Circulating Amino Acid Concentrations Research Articles

Intravenous infusion of 5-hydroxytryptophan to mid-lactation Holstein cows transiently affects milk production and circulating amino acid concentrations

In dairy cows, the lactating mammary glands synthesize serotonin, which acts in an autocrine-paracrine manner in the glands and is secreted into the periphery. Serotonin signaling during lactation modulates nutrient metabolism in peripheral tissues such as adipose and liver. We hypothesized that the elevation of circulating serotonin during lactation would increase nutrient partitioning to the mammary glands, thereby promoting milk production. Our objective was to elevate circulating serotonin via intravenous infusion of the serotonin precursor 5-hydroxytryptophan (5-HTP) to determine its effects on mammary supply and extraction efficiency of AA, and milk components production. Twenty-two multiparous mid-lactation Holstein cows were intravenously infused with 5-HTP (1 mg/kg body weight) or saline, in a crossover design with two 21-d periods. Treatments were infused via jugular catheters for 1 h/d, on d 1 to 3, 8 to 10, and 15 to 17 of each period, to maintain consistent elevation of peripheral serotonin throughout the period. Milk and blood samples were collected in the last 96 h of each period. Whole-blood serotonin concentration was elevated above saline control for 96 h after the last 5-HTP infusion. Dry matter intake was decreased for cows receiving 5-HTP, and on average they lost body weight over the 21-d period, in contrast to saline cows who gained body weight. Milk production and milk protein yield were lower in cows receiving 5-HTP during the 3 infusion days, but both recovered to saline cow yields in the days after. Although milk fat yield exhibited a day-by-treatment interaction, no significant difference occurred on any given day. Milk urea nitrogen concentration was lower in 5-HTP cows on the days following the end of infusions, but not different from saline cows on infusion days. Meanwhile, plasma urea nitrogen was not affected by 5-HTP infusion. Circulating concentrations of AA were overall transiently decreased by 5-HTP, with concentrations mostly returning to baseline within 7 h after the end of 5-HTP infusion. Mammary extraction efficiency of AA was unaffected by 5-HTP infusion. Overall, both lactation performance and circulating AA were transiently reduced in cows infused with 5-HTP, despite sustained elevation of circulating serotonin concentration.

70 Nutrient Restriction During Late Gestation Alters Maternal Circulating Amino Acid Concentrations in Primiparous Beef Females

Abstract We hypothesized that maternal circulating AA concentrations would be reduced by late gestational nutrient restriction, indicating less available nutrients for transport by the uteroplacenta to the growing fetus. Fall-calving Hereford-SimAngus heifers [single-sired; BW: 451 ± 28 (SD) kg; BCS: 5.4 ± 0.7] bred to a single sire were allocated by fetal sex and expected calving date to receive either 100% (control; CON; n = 12) or 70% (NR; n = 13) of NASEM metabolizable energy and metabolizable protein requirements for maintenance, pregnancy, and growth from day 160 of gestation to calving. Heifers were individually fed chopped sorghum sudan hay (1.74 Mcal ME, 6.66% CP, 72.0% NDF; DM basis) and based on individual intakes, supplemented to meet targeted nutritional planes. Jugular blood samples were obtained on days 159 (Pre-treatment), 202, and 244 of gestation, and 1 h post-calving to determine serum concentrations of the 20 common AA (except cysteine), 1-methyl histidine, and 3-methyl histidine. Gestational and post-calving AA were analyzed separately with nutritional plane, treatment initiation date, and calf sex (when P < 0.25) as fixed effects. Gestational AA included day and nutritional plane x day using repeated measures. We have previously reported that dam BCS was less (P ≤ 0.04) by day 202 of gestation and dam BW was less (P ≤ 0.01) by day 223 of gestation for NR dams. Post-calving, NR dams were 64 kg BW and 2.0 BCS lless (P < 0.001), but calf birth weight was not affected (P = 0.72) by nutritional plane. Histidine, lysine, and methionine were greater (P ≤ 0.03) in NR dams on day 202 of gestation. Tryptophan and valine were less (P ≤ 0.05) while methionine and total AA tended to be less (P ≤ 0.08) on day 244 of gestation in NR dams. Aspartic acid, glutamic acid, and tyrosine were less (P ≤ 0.03), but 3-methyl histidine was greater (P ≤ 0.01) on days 202 and 244 of gestation in NR dams. 1-methyl histidine was greater (P ≤ 0.05) at all 3 gestational timepoints but leucine was less (P = 0.03) in NR dams during gestation. Post-calving, glutamic acid, leucine, and valine were less (P ≤ 0.04), and methionine, threonine, tryptophan, tyrosine, and total AA tended to be less (P ≤ 0.10) in NR dams. Histidine, 1-methyl histidine, 3-methyl histidine, and serine were greater (P ≤ 0.03) in NR dams post-calving. In summary, late gestational nutrient restriction reduced total maternal circulating AA and altered the maternal serum AA profile, but calf birth weight was not affected. Individual AA that were greater or unaffected in NR dams were likely indicative of body protein catabolism occurring to meet nutrient requirements.

