Valerylcarnitine

Metabolomics Signatures in Type 2 Diabetes: A Systematic Review and Integrative Analysis

Objective: Metabolic signatures have emerged as valuable signaling molecules in the biochemical process of type 2 diabetes (T2D). To summarize and identify metabolic biomarkers in T2D, we performed a systematic review and meta-analysis of the associations between metabolites and T2D using high-throughput metabolomics techniques. Methods: We searched relevant studies from MEDLINE (PubMed), Embase, Web of Science, and Cochrane Library as well as Chinese databases (Wanfang, Vip, and CNKI) inception through 31 December 2018. Meta-analysis was conducted using STATA 14.0 under random effect. Besides, bioinformatic analysis was performed to explore molecule mechanism by MetaboAnalyst and R 3.5.2. Results: Finally, 46 articles were included in this review on metabolites involved amino acids, acylcarnitines, lipids, carbohydrates, organic acids, and others. Results of meta-analysis in prospective studies indicated that isoleucine, leucine, valine, tyrosine, phenylalanine, glutamate, alanine, valerylcarnitine (C5), palmitoylcarnitine (C16), palmitic acid, and linoleic acid were associated with higher T2D risk. Conversely, serine, glutamine, and lysophosphatidylcholine C18:2 decreased risk of T2D. Arginine and glycine increased risk of T2D in the Western countries subgroup, and betaine was negatively correlated with T2D in nested case-control subgroup. In addition, slight improvements in T2D prediction beyond traditional risk factors were observed when adding these metabolites in predictive analysis. Pathway analysis identified 17 metabolic pathways may alter in the process of T2D and metabolite-related genes were also enriched in functions and pathways associated with T2D. Conclusions: Several metabolites and metabolic pathways associated with T2D have been identified, which provide valuable biomarkers and novel targets for prevention and drug therapy.

Factors associated with elevated plasma phenylalanine in patients with heart failure

Elevated phenylalanine has been observed in patients with advanced heart failure (HF) and in community cohorts at risk of HF, and has been shown to have prognostic value. This study aimed to explore the factors associated with elevated phenylalanine in HF patients. Mass spectrometry was performed on blood from 669 participants, including 75 normal controls and 594 HF patients (stages A, B, and C). We measured phenylalanine and associated degradation products on the catecholamine pathway, C-reactive protein, valerylcarnitine, methionine sulfoxide, estimated glomerular filtration rate (eGFR), and B-type natriuretic peptide. Longitudinal analysis was conducted on 61 stage C HF patients who had recovered systolic function after 1 year. Phenylalanine and tyrosine levels increased from normal through stages A, B and C. Cross-sectional analysis in patients at stage C showed that phenylalanine levels were related to total bilirubin, eGFR, valerylcarnitine, methionine sulfoxide, C-reactive protein, and male gender. Longitudinal analysis in the patients at stage C with recovered systolic function after 1 year revealed that phenylalanine, tyrosine, methionine sulfoxide, total bilirubin, and C-reactive protein levels significantly decreased from baseline to 12 months. Based on a generalized estimating equations analysis model with time interaction considered, the only significant factor associated with changes in phenylalanine was changes in C-reactive protein concentrations from baseline to 12 months [B (coefficient) = 0.81, P < 0.001] after adjusting for methionine sulfoxide and total bilirubin levels. In conclusion, phenylalanine levels respond sensitively to HF improvement. Our findings suggest that inflammation plays a pivotal role in the elevation of phenylalanine levels in patients with HF.

Determinants of blood acylcarnitine concentrations in healthy individuals of the European Prospective Investigation into Cancer and Nutrition

