injections of recombinant human growth hormone ([rhGH] 12.5 to 24 microg/kg/d) and the other nine received placebo injections. GH/placebo injections were administered in a double-blind randomized fashion. The RE program was supervised and progressive in nature, consisting of both upper-and lower-body exercises, and significantly increased muscle strength (P < .05) with no additional benefit from rhGH except for a tendency toward a greater increase in fat-free mass (FFM) in the RE + GH group (P = .06). Peak glucose Rd increased following RE (P < 01), and there was a trend for an improved Si* (ie, from 6.79 +/- 1.14 to 8.42 +/- 0.89 x 10(4) per min/[microU/mL], P = .06). Peak glucose Rd and Si* were unchanged in the RE + GH group following treatment. First- and second-phase insulin secretion were not affected by RE or RE + GH. Glucose tolerance, quantified as the glucose disappearance constant (Kg) between 10 and 32 minutes of the IVGTT, was unchanged by exercise or hormone treatment. These findings support those of a recent study that used the hyperinsulinemic-euglycemic clamp technique (Miller et al, J Appl Physiol 77:1122-1127, 1994), and suggest that when healthy older men engage in RE, whole-body glucose Rd and Si* are improved, and these beneficial effects are not only due to the acute effects of the last bout of exercise. Additionally, in six subjects who received GH, glucose Rd and Si* were not significantly improved following the RE program. Although this may suggest that GH can diminish improvements in glucose Rd and Si* that result from RE, further study is needed to confirm this observation.

A model to measure insulin effects on glucose transport and phosphorylation in muscle: a three-tracer study.

We studied five healthy subjects with perfused forearm and euglycemic clamp techniques in combination with a three-tracer (D-[12C]mannitol, not transportable; 3-O-[14C]methyl-D-glucose, transportable but not metabolizable; D-[3-3H]glucose, transportable and metabolizable) intra-arterial pulse injection to assess transmembrane transport and intracellular phosphorylation of glucose in vivo in human muscle. The washout curves of the three tracers were analyzed with a multicompartmental model. A priori identifiability analysis of the tracer model shows that the rate constants of glucose transport into and out of the cells and of glucose phosphorylation are uniquely identifiable. Tracer model parameters were estimated by a nonlinear least-squares parameter estimation technique. We then solved for the tracee model and estimated bidirectional transmembrane transport glucose fluxes, glucose intracellular phosphorylation, extracellular and intracellular volumes of glucose distribution, and extracellular and intracellular glucose concentrations. Physiological hyperinsulinemia (473 +/- 22 pM) caused 2.7-fold (63.1 +/- 7.2 vs. 23.4 +/- 6.1 mumol.min-1.kg-1, P < 0.01) and 5.1-fold (42.5 +/- 5.8 vs. 8.4 +/- 2.2 mumol.min-1.kg-1, P < 0.01) increases in transmembrane influx and intracellular phosphorylation of glucose, respectively. Extracellular distribution volume and concentration of glucose were unchanged, whereas intracellular distribution volume of glucose was increased (approximately 2-fold) and intracellular glucose concentration was almost halved by hyperinsulinemia. In summary, 1) a multicompartment model of three-tracer kinetic data can quantify transmembrane glucose fluxes and intracellular glucose phosphorylation in human muscle; and 2) physiological hyperinsulinemia stimulates both transport and phosphorylation of glucose and, in doing so, amplifies the role of glucose transport as a rate-determining step of muscle glucose uptake.

Metabolic and clinical response to recombinant human insulin-like growth factor I in myotonic dystrophy--a clinical research center study.

Muscle weakness and wasting in myotonic dystrophy (MyD) are believed to be due to a decrease in muscle protein synthesis, secondary to insulin resistance. A 4-month, randomized, double blind, placebo-controlled trial was undertaken to assess whether recombinant human insulin-like growth factor I (rhIGF-I) may overcome the insulin resistance. Patients received either 5 mg rhIGF-I (n = 7) or placebo (n = 9), sc, twice daily. Glucose metabolism was assessed by stable label iv glucose tolerance test, amino acid metabolism by L-[13C] leucine turnover, body composition by dual energy x-ray absorptiometry and N excretion, and muscle response by manual muscle strength and neuromuscular function. In the treated group, the insulin sensitivity index, insulin action, and glucose disposal all increased (P < 0.05). Leucine flux and leucine incorporation into protein increased (P < 0.05), and the rate of leucine oxidation to leucine turnover decreased (P < 0.05), findings indicative of increased protein synthesis. Body weight and lean body mass increased, whereas percent body fat decreased (P < 0.05). An increase in manual muscle strength of 0.42 +/- 0.30 (P < 0.02) and in neuromuscular function of 17.5 +/- 11.7 (P < 0.02) occurred in the four patients who received a rhIGF-I dose greater than 70 micrograms/kg, whereas a more modest response occurred in the three patients who received a dose less than 70 micrograms/kg. Two patients showed dramatic improvement. Long term rhIGF-I therapy appears to cause metabolic and muscle improvement in optimally treated MyD patients.

