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The number of people affected by Type 2 diabetes mellitus (T2DM) is close to half a billion and is on a sharp rise, representing a major and growing public health burden. Given its mild initial symptoms, T2DM is often diagnosed several years after its onset, leaving half of diabetic individuals undiagnosed. While several classical clinical and genetic biomarkers have been identified, improving early diagnosis by exploring other kinds of omics data remains crucial. In this study, we have combined longitudinal data from two population-based cohorts CoLaus and DESIR (comprising in total 493 incident cases vs. 1360 controls) to identify new or confirm previously implicated metabolomic biomarkers predicting T2DM incidence more than 5 years ahead of clinical diagnosis. Our longitudinal data have shown robust evidence for valine, leucine, carnitine and glutamic acid being predictive of future conversion to T2DM. We confirmed the causality of such association for leucine by 2-sample Mendelian randomisation (MR) based on independent data. Our MR approach further identified new metabolites potentially playing a causal role on T2D, including betaine, lysine and mannose. Interestingly, for valine and leucine a strong reverse causal effect was detected, indicating that the genetic predisposition to T2DM may trigger early changes of these metabolites, which appear well-before any clinical symptoms. In addition, our study revealed a reverse causal effect of metabolites such as glutamic acid and alanine. Collectively, these findings indicate that molecular traits linked to the genetic basis of T2DM may be particularly promising early biomarkers.

It has been assumed that exercise intensity variation throughout a cycling time trial (TT) occurs in alignment of various metabolic changes to prevent premature task failure. However, this assumption is based on target metabolite responses, which limits our understanding of the complex interconnection of metabolic responses during exercise. The current study characterized the metabolomic profile, an untargeted metabolic analysis, after specific phases of a cycling 4‐km TT. Eleven male cyclists performed three separated TTs in a crossover counterbalanced design, which were interrupted at the end of the fast‐start (FS, 600 ± 205 m), even‐pace (EP, 3600 ± 190 m), or end‐spurt (ES, 4000 m) phases. Blood samples were taken before any exercise and 5 min after exercise cessation, and the metabolomic profile characterization was performed using Nuclear Magnetic Resonance metabolomics. Power output (PO) was also continually recorded. There were higher PO values during the FS and ES compared to the EP (all p < 0.05), which were accompanied by distinct metabolomic profiles. FS showed high metabolite expression in TCA cycle and its related pathways (e.g., glutamate, citric acid, and valine metabolism); whereas, the EP elicited changes associated with antioxidant effects and oxygen delivery adjustment. Finally, ES was related to pathways involved in NAD turnover and serotonin metabolism. These findings suggest that the specific phases of a cycling TT are accompanied by distinct metabolomic profiles, providing novel insights regarding the relevance of specific metabolic pathways on the process of exercise intensity regulation. Highlights Untargeted metabolomic profile analysis may reveal unexplored bioenergetic pathways activated throughout a self‐paced cycling time trial. Exercise intensity variations throughout a cycling time trial are accompanied by different blood serum metabolomic profiles. The current new insights may encourage future investigation on the underpinning mechanisms of specific metabolomic profiles according to each time trial phase.

Gulf War Illness (GWI) is a multisymptom disorder including widespread chronic pain, fatigue and gastrointestinal problems. The objective of this study was to examine the low glutamate diet as a treatment for GWI. Forty veterans with GWI were recruited from across the US. Outcomes included symptom score, myalgic score, tender point count, dolorimetry and the Chalder Fatigue Scale. Subjects were randomized to the low glutamate diet or a wait-listed control group, with symptom score being compared after one month. Subjects then went onto a double-blind, placebo-controlled crossover challenge with monosodium glutamate (MSG)/placebo to test for return of symptoms. Symptom score was compared between diet intervention and wait-listed controls with an independent t-test and effect size was calculated with Cohen’s d. Change scores were analyzed with Wilcoxon Signed Rank tests. Crossover challenge results were analyzed with General Linear Models and cluster analysis. The diet intervention group reported significantly less symptoms (p = 0.0009) than wait-listed controls, with a very large effect size, d = 1.16. Significant improvements in average dolorimetry (p = 0.0006), symptom score, tender point number, myalgic score and the Chalder Fatigue Scale (all p < 0.0001) were observed after the 1-month diet. Challenge with MSG/placebo resulted in significant variability in individual response. These results suggest that the low glutamate diet can effectively reduce overall symptoms, pain and fatigue in GWI, but differential results upon challenge suggest that other aspects of the diet, or underlying differences within the population, may be driving these changes. Future research is needed to identify potential nutrient effects, biomarkers, and underlying metabolic differences between responders and non-responders.

