Plasma Glutamine Concentration Research Articles

Exploring the causal relationship between glutamine metabolism and leukemia risk: a Mendelian randomization and LC-MS/MS analysis.

This investigation sought to delineate the causal nexus between plasma glutamine concentrations and leukemia susceptibility utilizing bidirectional Mendelian Randomization (MR) analysis and to elucidate the metabolic ramifications of asparaginase therapy on glutamine dynamics in leukemia patients. A bidirectional two-sample MR framework was implemented, leveraging genetic variants as instrumental variables from extensive genome-wide association studies (GWAS) tailored to populations of European descent. Glutamine quantification was executed through a rigorously validated Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS) protocol. Comparative analyses of glutamine levels were conducted across leukemia patients versus healthy controls, pre- and post-asparaginase administration. Statistical evaluations employed inverse variance weighted (IVW) models, MR-Egger regression, and sensitivity tests addressing pleiotropy and heterogeneity. The MR findings underscored a significant inverse association between glutamine levels and leukemia risk (IVW p = 0.03558833), positing lower glutamine levels as a contributory factor to heightened leukemia susceptibility. Conversely, the analysis disclosed no substantive causal impact of leukemia on glutamine modulation (IVW p = 0.9694758). Notably, post-asparaginase treatment, a marked decrement in plasma glutamine concentrations was observed in patients (p = 0.0068), underlining the profound metabolic influence of the therapeutic regimen. This study corroborates the hypothesized inverse relationship between plasma glutamine levels and leukemia risk, enhancing our understanding of glutamine's role in leukemia pathophysiology. The pronounced reduction in glutamine levels following asparaginase intervention highlights the critical need for meticulous metabolic monitoring to refine therapeutic efficacy and optimize patient management in clinical oncology. These insights pave the way for more tailored and efficacious treatment modalities in the realm of personalized medicine.

Associations of Plasma Glutamatergic Metabolites with Alpha Desynchronization during Cognitive Interference and Working Memory Tasks in Asymptomatic Alzheimer's Disease.

Electroencephalogram (EEG) studies have suggested compensatory brain overactivation in cognitively healthy (CH) older adults with pathological beta-amyloid(Aβ42)/tau ratios during working memory and interference processing. However, the association between glutamatergic metabolites and brain activation proxied by EEG signals has not been thoroughly investigated. We aim to determine the involvement of these metabolites in EEG signaling. We focused on CH older adults classified under (1) normal CSF Aβ42/tau ratios (CH-NATs) and (2) pathological Aβ42/tau ratios (CH-PATs). We measured plasma glutamine, glutamate, pyroglutamate, and γ-aminobutyric acid concentrations using tandem mass spectrometry and conducted a correlational analysis with alpha frequency event-related desynchronization (ERD). Under the N-back working memory paradigm, CH-NATs presented negative correlations (r = ~-0.74--0.96, p = 0.0001-0.0414) between pyroglutamate and alpha ERD but positive correlations (r = ~0.82-0.95, p = 0.0003-0.0119) between glutamine and alpha ERD. Under Stroop interference testing, CH-NATs generated negative correlations between glutamine and left temporal alpha ERD (r = -0.96, p = 0.037 and r = -0.97, p = 0.027). Our study demonstrated that glutamine and pyroglutamate levels were associated with EEG activity only in CH-NATs. These results suggest cognitively healthy adults with amyloid/tau pathology experience subtle metabolic dysfunction that may influence EEG signaling during cognitive challenge. A longitudinal follow-up study with a larger sample size is needed to validate these pilot studies.