Dietary Intake and Circulating Amino Acid Concentrations in Relation with Bone Metabolism Markers in Children Following Vegetarian and Omnivorous Diets.

Scientific studies reported that most vegetarians meet the total protein requirements; however, little is known about their amino acid intakes. We aimed to assess dietary intake and serum amino acid levels in relation to bone metabolism markers in prepubertal children on vegetarian and traditional diets. Data from 51 vegetarian and 25 omnivorous children aged 4-9 years were analyzed. Dietary intake of macro- and micronutrients were assessed using the nutritional program Dieta 5®. Serum amino acid analysis was performed using high-pressure liquid chromatography technique, 25-hydroxyvitamin D and parathormone-electrochemiluminescent immunoassay, and bone metabolism markers, albumin, and prealbumin levels using enzyme-linked immunosorbent assay. Vegetarian children had a significantly lower intake of protein and amino acids with median differences of about 30-50% compared to omnivores. Concentrations of four amino acids (valine, lysine, leucine, isoleucine) in serum varied significantly by diet groups and were lower by 10-15% in vegetarians than meat-eaters. Vegetarian children also had lower (p < 0.001) serum albumin levels compared to omnivores. Among bone markers, they had higher (p < 0.05) levels of C-terminal telopeptide of collagen type I (CTX-I) than omnivores. Correlation patterns between amino acids and bone metabolism markers differed in the vegetarian and omnivore groups. Out of bone markers, especially osteoprotegerin was positively correlated with several amino acids, such as tryptophan, alanine, aspartate, glutamine, and serine, and ornithine in vegetarians. Vegetarian children consumed apparently sufficient but lower protein and amino acids compared to omnivores. In circulation these differences were less marked than in the diet. Significantly lower amino acid intake and serum levels of valine, lysine, leucine, and isoleucine as well as the observed correlations between serum amino acids and biochemical bone marker levels indicated the relations between diet, protein quality, and bone metabolism.

Association between Circulating Amino Acids and COVID-19 Severity

The severity of the symptoms associated with COVID-19 is highly variable, and has been associated with circulating amino acids as a group of analytes in metabolomic studies. However, for each individual amino acid, there are discordant results among studies. The aims of the present study were: (i) to investigate the association between COVID-19-symptom severity and circulating amino-acid concentrations; and (ii) to assess the ability of circulating amino-acid levels to predict adverse outcomes (intensive-care-unit admission or hospital death). We studied a sample of 736 participants from the Biobanque Québécoise COVID-19. All participants tested positive for COVID-19, and the severity of symptoms was determined using the World-Health-Organization criteria. Circulating amino acids were measured by HPLC-MS/MS. We used logistic models to assess the association between circulating amino acids concentrations and the odds of presenting mild vs. severe or mild vs. moderate symptoms, as well as their accuracy in predicting adverse outcomes. Patients with severe COVID-19 symptoms were older on average, and they had a higher prevalence of obesity and type 2 diabetes. Out of 20 amino acids tested, 16 were significantly associated with disease severity, with phenylalanine (positively) and cysteine (inversely) showing the strongest associations. These associations remained significant after adjustment for age, sex and body mass index. Phenylalanine had a fair ability to predict the occurrence of adverse outcomes, similar to traditionally measured laboratory variables. A multivariate model including both circulating amino acids and clinical variables had a 90% accuracy at predicting adverse outcomes in this sample. In conclusion, patients presenting severe COVID-19 symptoms have an altered amino-acid profile, compared to those with mild or moderate symptoms.

Acute heat stress amplifies exercise-induced metabolomic perturbations and reveals variation in circulating amino acids in endurance-trained males.