Background Neurofibromatosis 1 (NF1) is a monogenic model for syndromic autism. Statins rescue the social and cognitive phenotype in animal knockout models, but translational trials with subjects > 8 years using cognition/behaviour outcomes have shown mixed results. This trial breaks new ground by studying statin effects for the first time in younger children with NF1 and co-morbid autism and by using multiparametric imaging outcomes. Methods A single-site triple-blind RCT of simvastatin vs. placebo was done. Assessment (baseline and 12-week endpoint) included peripheral MAPK assay, awake magnetic resonance imaging spectroscopy (MRS; GABA and glutamate+glutamine (Glx)), arterial spin labelling (ASL), apparent diffusion coefficient (ADC), resting state functional MRI, and autism behavioural outcomes (Aberrant Behaviour Checklist and Clinical Global Impression). Results Thirty subjects had a mean age of 8.1 years (SD 1.8). Simvastatin was well tolerated. The amount of imaging data varied by test. Simvastatin treatment was associated with (i) increased frontal white matter MRS GABA ( t (12) = − 2.12, p  = .055), GABA/Glx ratio ( t (12) = − 2.78, p  = .016), and reduced grey nuclei Glx (ANCOVA p < 0.05, Mann-Whitney p < 0.01); (ii) increased ASL perfusion in ventral diencephalon (Mann-Whitney p  < 0.01); and (iii) decreased ADC in cingulate gyrus (Mann-Whitney p  < 0.01). Machine-learning classification of imaging outcomes achieved 79% ( p  < .05) accuracy differentiating groups at endpoint against chance level (64%, p  = 0.25) at baseline. Three of 12 (25%) simvastatin cases compared to none in placebo met ‘clinical responder’ criteria for behavioural outcome. Conclusions We show feasibility of peripheral MAPK assay and autism symptom measurement, but the study was not powered to test effectiveness. Multiparametric imaging suggests possible simvastatin effects in brain areas previously associated with NF1 pathophysiology and the social brain network. Trial registration EU Clinical Trial Register (EudraCT) 2012-005742-38 ( www.clinicaltrialsregister.eu )

Marginal deficiency of vitamin B-6 is common among segments of the population worldwide. Because pyridoxal 5'-phosphate (PLP) serves as a coenzyme in the metabolism of amino acids, carbohydrates, organic acids, and neurotransmitters, as well as in aspects of one-carbon metabolism, vitamin B-6 deficiency could have many effects. Healthy men and women (age: 20-40 y; n = 23) were fed a 2-day controlled, nutritionally adequate diet followed by a 28-day low-vitamin B-6 diet (<0.5 mg/d) to induce marginal deficiency, as reflected by a decline of plasma PLP from 52.6±14.1 (mean ± SD) to 21.5±4.6 nmol/L (P<0.0001) and increased cystathionine from 131±65 to 199±56 nmol/L (P<0.001). Fasting plasma samples obtained before and after vitamin B6 restriction were analyzed by (1)H-NMR with and without filtration and by targeted quantitative analysis by mass spectrometry (MS). Multilevel partial least squares-discriminant analysis and S-plots of NMR spectra showed that NMR is effective in classifying samples according to vitamin B-6 status and identified discriminating features. NMR spectral features of selected metabolites indicated that vitamin B-6 restriction significantly increased the ratios of glutamine/glutamate and 2-oxoglutarate/glutamate (P<0.001) and tended to increase concentrations of acetate, pyruvate, and trimethylamine-N-oxide (adjusted P<0.05). Tandem MS showed significantly greater plasma proline after vitamin B-6 restriction (adjusted P<0.05), but there were no effects on the profile of 14 other amino acids and 45 acylcarnitines. These findings demonstrate that marginal vitamin B-6 deficiency has widespread metabolic perturbations and illustrate the utility of metabolomics in evaluating complex effects of altered vitamin B-6 intake.

The aim of this study was to identify indicators of non-functional overreaching (NFOR) in team sport athletes undertaking intensive training loads. Eighteen semi-professional rugby league players were randomly assigned into two pair matched groups. One group completed 6 weeks of normal training (NT) whilst the other group was deliberately overreached through intensified training (IT). Both groups then completed the same 7-day stepwise training load reduction taper. Multistage fitness test (MSFT) performance, VO2 (max), peak aerobic running velocity (V (max)), maximal heart rate, vertical jump, 10-s cycle sprint performance and body mass were measured pre- and post-training period and following the taper. Hormonal, haematological and immunological parameters were also measured pre-training and following weeks 2, 4 and 6 of training and post-taper. MANOVA for repeated measures with contrast analysis indicated that MSFT performance and VO2 (max) were significantly reduced in the IT group over time and condition, indicating that a state of overreaching was attained. However, the only biochemical measure that was significantly different between the IT and NT group was the glutamine to glutamate (Gln/Glu) ratio even though testosterone, testosterone to cortisol (T/C) ratio, plasma glutamate, and CK activity were significantly changed after training in both groups. Positive endurance and power performance changes were observed post-taper in the IT group confirming NFOR. These changes were associated with increases in the T/C ratio and the Gln/Glu ratio and decreases in plasma glutamate and CK activity. These results indicate that although there was no single reliable biochemical marker of NFOR in these athletes, the Gln/Glu ratio and MSFT test may be useful measures for monitoring responses to IT in team sport athletes.