Supplementing dietary betaine during late gestation increases plasma betaine and methionine concentrations in pregnant Merino ewes but not neonatal lambs

Supplementing dietary betaine during pregnancy has improved vigour and post-natal survival rates to day seven in twin lambs, potentially due to improvements in the circulating metabolite profile of these animals. This study determined whether maternal betaine supplementation during late gestation would increase circulating levels of betaine, creatinine and other amino acids in ewes and their newborn lambs, leading to subsequent improvements in lamb viability and growth. Twenty-five single-bearing Merino ewes received dietary betaine at either 0 (Control, CTL), 2 (Low Betaine, LB) or 4 g/day (High Betaine, HB) from day 125 of gestation (dG 125) until parturition (150.7 ± 0.6 days). Blood samples were collected from the ewes prior to feeding (0 h), and at 2, 4, 6, 8 and 24 h post-feeding on dG 125 and dG 140 prior to feeding and from the lamb within 2 h after birth. Lamb viability measures were taken at 2, 24 and 72 h and day 7 post-partum, marking (⁓30 days of age) and weaning (⁓104 days of age). Betaine supplementation at LB and HB increased plasma betaine levels at 6, 8 and 24 h post-feeding on dG 125 (P < 0.05) and tended to increase plasma betaine on dG 140 (P = 0.085). Plasma methionine levels increased at 2 and 4 h post-feeding on dG 125 relative to baseline levels (0 h) in LB ewes, yet remained unchanged in HB ewes. On dG 125, creatinine levels were higher in CTL ewes compared with betaine-supplemented ewes at 4 and 8 h post-feeding (both P < 0.05). While plasma betaine and methionine levels were unchanged in neonatal lambs, plasma concentrations of glutamine and lysine were higher (P < 0.05) in HB lambs compared to CTL and LB lambs. HB lambs tended to be heavier at marking (P = 0.057) and were heavier at weaning compared to CTL and LB lambs (P < 0.05). This study indicated that betaine supplementation increased plasma betaine and methionine levels in ewes, but not in neonatal lambs. Further research is warranted to determine whether higher levels of betaine supplementation increase neonatal concentrations.

PSV-29 Plasma Citrulline Is Strongly Correlated with Jejunum and Ileum Citrulline Concentrations in Pigs at Weaning

Abstract Pigs at weaning are abruptly exposed to numerous stressors that negatively affect gut health. While the term gut health lacks a clear definition, it is best measured by its key functions, including nutrient digestion, absorption, and metabolism, mucosal immunity, and barrier function. The gut is the main endogenous source of citrulline, a potential biomarker of gut function. The objective of this study was to determine the relationship between plasma and intestinal concentrations of citrulline and citrulline precursors in pigs. Pigs (initial BW = 7,233 ± 683 g) were either weaned at 21 d age and euthanized at 23 d age (W; n = 9) or were not weaned, remained with the sow, and euthanized at 23 d age (NW; n = 9). At euthanasia, blood, jejunum, and ileum tissue was collected and snap-frozen in liquid nitrogen; segments of mid jejunum and distal ileum were collected for morphological analysis. Plasma and tissue glutamine (Gln), glutamate (Glu), proline (Pro), ornithine (Orn), and citrulline (Cit) concentrations were determined by reverse-phase HPLC following pre-column derivatization with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate. Data were analyzed with the generalized linear mixed model and correlation procedures of SAS (version 9.4). Pearson correlation coefficients between 0.50 and 0.69 were considered as moderate, between 0.70 and 0.89 as strong, and between 0.90 to 1 as very strong. Jejunum villus height was reduced in W compared with NW pigs (370 versus 246 ± 18 µm; P &amp;lt; 0.001), whereas ileum villus height was not different between NW and W pigs (257 versus 215 ± 27 µm; P = 0.27). Among precursors for gut Cit synthesis, plasma Pro was strongly correlated with jejunum Pro (r = 0.83; P &amp;lt; 0.001) and very strongly correlated with ileum Pro (r = 0.91; P &amp;lt; 0.001). Plasma Glu was moderately correlated with ileum Glu (r = 0.58; P = 0.014), but not with jejunum Glu (r = 0.18, P = 0.48), whereas plasma Gln was moderately correlated with ileum Gln (r = 0.57; P = 0.016) and strongly correlated with jejunum Gln (r = 0.80; P &amp;lt; 0.001). Plasma Orn was strongly correlated with both jejunum Orn (r = 0.73; P &amp;lt; 0.001) and ileum Orn (r = 0.78; P &amp;lt; 0.001). Plasma Cit was strongly correlated with jejunum Cit (r = 0.77; P &amp;lt; 0.001) and very strongly correlated with ileum Cit (r = 0.95; P &amp;lt; 0.001). Plasma Cit can be used to estimate gut Cit content and may be predictive of gut function in nursery pigs undergoing weaning stress.