What is the central question of this study? Whole-body substrate utilisation is altered during exercise in hot environments, characterised by increased glycolytic metabolism: does heat stress alter the serum metabolome in response to high intensity exercise? What are the main finding and its importance? Alongside increases in glycolytic metabolite abundance, circulating amino acid concentrations are reduced following exercise under heat stress. Prior research has overlooked the impact of heat stress on protein metabolism during exercise, raising important practical implications for protein intake recommendations in the heat. Using untargeted metabolomics, we aimed to characterise the systemic impact of environmental heat stress during exercise. Twenty-three trained male triathletes ( =64.8±9.2mlkgmin-1 ) completed a 30-min exercise test in hot (35°C) and temperate (21°C) conditions. Venous blood samples were collected immediately pre- and post-exercise, and the serum fraction was assessed via untargeted 1 H-NMR metabolomics. Data were analysed via uni- and multivariate analyses to identify differences between conditions. Mean power output was higher in temperate (231±36W) versus hot (223±31W) conditions (P<0.001). Mean heart rate (temperate, 162±10beatsmin-1 , hot, 167±9beatsmin-1 , P<0.001), peak core temperature (Trec ), core temperature change (ΔTrec ) (P<0.001) and peak rating of perceived exertion (P=0.005) were higher in hot versus temperate conditions. Change in metabolite abundance following exercise revealed distinct clustering following multivariate analysis. Six metabolites increased (2-hydroxyvaleric acid, acetate, alanine, glucarate, glucose, lactate) in hot relative to temperate (P<0.05) conditions. Leucine and lysine decreased in both conditions but to a greater extent in temperate conditions (P<0.05). Citrate (P=0.04) was greater in temperate conditions whilst creatinine decreased in hot conditions only (P>0.05). Environmental heat stress increased glycolytic metabolite abundance and led to distinct alterations in the circulating amino acid availability, including increased alanine, glutamine, leucine and isoleucine. The data highlight the need for additional exercise nutrition and metabolism research, specifically focusing on protein requirements for exercise under heat stress.

Effect of Okara and Biovalorized Okara Biscuits Consumption on Postprandial Circulating Amino Acid Concentrations: A Crossover Randomized Controlled Trial

ObjectivesSoymilk or tofu production results in considerable okara (soybean pulp) generation. Although okara has a high protein content and contains all essential amino acids, its low water solubility and anti-nutrient presence reduces its protein digestibility. Okara fermented with Rhizopus oligosporus can increase its digestibility by lowering anti-nutrient content and liberating free amino acids. However, neither okara nor biovalorized okara has been evaluated for its effect on postprandial blood amino acids. This study hence explored this gap in knowledge with okara- and biovalorized okara- containing biscuits consumption. MethodsThe randomized controlled crossover trial involved 15 middle-aged and older Singaporean adults. Each participant undertook 3 separate 2-hour meal tolerance test with 100 g of control biscuits (C), biovalorized okara biscuits (RO), and autoclaved okara biscuits (AOK). RO and AOK were developed with the same recipe as C, utilizing a 20% wheat flour substitution with R. oligosporus fermented okara or autoclaved okara respectively. Biscuit total and free amino acids contents were analyzed by cation-exchange chromatography. Circulating free amino acids concentrations were assessed at timepoints 0, 15, 30, 45, 60, 90, and 120 min. Incremental area under curve (iAUC) and peak concentration were assessed, with results presented as mean (95% confidence interval). ResultsBiscuit total amino acid content (mean ± standard deviation, g/100 g) was significantly greater for RO (7.51 ± 0.22) and AOK (6.78 ± 0.39) compared to C (5.93 ± 0.33), with RO having notably greater alanine, cysteine, and proline content over AOK. Free amino acid content in biscuit (nmol/g) in ascending order was C (485 ± 11), AOK (698 ± 13), and RO (3414 ± 97). Amino acid iAUC had no significant difference, as demonstrated with total amino acids iAUC (μmol/L·min) (P = 0.568, C: 23 649 (13 738, 33 560), RO: 23 284 (13 374, 33 195) & AOK: 17 257 (7 346, 27 168)). Peak iAUC concentration also showed no significant difference across all amino acids, with total amino acids peak iAUC concentration (μmol/L) as P = 0.560, C: 387 (233,540), RO: 456 (303,610) & AOK: 343 (189,497). ConclusionsConsumption of okara- or biovalorized okara- containing biscuits does not alter postprandial amino acid responses in middle-aged and older Singaporeans. Funding SourcesSingapore Ministry of Education.