Background & aims: Circulating levels of acylcarnitines (ACs) have been associated with the risk of various diseases such as cancer and type 2 diabetes. Diet and lifestyle factors have been shown to influence AC concentrations but a better understanding of their biological, lifestyle and metabolic determinants is needed.
Methods: Circulating ACs were measured in blood by targeted (15 ACs) and untargeted metabolomics (50 ACs) in 7770 and 395 healthy participants of the European Prospective Investigation into Cancer and Nutrition (EPIC), respectively. Associations with biological and lifestyle characteristics, dietary patterns, self-reported intake of individual foods, estimated intake of carnitine and fatty acids, and fatty acids in plasma phospholipid fraction and amino acids in blood were assessed.
Results: Age, sex and fasting status were associated with the largest proportion of AC variability (partial-r up to 0.19, 0.18 and 0.16, respectively). Some AC species of medium or long-chain fatty acid moiety were associated with the corresponding fatty acids in plasma (partial-r = 0.24) or with intake of specific foods such as dairy foods containing the same fatty acid. ACs of short-chain fatty acid moiety (propionylcarnitine and valerylcarnitine) were moderately associated with concentrations of branched-chain amino acids (partial-r = 0.5). Intake of most other foods and of carnitine showed little association with AC levels.
Conclusions: Our results show that determinants of ACs in blood vary according to their fatty acid moiety, and that their concentrations are related to age, sex, diet, and fasting status. Knowledge on their potential determinants may help interpret associations of ACs with disease risk and inform on potential dietary and lifestyle factors that might be modified for disease prevention.

A Plasma Metabolomic Profiling of Exudative Age-Related Macular Degeneration Showing Carnosine and Mitochondrial Deficiencies

To determine the plasma metabolomic profile of exudative age-related macular degeneration (AMD), we performed a targeted metabolomics study on the plasma from patients (n = 40, mean age = 81.1) compared to an age- and sex-matched control group (n = 40, mean age = 81.8). All included patients had documented exudative AMD, causing significant visual loss (mean logMAR visual acuity = 0.63), compared to the control group. Patients and controls did not differ in terms of body mass index and co-morbidities. Among the 188 metabolites analyzed, 150 (79.8%) were accurately measured. The concentrations of 18 metabolites were significantly modified in the AMD group, but only six of them remained significantly different after Benjamini-Hochberg correction. Valine, lysine, carnitine, valerylcarnitine and proline were increased, while carnosine, a dipeptide disclosing anti-oxidant and anti-glycating properties, was, on average, reduced by 50% in AMD compared to controls. Moreover, carnosine was undetectable for 49% of AMD patients compared to 18% in the control group (p-value = 0.0035). Carnitine is involved in the transfer of fatty acids within the mitochondria; proline, lysine and valerylcarnitine are substrates for mitochondrial electrons transferring flavoproteins, and proline is one of the main metabolites supplying energy to the retina. Overall, our results reveal six new metabolites involved in the plasma metabolomic profile of exudative AMD, suggesting mitochondrial energetic impairments and carnosine deficiency.

Targeted Metabolomics of Nonhuman Primate Serum after Exposure to Ionizing Radiation: Potential Tools for High-throughput Biodosimetry

There is a need for research to rapidly determine an individual's absorbed dose and its potential health effects after a potential radiological or nuclear event that could expose large portions of a population to ionizing radiation (IR). Studies on biomarker identification after radiation exposure could aid in biodosimetry, identifying individual dose absorbed, as well as biologic response, and administering immediate and proper medical care. Metabolomics on easily accessible biofluids is an emerging field with potential for high-throughput biodosimetry. While tremendous effort has been put into obtaining discovery based global radiation signatures from a number of biofluids and model organisms, quantitative targeted analysis on a subset of known radiation biomarkers is required to develop an optimized panel of biomarkers for future clinical applications. The current study analyzes levels of several known broad chemical groups (acylcarnitines, amino acids, phosphatidylcholines, and biogenic amines) affected by IR in serum from nonhuman primates (NHP) 7 days after exposure through multiple reaction monitoring (MRM) analysis with a triple quadrupole mass spectrometry (MS) platform. We identified several novel metabolites affected by IR exposure through univariate and unsupervised multivariate analyses. Levels of acylcarnitines, amino acids, and phospholipids were perturbed indicating altered protein metabolism, fatty acid β-oxidation, and inflammation. Fold changes in carnitine and short-chain acylcarnitines (acetylcarnitine, propionylcarnitine, butyrylcarnitine, and valerylcarnitine) complement previous global radiation signatures on NHP; notably, the levels of change were lower than previously observed in urine. Decreased levels of glutamate, citrulline, and arginine after IR are biomarkers indicating gastrointestinal syndrome and perturbations to the urea cycle. Sex differences were also assessed and were more prevalent in circulating acylcarnitines and phospholipids after IR exposure. These biomarkers may be combined with previously described compounds from DNA damage to develop a defined metabolomic biodosimetry panel to be analyzed by MS platforms, which are increasingly available in clinical laboratories.