A cell-penetrating PHLPP peptide improves cardiac arrest survival in murine and swine models.

Out-of-hospital cardiac arrest is a leading cause of death in the US, with a mortality rate over 90%. Preclinical studies demonstrate that cooling during cardiopulmonary resuscitation (CPR) is highly beneficial, but can be challenging to implement clinically. No medications exist for improving long-term cardiac arrest survival. We have developed a 20-amino acid peptide, TAT-PHLPP9c, that mimics cooling protection by enhancing AKT activation via PH domain leucine-rich repeat phosphatase 1 (PHLPP1) inhibition. Complementary studies were conducted in mouse and swine. C57BL/6 mice were randomized into blinded saline control and peptide-treatment groups. Following a 12-minute asystolic arrest, TAT-PHLPP9c was administered intravenously during CPR and significantly improved the return of spontaneous circulation, mean arterial blood pressure and cerebral blood flow, cardiac and neurological function, and survival (4 hour and 5 day). It inhibited PHLPP-NHERF1 binding, enhanced AKT but not PKC phosphorylation, decreased pyruvate dehydrogenase phosphorylation and sorbitol production, and increased ATP generation in heart and brain. TAT-PHLPP9c treatment also reduced plasma taurine and glutamate concentrations after resuscitation. The protective benefit of TAT-PHLPP9c was validated in a swine cardiac arrest model of ventricular fibrillation. In conclusion, TAT-PHLPP9c may improve neurologically intact cardiac arrest survival without the need for physical cooling.

Arginine Dysregulation and Myocardial Dysfunction in a Mouse Model and Children with Chronic Kidney Disease.

Cardiovascular disease is the leading cause of death in chronic kidney disease (CKD). Arginine, the endogenous precursor for nitric oxide synthesis, is produced in the kidneys. Arginine bioavailability contributes to endothelial and myocardial dysfunction in CKD. Plasma from 129X1/SvJ mice with and without CKD (5/6th nephrectomy), and banked plasma from children with and without CKD were analyzed for amino acids involved in arginine metabolism, ADMA, and arginase activity. Echocardiographic measures of myocardial function were compared with plasma analytes. In a separate experiment, a non-specific arginase inhibitor was administered to mice with and without CKD. Plasma citrulline and glutamine concentrations correlated with multiple measures of myocardial dysfunction. Plasma arginase activity was significantly increased in CKD mice at 16 weeks vs. 8 weeks (p = 0.002) and ventricular strain improved after arginase inhibition in mice with CKD (p = 0.03). In children on dialysis, arginase activity was significantly increased vs. healthy controls (p = 0.04). Increasing ADMA correlated with increasing RWT in children with CKD (r = 0.54; p = 0.003). In a mouse model, and children, with CKD, arginine dysregulation correlates with myocardial dysfunction.

Glutamine Deficiency Promotes Immune and Endothelial Cell Dysfunction in COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic has caused the death of almost 7 million people worldwide. While vaccinations and new antiviral drugs have greatly reduced the number of COVID-19 cases, there remains a need for additional therapeutic strategies to combat this deadly disease. Accumulating clinical data have discovered a deficiency of circulating glutamine in patients with COVID-19 that associates with disease severity. Glutamine is a semi-essential amino acid that is metabolized to a plethora of metabolites that serve as central modulators of immune and endothelial cell function. A majority of glutamine is metabolized to glutamate and ammonia by the mitochondrial enzyme glutaminase (GLS). Notably, GLS activity is upregulated in COVID-19, favoring the catabolism of glutamine. This disturbance in glutamine metabolism may provoke immune and endothelial cell dysfunction that contributes to the development of severe infection, inflammation, oxidative stress, vasospasm, and coagulopathy, which leads to vascular occlusion, multi-organ failure, and death. Strategies that restore the plasma concentration of glutamine, its metabolites, and/or its downstream effectors, in conjunction with antiviral drugs, represent a promising therapeutic approach that may restore immune and endothelial cell function and prevent the development of occlusive vascular disease in patients stricken with COVID-19.

Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.

Pathogenic biallelic variants in PCK1 coding for the cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) cause PEPCK-C deficiency, a rare disorder of gluconeogenesis presenting with hypoglycemia, lactic acidosis, and hepatopathy. To date, there has been no systematic analysis of its phenotypic, biochemical, and genetic spectrum. All currently published individuals and a novel patient with genetically confirmed PEPCK-C deficiency were included. Clinical, biochemical, and genetic findings were analyzed. Protein and in-silico prediction score modeling was applied to analyze potential variant effects. Thirty-two individuals from 25 families were found, including one previously unreported patient. The typical biochemical pattern was hypoglycemia triggered by catabolic situations, elevated urinary concentrations of tricarboxylic acid cycle metabolites, mildly elevated alanine and aspartate aminotransferase and elevated lactate concentrations in serum. Plasma glutamine concentrations were elevated in some patients and may be a suitable marker for newborn screening. With adequate treatment, biochemical abnormalities usually normalized following a hypoglycemic episode. Symptom onset usually occurred in infancy with a broad range from neonatal age to adulthood. Regardless of the genotype, different phenotypes with a broad clinical spectrum were found. To date, eight genotypes with nine different PCK1 variants were identified, of which alleles with the recurrent variant c.925G > A; p.(Gly309Arg) are predominant and appear to be endemic in the Finnish population. Protein modeling suggests altered manganese- and substrate-binding as superordinate pathomechanisms. Environmental factors appear to be the main determinant for the phenotype in patients with biallelic variants in PCK1. Based on the biochemical pattern, PEPCK-C deficiency is a recognizable cause of childhood hypoglycemia. It is a treatable disease and early diagnosis is important to prevent metabolic derailment and morbidity. Newborn screening can identify at least a sub-cohort of affected individuals through elevated glutamine concentrations in dry blood.

The Role of Comorbidities on Aging-Induced Changes in Muscle Health and Amino Acid Kinetics

ObjectivesAging and comorbidities are known to influence amino acid metabolism, contributing to reduced muscle and cognitive dysfunction in older adults. Whether these aging-induced manifestations remain after correction for the presence of comorbidities is unclear. MethodsOlder adults were selected from the MEDIT database. The subjects were divided into two age groups: 264 young old (age 50–70 y: n = 149 with at least 1 comorbidity based on Charlson comorbidity index (CCI > 0) and n = 115 with CCI = 0), and 196 middle old (age 70–85 y: n = 119 with CCI > 0 and n = 77 with CCI = 0). Body composition was assessed by DXA, respiratory and skeletal muscle strength by mouth pressures and dynamometry, and cognition and mood by assessments and questionnaires. Postabsorptive kinetics of multiple amino acids were measured by pulse stable isotope administration and subsequent blood sampling. Plasma amino acid concentrations and enrichments were analyzed by LC-MS/MS to measure whole-body protein production (WBP) and conversion rates. Statistics are done with ANCOVA with sex and BMI and age group as independents. Results expressed as means [95% CI]. ResultsThe middle old had lower lean mass on whole body level and in the extremities (p < 0.0001), and lower respiratory (p = 0.05) and handgrip (p = 0.005) strength compared to the young old, independent of muscle health lowering effects of CCI. Although no differences were observed in cognition and mood between the groups, an age x CCI interaction was found for depression, anxiety (p = 0.03), and lean mass extremity (p = 0.04). The middle old had lower values for WBP of tau-methylhistidine (p = 0.01), hydroxyproline (P = 0.008), and taurine (p = 0.004), and plasma glutamine concentration (P = 0.016). In addition, the middle old showed higher glutamine to glutamate conversion (p = 0.02). Age x CCI interaction was observed for plasma concentration of tyrosine (p = 0.04). No differences were observed in plasma concentrations and WBP of phenylalanine and the branched-chain amino acids (leucine, valine, and isoleucine) between the groups. ConclusionsMuscle loss and weakness and specific disturbances in amino acid kinetics due to aging exist even after correction for the presence of comorbidities. Funding SourcesNone

High Protein Diet Feeding Aggravates Hyperaminoacidemia in Mice Deficient in Proglucagon-Derived Peptides.