Serum tyrosine is associated with better cognition in Lewy body dementia

Amino acids’ neuroactivity, and roles in excitotoxity and oxidative stress are linked to dementia. We aimed to investigate whether circulating amino acid concentrations were associated with cognitive decline in patients with mild Alzheimer’s disease (AD) and Lewy body dementia (LBD). Baseline serum amino acid concentrations were measured in 89 patients with AD and 65 with LBD (13 with Parkinson’s disease dementia and 52 with dementia with Lewy bodies). The Mini-Mental State Examination (MMSE) was administered at baseline and annually for five years. Associations between baseline amino acid concentrations and longitudinal MMSE score were assessed using a linear-mixed effects model stratified by diagnosis with adjustment for multiple comparisons. The results of the study indicated that serum tyrosine was positively associated with MMSE performance during the five-year follow-up period in patients with LBD (q-value = 0.012), but not AD. In conclusion, higher baseline serum concentrations of tyrosine, the precursor amino acid in dopamine and norepinephrine synthesis, was associated with better cognitive performance in patients with LBD, but not AD, throughout the 5-year follow-up period.

Circulating nutrient concentrations in free‐ranging Humboldt penguins (Spheniscus humboldti) in Punta San Juan, Peru

Free-ranging Humboldt penguin (HP, Spheniscus humboldti) populations are under pressure from resource competition with industrial fisheries, habitat loss, and El Niño Southern Oscillation events. Foraging patterns for this top marine predator change during periods of aberrant oceanographic conditions and scarce fish stock numbers. These radical dietary fluctuations can lead to poor fertility, early embryonic death, poor hatchability, suppressed immune function, high chick mortality, and illness. To understand the variability of nutrient status in reproductive seasons, we measured select circulating nutrient concentrations (fat-soluble vitamins A, D, E, and carotenoids, fatty acids, amino acids, minerals, and electrolytes) of 105 HP at Punta San Juan, Peru during the first reproductive seasons of 2007 and 2008. We determined significant differences in nutrient status between sexes, years of sampling, and reproductive stages. Males (4.5 ± 0.38 kg) weighed more than females (4.0 ± 0.29 kg) and exhibited higher concentrations of vitamin A (0.71 ± 0.11 vs. 0.61 ± 0.12 µg/ml) and docosahexaenoic acid (6.70 ± 1.61 vs. 5.65 ± 1.59%). Males also displayed lower concentrations of β-carotene (0.01 ± 0.01 vs. 0.012 ± 0.001 µg/ml) and phosphorus (3.43 ± 0.83 vs. 4.40 ± 1.66 mg/dl). Comparison between the 2 years showed most circulating amino acid concentrations were higher in 2007. Significant differences in circulating amino acids and vitamins were also noted between different reproductive stages. These results demonstrate concentrations of nutrients can vary due to the physiological state of the animal, as well as the overall dynamics of their marine ecosystem habitat.

Branched-chain amino acid and branched-chain ketoacid ingestion increases muscle protein synthesis rates in vivo in older adults: a double-blind, randomized trial

ABSTRACTBackgroundProtein ingestion increases muscle protein synthesis rates. However, limited data are currently available on the effects of branched-chain amino acid (BCAA) and branched-chain ketoacid (BCKA) ingestion on postprandial muscle protein synthesis rates.ObjectiveThe aim of this study was to compare the impact of ingesting 6 g BCAA, 6 g BCKA, and 30 g milk protein (MILK) on the postprandial rise in circulating amino acid concentrations and subsequent myofibrillar protein synthesis rates in older males.MethodsIn a parallel design, 45 older males (age: 71 ± 1 y; BMI: 25.4 ± 0.8 kg/m2) were randomly assigned to ingest a drink containing 6 g BCAA, 6 g BCKA, or 30 g MILK. Basal and postprandial myofibrillar protein synthesis rates were assessed by primed continuous l-[ring-13C6]phenylalanine infusions with the collection of blood samples and muscle biopsies.ResultsPlasma BCAA concentrations increased following test drink ingestion in all groups, with greater increases in the BCAA and MILK groups compared with the BCKA group (P < 0.05). Plasma BCKA concentrations increased following test drink ingestion in all groups, with greater increases in the BCKA group compared with the BCAA and MILK groups (P < 0.05). Ingestion of MILK, BCAA, and BCKA significantly increased early myofibrillar protein synthesis rates (0–2 h) above basal rates (from 0.020 ± 0.002%/h to 0.042 ± 0.004%/h, 0.022 ± 0.002%/h to 0.044 ± 0.004%/h, and 0.023 ± 0.003%/h to 0.044 ± 0.004%/h, respectively; P < 0.001), with no differences between groups (P > 0.05). Myofibrillar protein synthesis rates during the late postprandial phase (2–5 h) remained elevated in the MILK group (0.039 ± 0.004%/h; P < 0.001), but returned to baseline values following BCAA and BCKA ingestion (0.024 ± 0.005%/h and 0.024 ± 0.005%/h, respectively; P > 0.05).ConclusionsIngestion of 6 g BCAA, 6 g BCKA, and 30 g MILK increases myofibrillar protein synthesis rates during the early postprandial phase (0–2 h) in vivo in healthy older males. The postprandial increase following the ingestion of 6 g BCAA and BCKA is short-lived, with higher myofibrillar protein synthesis rates only being maintained following the ingestion of an equivalent amount of intact milk protein. This trial was registered at Nederlands Trial Register (www.trialregister.nl) as NTR6047.