Comparison of serine and hippurate as precursor equivalents during infusion of [15N]glycine for measurement of fractional synthetic rates of apolipoprotein B of very-low-density lipoprotein.

Enrichment in hippurate has been measured to indicate precursor enrichment during glycine tracer infusion studies to estimate fractional synthetic rates of individual hepatic export proteins. However, hippurate tends to overestimate precursor enrichment. Since glycine is rapidly converted to serine by liver cells, we compared tracer enrichment in hippurate and serine with that of glycine incorporated into apolipoprotein (apo) B-100. Ten healthy control subjects were studied in the postabsorptive state during an 8-hour primed-constant infusion of [15N]glycine (10 mumol.kg-1.h-1). Apo B of very-low-density lipoprotein (VLDL) was isolated by standard ultracentrifugation and isopropanol precipitation. Glycine and serine were isolated from plasma and hydrolyzed apo B, hippurate was isolated from plasma, and [15N]enrichment was determined by gas chromatography-mass spectrometry. Enrichment in serine and glycine isolated from apo B was identical at all time points, and their enrichment in apo B increased asymptotically, approaching an apparent plateau (mean +/- SD: 91% +/- 10% of calculated plateau at 8 hours) that was taken to represent hepatic protein precursor enrichment. Enrichment in both plasma serine and hippurate followed a biphasic pattern and continued to increase until the end of the study, raising the possibility that precursor enrichment had not reached a steady state during the study. The apo B plateau was lower (factor 0.76 +/- 0.27) than the final enrichment in hippurate and higher (factor 1.38 +/- 0.36) than that in plasma serine; however, predictions of protein precursor enrichment based on either metabolite were flawed by a large coefficient of variation (35% v 26%).(ABSTRACT TRUNCATED AT 250 WORDS)

Estimation of glucose-alanine-lactate-glutamine cycles in postabsorptive humans: role of skeletal muscle.

To evaluate transfer of carbon between plasma glucose and plasma alanine (glucose-alanine cycle) and lactate (Cori cycle), to assess the contribution of skeletal muscle to these cycles, and to determine whether a glucose-glutamine cycle exists in postabsorptive humans, we infused 11 normal overnight-fasted volunteers with [2-3H]glucose, [6-14C]glucose, and [3-13C]alanine to isotopic steady state and in 7 of these simultaneously measured forearm net balance, uptake, and release of labeled and unlabeled glucose, lactate, and alanine. We found that 40.9 +/- 3.3, 66.8 +/- 3.2, and 13.4 +/- 1.1%, respectively, of plasma alanine, lactate, and glutamine carbon came from plasma glucose. More plasma glucose was converted to plasma alanine than could be derived from plasma alanine (1.89 +/- 0.20 vs. 1.48 +/- 0.15 mumol.kg-1.min-1, P < 0.001). A similar direction of net carbon flux was found for lactate (8.5 vs. 4.2 mumol.kg-1.min-1), with only glutamine adding more carbon to plasma glucose than was received from it (1.0 vs. 0.75 mumol.kg-1.min-1). Skeletal muscle accounted for 50.2 +/- 3.9 and 45.5 +/- 5.7% of the overall appearance of alanine and lactate in plasma and 54.2 +/- 5.4 and 36.4 +/- 4.2% of their respective origins from plasma glucose. Skeletal muscle release of alanine and lactate that had been formed from plasma glucose accounted for 19.1 +/- 2.1 and 48.4 +/- 4.8%, respectively, of muscle glucose uptake and 42.4 +/- 5.5 and 49.9 +/- 5.8% of the overall release of alanine and lactate from muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Phenylalanine hydroxylase activity in preterm infants: is tyrosine a conditionally essential amino acid?

To assess the production of the nonessential amino acid tyrosine in preterm infants, we estimated the activity of phenylalanine hydroxylase (PAH) in three groups of infants by measuring the conversion of phenylalanine to tyrosine, using a model based on a primed constant 200-min intravenous infusion of [2H5]phenylalanine. We determined the isotopic enrichments of [2H5]phenylalanine and [2H4]tyrosine by selected-ion-monitoring gas chromatography-mass spectrometry (GCMS). Group 1 (n = 7, mean gestational age 29.7 +/- 1.5 wk, mean birth weight 1.4 +/- 0.4 kg) was studied during the first 4 d of life before initiation of amino acid nutrition. Group 2 (n = 7, mean gestational age 29.7 +/- 1.5 wk, mean birth weight 1.4 +/- 0.4 kg) was studied at 4-6 d of life after receiving amino acid nutrition. Group 3 (n = 4, mean gestational age 28.5 +/- 0.9 wk, mean birth weight 1.1 +/- 0.1 kg) was studied during the first 4 d of life after receiving amino acid nutrition. Calculated from the observed enrichments, phenylalanine conversion to tyrosine was 5.9 +/- 2.6, 19.4 +/- 8.8 and 11 +/- 1.8 mumol.kg-1l.h-1 in groups 1, 2, and 3, respectively. The rate of conversion of phenylalanine to tyrosine increased significantly after initiation of amino acid nutrition. We conclude that preterm infants are capable of converting phenylalanine to tyrosine. Provision of phenylalanine in the context of parenteral amino acid nutrition solution accelerated PAH conversion of phenylalanine to tyrosine, suggesting that the enzyme system is capable of responding normally to provision of substrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of malnourished CAPD patients with an amino acid based dialysate.