(1) Background: Protein stimulates the secretion of glucagon (GCG), which can affect glucose metabolism. This study aimed to analyze the metabolic effect of a high-protein diet (HPD) in the presence or absence of proglucagon-derived peptides, including GCG and GLP-1. (2) Methods: The response to HPD feeding for 7 days was analyzed in mice deficient in proglucagon-derived peptides (GCGKO). (3) Results: In both control and GCGKO mice, food intake and body weight decreased with HPD and intestinal expression of Pepck increased. HPD also decreased plasma FGF21 levels, regardless of the presence of proglucagon-derived peptides. In control mice, HPD increased the hepatic expression of enzymes involved in amino acid metabolism without the elevation of plasma amino acid levels, except branched-chain amino acids. On the other hand, HPD-induced changes in the hepatic gene expression were attenuated in GCGKO mice, resulting in marked hyperaminoacidemia with lower blood glucose levels; the plasma concentration of glutamine exceeded that of glucose in HPD-fed GCGKO mice. (4) Conclusions: Increased plasma amino acid levels are a common feature in animal models with blocked GCG activity, and our results underscore that GCG plays essential roles in the homeostasis of amino acid metabolism in response to altered protein intake.

Glutaminase 2 knockdown reduces hyperammonemia and associated lethality of urea cycle disorder mouse model.

Amino acids, the building blocks of proteins in the cells and tissues, are of fundamental importance for cell survival, maintenance, and proliferation. The liver plays a critical role in amino acid metabolism and detoxication of byproducts such as ammonia. Urea cycle disorders with hyperammonemia remain difficult to treat and eventually necessitate liver transplantation. In this study, ornithine transcarbamylase deficient (Otc spf‐ash ) mouse model was used to test whether knockdown of a key glutamine metabolism enzyme glutaminase 2 (GLS2, gene name: Gls2) or glutamate dehydrogenase 1 (GLUD1, gene name: Glud1) could rescue the hyperammonemia and associated lethality induced by a high protein diet. We found that reduced hepatic expression of Gls2 but not Glud1 by AAV8‐mediated delivery of a short hairpin RNA in Otc spf‐ash mice diminished hyperammonemia and reduced lethality. Knockdown of Gls2 but not Glud1 in Otc spf‐ash mice exhibited reduced body weight loss and increased plasma glutamine concentration. These data suggest that Gls2 hepatic knockdown could potentially help alleviate risk for hyperammonemia and other clinical manifestations of patients suffering from defects in the urea cycle.

Systemic administration of monosodium glutamate induces sexually dimorphic headache- and nausea-like behaviours in rats.

Ingestion of monosodium glutamate (MSG) causes headache, nausea, and craniofacial tenderness in healthy individuals. The present study explored whether MSG produces behavioural signs of headache, nausea, and changes in craniofacial sensitivity in rats. The behavior of male and female Sprague-Dawley rats was video recorded before and after intraperitoneal (i.p.) injections of MSG (1-1000 mg/kg), nitroglycerin (GTN, 10 mg/kg), or normal saline. Behaviors (grimace score, head-flicks, rearing, head scratches, facial grooming, lying-on-belly, and temporalis muscle region mechanical withdrawal threshold) were evaluated. Facial cutaneous temperature of the nose and forehead was measured before and after i.p. injections via infrared thermography. Plasma glutamate and calcitonin gene-related peptide concentrations after administration of 1000 mg/kg MSG were measured in anesthetized rats. Monosodium glutamate induced nocifensive, headache-like, and nausea-like behaviors in a dose-related manner but had no effect on mechanical threshold. Monosodium glutamate (1000 mg/kg) induced a significantly greater frequency of headache-like behavior in females but a longer duration of nausea-like behavior in males. Monosodium glutamate produced a prolonged increase in plasma glutamate and calcitonin gene-related peptide concentrations. Co-administration of the median effective dose of MSG (350 mg/kg) with GTN (10 mg/kg) amplified headache-like behaviors, induced significant craniofacial sensitivity, and produced increased nausea-like behaviour. Co-administration of sumatriptan or naproxen with MSG (1000 mg/kg) significantly attenuated MSG-induced nocifensive and headache-like behaviors. Our data suggest that systemic administration of MSG to rats induces behavioral correlates of headache and nausea. This model may offer another avenue for research on the mechanism and treatment of primary headache disorders such as migraine.