Amino acid transporters in the regulation of insulin secretion and signalling.

Amino acids are increasingly recognised as modulators of nutrient disposal, including their role in regulating blood glucose through interactions with insulin signalling. More recently, cellular membrane transporters of amino acids have been shown to form a pivotal part of this regulation as they are primarily responsible for controlling cellular and circulating amino acid concentrations. The availability of amino acids regulated by transporters can amplify insulin secretion and modulate insulin signalling in various tissues. In addition, insulin itself can regulate the expression of numerous amino acid transporters. This review focuses on amino acid transporters linked to the regulation of insulin secretion and signalling with a focus on those of the small intestine, pancreatic β-islet cells and insulin-responsive tissues, liver and skeletal muscle. We summarise the role of the amino acid transporter B0AT1 (SLC6A19) and peptide transporter PEPT1 (SLC15A1) in the modulation of global insulin signalling via the liver-secreted hormone fibroblast growth factor 21 (FGF21). The role of vesicular vGLUT (SLC17) and mitochondrial SLC25 transporters in providing glutamate for the potentiation of insulin secretion is covered. We also survey the roles SNAT (SLC38) family and LAT1 (SLC7A5) amino acid transporters play in the regulation of and by insulin in numerous affective tissues. We hypothesise the small intestine amino acid transporter B0AT1 represents a crucial nexus between insulin, FGF21 and incretin hormone signalling pathways. The aim is to give an integrated overview of the important role amino acid transporters have been found to play in insulin-regulated nutrient signalling.

Effects of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus.

To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus (T2DM). Patients were randomized to oral PF-06291874 or placebo on a background of either metformin (Part A, Cohorts 1-5: 5-150 mg once daily), or metformin and sulphonylurea (Part B, Cohorts 1-2: 15 or 30 mg once daily) for 14-28 days. A mixed-meal tolerance test (MMTT) was administered on days -1 (baseline), 14 and 28. Assessments were conducted with regard to pharmacokinetics, various pharmacodynamic variables, safety and tolerability. Circulating amino acid concentrations were also measured. PF-06291874 exposure was approximately dose-proportional with a half-life of ∼19.7-22.7 h. Day 14 fasting plasma glucose and mean daily glucose values were reduced from baseline in a dose-dependent manner, with placebo-corrected decreases of 34.3 and 42.4 mg/dl, respectively, at the 150 mg dose. After the MMTT, dose-dependent increases in glucagon and total glucagon-like peptide-1 (GLP-1) were observed, although no meaningful changes were noted in insulin, C-peptide or active GLP-1 levels. Small dose-dependent increases in LDL cholesterol were observed, along with reversible increases in serum aminotransferases that were largely within the laboratory reference range. An increase in circulating gluconeogenic amino acids was also observed on days 2 and 14. All dose levels of PF-06291874 were well tolerated. PF-06291874 was well tolerated, has a pharmacokinetic profile suitable for once-daily dosing, and results in reductions in glucose with minimal risk of hypoglycaemia.

Older Adults Have Delayed Amino Acid Absorption after a High Protein Mixed Breakfast Meal.