Plasma total cysteine (tCys) concentrations are associated with BMI. To study the relationship between tCys and BMI, we monitored the changes in serum concentrations of tCys and metabolically related compounds in sixty obese patients (BMI 50–60 kg/m2) from before to 1 year after either gastric bypass surgery (mean 30 % weight loss) or duodenal switch surgery (mean 41 % weight loss). A total of fifty-eight healthy persons (BMI 17–31 kg/m2) served as controls. Before surgery, obese patients had modestly (approximately 17 %) higher mean serum tCys, and markedly (>2-fold) higher glutamate concentrations, than controls (P ≤ 0·001 for both). Serial examinations after surgery revealed that gastric bypass patients had no change in tCys concentrations (P = 0·22), while duodenal switch patients showed a modest (approximately 12 %) but significant decrease in tCys (P < 0·001). Total homocysteine concentrations increased in duodenal switch patients but not in gastric bypass patients. Independent of surgery type, serum concentrations of methionine and cystathionine decreased (P < 0·05 for both), while serum glutathione and taurine remained stable. Glutamate concentrations declined, as did γ-glutamyltransferase activity (P < 0·001 for both). These results show that despite 30 % weight loss, and decreases in methionine, cystathionine and glutamate, there was no significant change in serum tCys in patients after gastric bypass surgery. The decrease in tCys in patients undergoing duodenal switch could be related to malabsorption. The present findings do not suggest that BMI is a causal determinant of plasma tCys.

The gut microbiome has been implicated in a variety of physiological states, but controversy over causality remains unresolved. Here, we performed bidirectional Mendelian randomization analyses on 3,432 Chinese individuals with whole-genome, whole-metagenome, anthropometric and blood metabolic trait data. We identified 58 causal relationships between the gut microbiome and blood metabolites, and replicated 43 of them. Increased relative abundances of fecal Oscillibacter and Alistipes were causally linked to decreased triglyceride concentration. Conversely, blood metabolites such as glutamic acid appeared to decrease fecal Oxalobacter , and members of Proteobacteria were influenced by metabolites such as 5-methyltetrahydrofolic acid, alanine, glutamate and selenium. Two-sample Mendelian randomization with data from Biobank Japan partly corroborated results with triglyceride and with uric acid, and also provided causal support for published fecal bacterial markers for cancer and cardiovascular diseases. This study illustrates the value of human genetic information to help prioritize gut microbial features for mechanistic and clinical studies. Bidirectional Mendelian randomization analyses in 3,432 Chinese individuals identify putative causal relationships between the gut microbiome and blood metabolite levels.

Objectives: L-ornithine has an important role in ammonia metabolism via the urea cycle. This study aimed to examine the effect of L-ornithine hydrochloride ingestion on performance during incremental exhaustive ergometer bicycle exercise and ammonia metabolism during and after exercise. Subjects/Methods: In all, 14 healthy young adults (age: 22.2±1.0 years, height: 173.5±4.6 cm, body mass: 72.5±12.5 kg) who trained regularly conducted incremental exhaustive ergometer bicycle exercises after -ornithine hydrochloride supplementation (0.1 g/kg, body mass) and placebo conditions with a cross-over design. The exercise time (sec) of the incremental ergometer exercise, exercise intensity at exhaustion (watt), maximal oxygen uptake (ml per kg per min), maximal heart rate (beats per min) and the following serum parameters were measured before ingestion, 1 h after ingestion, just after exhaustion and 15 min after exhaustion: ornithine, ammonia, urea, lactic acid and glutamate. All indices on maximal aerobic capacity showed insignificant differences between both the conditions. Results: Plasma ammonia concentrations just after exhaustion and at 15 min after exhaustion were significantly more with ornithine ingestion than with placebo. Plasma glutamate concentrations were significantly higher after exhaustion with ornithine ingestion than with placebo. Conclusions: It was suggested that, although the ingestion of L-ornithine hydrochloride before the exercise cannot be expected to improve performance, it does increase the ability to buffer ammonia, both during and after exercise.

Composition of gut bacteria and serum metabolites in young, obese individuals is partially restored following weight loss surgery, including Bacteroides thetaiotaomicron , which decreases serum glutamate levels and fat mass gain in mice. Emerging evidence has linked the gut microbiome to human obesity. We performed a metagenome-wide association study and serum metabolomics profiling in a cohort of lean and obese, young, Chinese individuals. We identified obesity-associated gut microbial species linked to changes in circulating metabolites. The abundance of Bacteroides thetaiotaomicron , a glutamate-fermenting commensal, was markedly decreased in obese individuals and was inversely correlated with serum glutamate concentration. Consistently, gavage with B. thetaiotaomicron reduced plasma glutamate concentration and alleviated diet-induced body-weight gain and adiposity in mice. Furthermore, weight-loss intervention by bariatric surgery partially reversed obesity-associated microbial and metabolic alterations in obese individuals, including the decreased abundance of B. thetaiotaomicron and the elevated serum glutamate concentration. Our findings identify previously unknown links between intestinal microbiota alterations, circulating amino acids and obesity, suggesting that it may be possible to intervene in obesity by targeting the gut microbiota.