Implications for the metabolic fate of oral glutamine supplementation within plasma and erythrocytes of patients with sickle cell disease: A pharmacokinetics study

ObjectivesL-Glutamine is FDA-approved for sickle cell disease (SCD), yet the mechanism(s)-of-action are poorly understood. We performed a pharmacokinetics (pK) study to determine the metabolic fate of glutamine supplementation on plasma and erythrocyte amino acids in patients with SCD. DesignA pK study was performed where patients with SCD fasting for > 8 h received oral L-glutamine (10 g). Blood was analyzed at baseline, 30/60/90 min/2/3/4/8 hrs. A standardized diet was administered to all participants at 3 established time-points (after 2/5/7hrs). A subset of patients also had pK studies performed without glutamine supplementation to follow normal diurnal fluctuations in amino acids. SettingComprehensive SCD Center in Oakland, California ResultsFive patients with SCD were included, three of whom performed pK studies both with and without glutamine supplementation. Average age was 50.6 ± 5.6 years, 60% were female, 40% SS, 60% SC. Plasma glutamine levels increased significantly after oral glutamine supplementation, compared to minimal fluctuations with diet. Plasma glutamine concentration peaked within 30-min of ingestion (p = 0.01) before decreasing to a plateau by 2-h that remained higher than baseline by 8 h. Oral glutamine also increased plasma arginine concentration, which peaked by 4-h (p = 0.03) and remained elevated through 8-h. Erythrocyte glutamine levels began to increase by 8-h, while erythrocyte arginine concentration peaked at 4-h. ConclusionsOral glutamine supplementation acutely improved glutamine and arginine bioavailability in both plasma and erythrocytes. This is the first study to demonstrate that glutamine therapy increases arginine bioavailability and may provide insight into shared mechanisms-of-action between these conditionally-essential amino acids.

Alterations of Plasma Glutamine and Surgical Stress in Gastric Cancer Surgery

Background: The plasma glutamine levels are known to decrease after major surgery, which is related to a negative clinical outcome. However, the influence of surgical stress on the decrease in the plasma glutamine concentration is unclear. The aim of this study was to evaluate the change in glutamine in relation to the types of gastrectomy and approaches as well as the amount of surgical stress evaluated by serum interleukin-6(IL-6) as an objective indicator.

Plasma glutamine status at intensive care unit admission: an independent risk factor for mortality in critical illness

BackgroundA plasma glutamine concentration outside the normal range at Intensive Care Unit (ICU) admission has been reported to be associated with an increased mortality rate. Whereas hypoglutaminemia has been frequently reported, the number of patients with hyperglutaminemia has so far been quite few. Therefore, the association between hyperglutaminemia and mortality outcomes was studied in a prospective, observational study.Patients and methodsConsecutive admissions to a mixed general ICU were eligible. Exclusion criteria were < 18 years of age, readmissions, no informed consent, or a ‘do not resuscitate’ order at admission. A blood sample was saved within one hour from admission to be analysed by high-pressure liquid chromatography for glutamine concentration. Conventional risk scoring (Simplified Acute Physiology Score and Sequential Organ Failure Assessment) at admission, and mortality outcomes were recorded for all included patients.ResultsOut of 269 included patients, 26 were hyperglutaminemic (≥ 930 µmol/L) at admission. The six-month mortality rate for this subgroup was 46%, compared to 18% for patients with a plasma glutamine concentration < 930 µmol/L (P = 0.002). A regression analysis showed that hyperglutaminemia was an independent mortality predictor that added prediction value to conventional admission risk scoring and age.ConclusionHyperglutaminemia in critical illness at ICU admission was an independent mortality predictor, often but not always, associated with an acute liver condition. The mechanism behind a plasma glutamine concentration outside normal range, as well as the prognostic value of repeated measurements of plasma glutamine during ICU stay, remains to be investigated.