To measure the postprandial plasma amino acid appearance in younger and older adults following a high protein mixed meal. Cross-sectional study. Clinical research setting. Healthy men and women aged 60-75 (n=15) years, and young controls aged 20-25 years (n=15) matched for body mass index and insulin sensitivity based on the homeostatic model assessment of insulin resistance. High protein mixed meal of complete food products. Circulating amino acid concentrations were determined hourly before and for 5 hours after meal ingestion. There was no difference between cohorts in postprandial appearance of non-essential amino acids, or area under the curve of any individual amino acid or amino acid class. However, older adults had higher baseline concentrations of aspartic acid, glutamic acid, glycine, ornithine, threonine and tyrosine and lower baseline concentrations of hydroxyproline, isoleucine, leucine, methionine and valine compared to younger adults. Younger adults showed peak essential (EAA) and branched-chain amino acid (BCAA) concentrations at 1 hour post meal while older adults' peak EAA and BCAA concentration was at 3 hours. Similarly, peak total amino acid concentrations were at 3 hours in older adults. Older adults digested and absorbed the protein within a mixed meal more slowly than younger adults. Delayed absorption of AA following a mixed meal of complete food products may suppress or delay protein synthesis in senescent muscle.

Pharmacological PPARα activation markedly alters plasma turnover of the amino acids glycine, serine and arginine in the rat.

The current study extends previously reported PPARα agonist WY 14,643 (30 µmol/kg/day for 4 weeks) effects on circulating amino acid concentrations in rats fed a 48% saturated fat diet. Steady-state tracer experiments were used to examine in vivo kinetic mechanisms underlying altered plasma serine, glycine and arginine levels. Urinary urea and creatinine excretion were measured to assess whole-body amino acid catabolism. WY 14,643 treated animals demonstrated reduced efficiency to convert food consumed to body weight gain while liver weight was increased compared to controls. WY 14,643 raised total amino acid concentration (38%), largely explained by glycine, serine and threonine increases. 3H-glycine, 14C-serine and 14C-arginine tracer studies revealed elevated rates of appearance (Ra) for glycine (45.5±5.8 versus 17.4±2.7 µmol/kg/min) and serine (21.0±1.4 versus 12.0±1.0) in WY 14,643 versus control. Arginine was substantially decreased (−62%) in plasma with estimated Ra reduced from 3.1±0.3 to 1.2±0.2 µmol/kg/min in control versus WY 14,643. Nitrogen excretion over 24 hours was unaltered. Hepatic arginase activity was substantially decreased by WY 14,643 treatment. In conclusion, PPARα agonism potently alters metabolism of several specific amino acids in the rat. The changes in circulating levels of serine, glycine and arginine reflected altered fluxes into the plasma rather than changes in clearance or catabolism. This suggests that PPARα has an important role in modulating serine, glycine and arginine de novo synthesis.

Amino Acid Concentrations in Critically Ill Children Following Cardiac Surgery*

Guidelines for administering amino acids to critically ill children are largely based on uncontrolled observational studies and expert opinion, without support from rigorous outcome studies. Also, data on circulating amino acid concentrations during critical illness are scarce. We thoroughly studied the time profiles of circulating amino acid concentrations in critically ill children who received standard nutritional care according to international guidelines. This is a subanalysis of pediatric critically ill patients included in a large (n = 700) randomized controlled study on intensive insulin therapy. The study was conducted at a university hospital PICU. We studied 100 patients in PICU for at least 3 days following cardiac surgery. Patients were assigned to intensive insulin therapy targeting normal-for-age fasting blood glucose concentrations or insulin infusion only to prevent excessive hyperglycemia. Plasma amino acid concentrations were measured at admission, day 3, and day 7 in PICU. At admission, the concentrations of most amino acids were comparable to those reported for healthy children. Total amino acid concentrations remained stable during ICU stay, but individual amino acids showed different time profiles with eight of them showing an increase and five a decrease. Nonsurviving children had higher total amino acid concentrations and individual amino acids compared with survivors at admission and/or during ICU stay. Intensive insulin therapy lowered the concentrations of total amino acids and several individual amino acids. Neonates showed somewhat different amino acid profiles with rather increased concentrations from baseline with time in ICU for total amino acids and several individual amino acids as compared with older infants and children. Circulating amino acid concentrations in critically ill children after cardiac surgery differ according to survival status, blood glucose control with intensive insulin therapy, and age.