Nineteen malnourished chronic peritoneal dialysis patients who were ingesting a low protein intake underwent metabolic balance studies to test whether a dialysate that contained amino acids would improve their protein nutrition. Patients lived in the hospital for 35 days while they ate a constant diet and underwent their usual regimen of continuous ambulatory peritoneal dialysis (CAPD). The first 15 days served as a Baseline Phase. For the last 20 days, the usual dialysate was substituted with a dialysate of essentially the same composition except that it contained 1.1% essential and nonessential amino acids and no glucose. Patients received one or two dialysate exchanges with amino acids each day depending on the amount necessary to bring the individual's dietary protein plus dialysate amino acid intake to 1.1 to 1.3 g/kg body weight/day. During Baseline, patients were in neutral nitrogen balance; net protein anabolism was positive, as determined from 15N-glycine studies. After commencing intraperitoneal amino acid therapy, nitrogen balance became significantly positive, there was a significant increase in net protein anabolism, the fasting morning plasma amino acid pattern became more normal, and serum total protein and transferrin concentrations rose. Patients generally tolerated the treatment well, although some patients developed mild metabolic acidemia. These findings indicate that a dialysate containing amino acids may improve protein malnutrition in CAPD patients ingesting low protein intakes.

Effect of growth hormone and resistance exercise on muscle growth and strength in older men.

The purpose of this study was to determine whether growth hormone (GH) administration enhances the muscle protein anabolism associated with heavy-resistance exercise training in older men. Twenty-three healthy, sedentary men (67 +/- 1 yr) with low serum insulin-like growth factor I levels followed a 16-wk progressive resistance exercise program (75-90% max strength, 4 days/wk) after random assignment to either a GH (12.5-24 micrograms.kg-1.day-1; n = 8) or placebo (n = 15) group. Fat-free mass (FFM) and total body water increased more in the GH group. Whole body protein synthesis and breakdown rates increased in the GH group after treatment. However, increments in vastus lateralis muscle protein synthesis rate, urinary creatinine excretion, and training-specific isotonic and isokinetic muscle strength were similar in both groups, while 24-h urinary 3-methylhistidine excretion was unchanged after treatment. These observations suggest that resistance exercise training improved muscle strength and anabolism in older men, but these improvements were not enhanced when exercise was combined with daily GH administration. The greater increase in FFM with GH treatment may have been due to an increase in noncontractile protein and fluid retention.

Glutamine: a major gluconeogenic precursor and vehicle for interorgan carbon transport in man.

To compare glutamine and alanine as gluconeogenic precursors, we simultaneously measured their systemic turnovers, clearances, and incorporation into plasma glucose, their skeletal muscle uptake and release, and the proportion of their appearance in plasma directly due to their release from protein in postabsorptive normal volunteers. We infused the volunteers with [U-14C] glutamine, [3-13C] alanine, [2H5] phenylalanine, and [6-3H] glucose to isotopic steady state and used the forearm balance technique. We found that glutamine appearance in plasma exceeded that of alanine (5.76 +/- 0.26 vs. 4.40 +/- 0.33 mumol.kg-1.min-1, P < 0.001), while alanine clearance exceeded glutamine clearance (14.7 +/- 1.3 vs. 9.3 +/- 0.8 ml.kg-1.min-1, P < 0.001). Glutamine appearance in plasma directly due to its release from protein was more than double that of alanine (2.45 +/- 0.25 vs. 1.16 +/- 0.12 mumol.kg-1.min-1, P < 0.001). Although overall carbon transfer to glucose from glutamine and alanine was comparable (3.53 +/- 0.24 vs 3.47 +/- 0.32 atoms.kg-1.min-1), nearly twice as much glucose carbon came from protein derived glutamine than alanine (1.48 +/- 0.15 vs 0.88 +/- 0.09 atoms.kg-1.min-1, P < 0.01). Finally, forearm muscle released more glutamine than alanine (0.88 +/- 0.05 vs 0.48 +/- 0.05 mumol.100 ml-1.min-1, P < 0.01). We conclude that in postabsorptive humans glutamine is quantitatively more important than alanine for transporting protein-derived carbon through plasma and adding these carbons to the glucose pool.