Amino Acid Profile in 18 Patients with Rheumatic Diseases Treated with Glucocorticoids and BCAAs.

The administration of glucocorticoids to patients with rheumatic diseases often results in glucocorticoid-induced myopathy. We previously found that administration of branched-chain amino acids (BCAA) to such patients improves the loss of skeletal muscle, however, their individual differences were often observed. The present study, therefore, aims to identify specific parameters associated with BCAA-induced increases in skeletal muscle mass. Eighteen patients with rheumatic diseases treated with prednisolone were randomly assigned to receive additional BCAAs for 12 wk. Serum biochemistry, plasma fibroblast growth factor (FGF) 19 and 21, and plasma and urinary amino acid concentrations were assessed. The relationship between these parameters and the cross-sectional area (CSA) of the biceps femoris (slow-twitch muscle) and rectus femoris (fast-twitch muscle) was assessed using computed tomography. BCAA supplementation increased serum levels of creatinine and albumin and decreased ammonia and urinary 3-methylhistidine levels. With or without BCAA supplementation, each plasma amino acid concentration decreased during the study period, but the decrease was lower in patients receiving BCAA. Interestingly, a positive correlation was observed between plasma isoleucine, aspartate, and glutamate concentrations and improvement in the biceps femoris muscle atrophy. Plasma amino acid concentrations in patients with rheumatic diseases treated with glucocorticoids decreased despite tapering the dose of glucocorticoids, with a smaller decrease in the BCAA-treated group. Plasma BCAA, aspartic acid, and glutamate concentrations correlated positively with the rate of improvement in biceps femoris muscle atrophy, suggesting that these amino acids are associated with the BCAA-induced increase in muscle mass.

Altered Glutamate and Glutamine Kinetics in Autism Spectrum Disorder

ObjectivesRecent studies suggest that glutamate (GLU) signaling abnormalities are involved in the etiology of Autism Spectrum Disorder (ASD), suggesting perturbations in GLU and glutamine (GLN) metabolism. Although GLU and GLN plasma concentrations have been linked to cognitive decline, the actual production of GLU and GLN have never been measured in ASD and linked to ASD severity score and neurocognitive and mood changes. Methods19 young adults with high functioning ASD (age 24.3 ± 1.0y, Autism Quotient (AQ): 31.4 ± 1.7), and 46 control subjects (age 23.4 ± 0.3y)) were enrolled. ASD severity and subscores as well as cognitive function and mood were assessed (MOCA, TMT, word fluency, Stroop, HADS). Postabsorptive amino acid kinetics (production of GLU and GLN, and its interconversion rates (GLU > >GLN and GLN > >GLU)) were measured by pulse stable isotope administration and subsequent blood sampling for 4 hours. Plasma amino acid enrichments and concentrations were analyzed by LC-MS/MS. Stats were done by ANCOVA, post hoc analysis and Pearson correlation. Significance was set at p < 0.05. ResultsNo differences were present in word fluency, but higher values in ASD for TMTb (p = 0.066), depression (p = 0.0004), anxiety (p = 0.0006) and lower values for MOCA (0.0054). The ASD group was characterized by lower plasma GLN and GLU concentrations (p < 0.05). Although the production rates of GLN and GLU were not different between the groups, in ASD GLN > >GLU was higher (p = 0.0018) and GLU > >GLN lower (p = 0.016) and a higher GLN clearance rate (p = 0.006). Significant relationships were found in the ASD group between several GLU and GLN kinetic markers and AQ subscores (e.g., attention to detail, attention switching and/or communication) and word fluency (p < 0.05). ConclusionsDisturbances in GLN and GLU metabolism in ASD are associated with changes in ASD subscores but less with neurocognitive dysfunction or mood changes. Funding SourcesNone.