Effect of 30 % nutrient restriction in the first half of gestation on maternal and fetal baboon serum amino acid concentrations

Mechanisms linking maternal nutrient restriction (MNR) to intra-uterine growth restriction (IUGR) and programming of adult disease remain to be established. The impact of controlled MNR on maternal and fetal amino acid metabolism has not been studied in non-human primates. We hypothesised that MNR in pregnant baboons decreases fetal amino acid availability by mid-gestation. We determined maternal and fetal circulating amino acid concentrations at 90 d gestation (90dG, term 184dG) in control baboons fed ad libitum (C, n 8) or 70% of C (MNR, n 6). Before pregnancy, C and MNR body weights and circulating amino acids were similar. At 90dG, MNR mothers had lower body weight than C mothers (P< 0·05). Fetal and placental weights were similar between the groups. MNR reduced maternal blood urea N (BUN), fetal BUN and fetal BUN:creatinine. Except for histidine and lysine in the C and MNR groups and glutamine in the MNR group, circulating concentrations of all amino acids were lower at 90dG compared with pre-pregnancy. Maternal circulating amino acids at 90dG were similar in the MNR and C groups. In contrast, MNR fetal β-alanine, glycine and taurine all increased. In conclusion, maternal circulating amino acids were maintained at normal levels and fetal amino acid availability was not impaired in response to 30% global MNR in pregnant baboons. However, MNR weight gain was reduced, suggesting adaptation in maternal-fetal resource allocation in an attempt to maintain normal fetal growth. We speculate that these adaptive mechanisms may fail later in gestation when fetal nutrient demands increase rapidly, resulting in IUGR.

Two Roads Diverge: Weight Loss Interventions and Circulating Amino Acids

In this issue of Science Translational Medicine, Laferrère and colleagues describe a metabolite profiling approach to investigate changes in the circulating metabolome after equivalent weight loss spurred by either gastric bypass surgery (GBP) or dietary intervention. The results reveal that GBP enhances branched chain amino acid metabolism by mechanisms separate from weight loss. These observations raise the possibility that changes in circulating amino acids play a role in the correction of glycemic control observed shortly after GBP.

Hyperaminoacidaemia at postprandial levels does not modulate glucose metabolism in type 2 diabetes mellitus

Hyperaminoacidaemia attenuates glucose disposal during hyperinsulinaemic clamps in healthy lean individuals, an effect thought to be mediated by negative feedback on insulin signalling, downstream of the mammalian target of rapamycin (mTOR) signalling pathway. This has been interpreted as amino acids causing insulin resistance in healthy people, and contributing to it in type 2 diabetes. However, the effect of hyperaminoacidaemia on glucose disposal in type 2 diabetic individuals remains to be determined. Eight obese men with type 2 diabetes underwent a two-step hyperinsulinaemic-hyperglycaemic (8 mmol/l) clamp, first with amino acids at postabsorptive concentrations, followed by postprandial concentrations. Whole-body glucose turnover was assessed using D: -[3-(3)H]glucose. Vastus lateralis biopsies were obtained at baseline and during each step of the clamp to determine the phosphorylation states of AKT, mTOR, ribosomal protein (rp) S6, and insulin receptor substrate (IRS)-1. Rates of glucose infusion (1.30 ± 0.19 vs 1.15 ± 0.13 mmol/min), endogenous glucose production (0.48 ± 0.06 vs 0.53 ± 0.05 mmol/min) and disposal (1.24 ± 0.17 vs 1.17 ± 0.14 mmol/min) did not differ between postabsorptive and postprandial amino acid concentrations (p > 0.05). Whereas phosphorylation of AKT(Ser473), AKT(Thr308) mTOR(Ser2448) and rpS6(Ser235/236) increased (p < 0.05) with elevated amino acids, that of IRS-1(Ser636/639) and IRS-1(Ser1101) did not change. Postprandial circulating amino acid concentrations do not worsen the already attenuated glucose disposal in hyperglycaemic type 2 diabetic men, and cell-signalling events are consistent with this. Our results do not support recommendations to restrict dietary protein in type 2 diabetes.

Maternal Insulin-Like Growth Factors-I and -II Act via Different Pathways to Promote Fetal Growth

The placenta transports substrates and wastes between the maternal and fetal circulations. In mice, placental IGF-II is essential for normal placental development and function but, in other mammalian species, maternal circulating IGF-II is substantial and may contribute. Maternal circulating IGFs increase in early pregnancy, and early treatment of guinea pigs with either IGF-I or IGF-II increases placental and fetal weights by mid-gestation. We now show that these effects persist to enhance placental development and fetal growth and survival near term. Pregnant guinea pigs were infused with IGF-I, IGF-II (both 1 mg/kg.d), or vehicle sc from d 20-38 of pregnancy and killed on d 62 (term = 69 d). IGF-II, but not IGF-I, increased the mid-sagittal area and volume of placenta devoted to exchange by approximately 30%, the total volume of trophoblast and maternal blood spaces within the placental exchange region (+29% and +46%, respectively), and the total surface area of placenta for exchange by 39%. Both IGFs reduced resorptions, and IGF-II increased the number of viable fetuses by 26%. Both IGFs increased fetal weight by 11-17% and fetal circulating amino acid concentrations. IGF-I, but not IGF-II, reduced maternal adipose depot weights by approximately 30%. In conclusion, increased maternal IGF-II abundance in early pregnancy promotes fetal growth and viability near term by increasing placental structural and functional capacity, whereas IGF-I appears to divert nutrients from the mother to the conceptus. This suggests major and complementary roles in placental and fetal growth for increased circulating IGFs in early to mid-pregnancy.

Effects of electromagnetic fields and gender on neurotransmitters and amino acids in rats

Epidemiological studies have linked electromagnetic field (EMF) exposure to certain forms of cancer, however only limited laboratory evidence supports a connection between EMF and biological effects. In the present study we exposed male and female rats to low level, 1000 milli-Gauss (mGs), direct current EMF generated with Helmholtz coils for 1 mo or 4 mo. The effects of these EMF exposures on regional brain neurotransmitter metabolism and circulating amino acid concentrations were determined. After 1 mo of EMF exposure the concentration of serotonin was elevated in the hypothalamus of male rats. Levels of the dopamine metabolite, 3-methoxytyramine, were increased in the corpus striatum of male and female rats that were exposed to EMF for 1 mo. Hypothalamic concentration of norepinephrine was elevated in both groups of male rats, as compared to respective female groups, but was not affected by EMF. Similarly, levels of tyrosine were increased in hypothalamus, corpus striatum and nucleus accumbens of male rats, but were not affected by EMF exposure. Following 4 mo of EMF exposure, no significant effect of EMF was observed. Significant sex differences in plasmaamino acid concentrations were observed in both studies, with female rats exhibiting decreases in a majority of the amino acids measured. These results are suggestive that short-term exposure may cause small alterations in neurotransmitter metabolism and in circulating amino acids, which dissipate when exposure duration is increased.

Protein and amino acid metabolism in cancer cachexia: investigative techniques and therapeutic interventions.

Cancer cachexia is a complex syndrome characterized primarily by diminished nutrient intake and progressive tissue depletion that is manifest clinically as anorexia and host weight loss. The gradual loss of host protein stores is central to this process. This review outlines the techniques that have been used to evaluate human amino acid metabolism, their application in patients with cancer cachexia, and possible therapeutic interventions designed to overcome alterations in host protein and amino acid metabolism associated with malignant cachexia. The techniques of nitrogen balance and 3-methylhistidine excretion provide indirect estimates of overall nitrogen metabolism and skeletal muscle myofibrillar protein breakdown. Measurement of circulating amino acid concentrations, particularly when combined with assessment of arterial-venous differences and regional amino acid balance allows for investigation of interorgan amino acid metabolism. One of the most significant advances in in vivo amino acid metabolic research has been the development of labeled amino acid tracer studies to evaluate whole body and regional amino acid kinetics. The use of stable and unstable amino acid isotopes in these techniques is reviewed in detail. Virtually all of these techniques have now been employed in the evaluation of human cancer cachexia. The results of studies evaluating amino acid concentrations, regional amino acid balance, and 3-methylhistidine excretion are summarized. The use of regional and whole body kinetic studies in cancer cachexia are reviewed extensively. Most investigators have observed increased rates of whole body protein turnover, synthesis, and catabolism in both weight-stable and weight-losing cancer patients. Some studies have suggested a relationship between the extent of disease and the degree of aberration in amino acid kinetic parameters. Investigators have attempted to reverse some of these alterations by provision of substrate (nutritional support) or administration of specific pharmacologic or anabolic agents such as hydrazine sulfate, insulin, growth hormone, and beta-2 agonists. The role of total parenteral nutrition (TPN) in cancer and its effects on protein and amino acid kinetics and tumor growth are addressed. The possible benefits of specific amino acid nutritional formulations with increased branched chain amino acids, arginine, and glutamine are reviewed. Although many of these approaches appear promising, significant impact on clinically definable parameters remains to be demonstrated. A better understanding of the underlying protein catabolic mechanisms of cancer cachexia will likely lead to more effective therapies to reverse the protein calorie malnutrition associated with cancer cachexia.