Novel associations between parental and newborn cord blood metabolic profiles in the Norwegian Mother, Father and Child Cohort Study

BackgroundMore than one third of Norwegian women and men between 20 and 40 years of age have elevated cholesterol concentration. Parental metabolic health around conception or during pregnancy may affect the offspring’s cardiovascular disease risk. Lipids are important for fetal development, but the determinants of cord blood lipids have scarcely been studied. We therefore aimed to describe the associations between maternal and paternal peri-pregnancy lipid and metabolic profile and newborn cord blood lipid and metabolic profile.MethodsThis study is based on 710 mother–father–newborn trios from the Norwegian Mother, Father and Child Cohort Study (MoBa) and uses data from the Medical Birth Registry of Norway (MBRN). The sample included in this study consisted of parents with and without self-reported hypercholesterolemia the last 6 months before pregnancy and their partners and newborns. Sixty-four cord blood metabolites detected by nuclear magnetic resonance spectroscopy were analyzed by linear mixed model analyses. The false discovery rate procedure was used to correct for multiple testing.ResultsAmong mothers with hypercholesterolemia, maternal and newborn plasma high-density lipoprotein cholesterol, apolipoprotein A1, linoleic acid, docosahexaenoic acid, alanine, glutamine, isoleucine, leucine, valine, creatinine, and particle concentration of medium high-density lipoprotein were significantly positively associated (0.001 ≤ q ≤ 0.09). Among mothers without hypercholesterolemia, maternal and newborn linoleic acid, valine, tyrosine, citrate, creatinine, high-density lipoprotein size, and particle concentration of small high-density lipoprotein were significantly positively associated (0.02 ≤ q ≤ 0.08). Among fathers with hypercholesterolemia, paternal and newborn ratio of apolipoprotein B to apolipoprotein A1 were significantly positively associated (q = 0.04). Among fathers without hypercholesterolemia, no significant associations were found between paternal and newborn metabolites. Sex differences were found for many cord blood lipids.ConclusionsMaternal and paternal metabolites and newborn sex were associated with several cord blood metabolites. This may potentially affect the offspring’s long-term cardiovascular disease risk.

Optimization of the Design and Operating Conditions of an Amperometric Biosensor for Glutamate Concentration Measurements in the Blood Plasma

AbstractToday, the concentration of glutamate in the patient′s blood is an important indicator in medical diagnostics; therefore, it is necessary to have a simple, accurate, and fast tool to obtain the data. Here, a recently developed amperometric glutamate‐sensitive biosensor was optimized to improve its characteristics. The platinum disk electrode was used as a transducer. As a bioselective element we used the enzyme glutamate oxidase, covalently crosslinked with bovine serum albumin by glutaraldehyde. Circumstances of enzyme immobilization on the transducer‘s surface were optimized (enzyme and glutaraldehyde concentrations and immobilization duration). To test the ability of this biosensor to work in biological environments containing complex biological substances, the influence of the working solution was investigated (concentration of the working buffer, its temperature, presence of the protein in the analyzed sample). The linear range of biosensor was from 5 to 600 μM of glutamate and the sensitivity was 150–200 nA/mM. Measurements of glutamate concentrations in the blood plasma were performed by biosensor and glutamate dehydrogenase assay. The linear correlation between the methods was found in a range of 50.4–182.5 μM (R2=0.99). Thus, it has been shown that the developed biosensor makes it possible to measure the concentration of glutamate in blood plasma.

Amino acids profile in girls with Turner syndrome during growth hormone therapy.

The influence of growth hormone (GH) treatment on amino acids (AAs) profile in patients with Turner syndrome (TS) was investigated. The study group included girls with TS: treated with GH (GH+) and girls with no GH treatment (GH-). The control group consisted of healthy girls. Free plasma AAs were measured by the LC/MS/MS. The plasma concentrations of glutamine, threonine were significantly higher in group GH+ than in group GH- (p < 0.05). In group GH- the values of glutamine, alanine, isoleucine, glutamic acid were significantly different than in the control (p < 0.05-p < 0.008). AAs profile in girls with TS might be characteristic for the disease but also depends on GH treatment.