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1.
Genetic Studies of Metabolomics Change After a Liquid Meal Illuminate Novel Pathways for Glucose and Lipid Metabolism.
Li-Gao, R, Hughes, DA, van Klinken, JB, de Mutsert, R, Rosendaal, FR, Mook-Kanamori, DO, Timpson, NJ, Willems van Dijk, K
Diabetes. 2021;(12):2932-2946
Abstract
Humans spend the greater part of the day in a postprandial state. However, the genetic basis of postprandial blood measures is relatively uncharted territory. We examined the genetics of variation in concentrations of postprandial metabolites (t = 150 min) in response to a liquid mixed meal through genome-wide association studies (GWAS) performed in the Netherlands Epidemiology of Obesity (NEO) study (n = 5,705). The metabolite response GWAS identified an association between glucose change and rs10830963:G in the melatonin receptor 1B (β [SE] -0.23 [0.03], P = 2.15 × 10-19). In addition, the ANKRD55 locus led by rs458741:C showed strong associations with extremely large VLDL (XXLVLDL) particle response (XXLVLDL total cholesterol: β [SE] 0.17 [0.03], P = 5.76 × 10-10; XXLVLDL cholesterol ester: β [SE] 0.17 [0.03], P = 9.74 × 10-10), which also revealed strong associations with body composition and diabetes in the UK Biobank (P < 5 × 10-8). Furthermore, the associations between XXLVLDL response and insulinogenic index, HOMA-β, Matsuda insulin sensitivity index, and HbA1c in the NEO study implied the role of chylomicron synthesis in diabetes (with false discovery rate-corrected q <0.05). To conclude, genetic studies of metabolomics change after a liquid meal illuminate novel pathways for glucose and lipid metabolism. Further studies are warranted to corroborate biological pathways of the ANKRD55 locus underlying diabetes.
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Effect of Dapagliflozin on Urine Metabolome in Patients with Type 2 Diabetes.
Bletsa, E, Filippas-Dekouan, S, Kostara, C, Dafopoulos, P, Dimou, A, Pappa, E, Chasapi, S, Spyroulias, G, Koutsovasilis, A, Bairaktari, E, et al
The Journal of clinical endocrinology and metabolism. 2021;(5):1269-1283
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Abstract
CONTEXT Inhibitors of sodium-glucose cotransporters-2 have cardio- and renoprotective properties. However, the underlying mechanisms remain indeterminate. OBJECTIVE To evaluate the effect of dapagliflozin on renal metabolism assessed by urine metabolome analysis in patients with type 2 diabetes. DESIGN Prospective cohort study. SETTING Outpatient diabetes clinic of a tertiary academic center. PATIENTS Eighty patients with hemoglobin A1c > 7% on metformin monotherapy were prospectively enrolled. INTERVENTION Fifty patients were treated with dapagliflozin for 3 months. To exclude that the changes observed in urine metabolome were merely the result of the improvement in glycemia, 30 patients treated with insulin degludec were used for comparison. MAIN OUTCOME MEASURE Changes in urine metabolic profile before and after the administration of dapagliflozin and insulin degludec were assessed by proton-nuclear magnetic resonance spectroscopy. RESULTS In multivariate analysis urine metabolome was significantly altered by dapagliflozin (R2X = 0.819, R2Y = 0.627, Q2Y = 0.362, and coefficient of variation analysis of variance, P < 0.001) but not insulin. After dapagliflozin, the urine concentrations of ketone bodies, lactate, branched chain amino acids (P < 0.001), betaine, myo-inositol (P < 0001), and N-methylhydantoin (P < 0.005) were significantly increased. Additionally, the urine levels of alanine, creatine, sarcosine, and citrate were also increased (P < 0001, P <0.0001, and P <0.0005, respectively) whereas anserine decreased (P < 0005). CONCLUSIONS Dapagliflozin significantly affects urine metabolome in patients with type 2 diabetes in a glucose lowering-independent way. Most of the observed changes can be considered beneficial and may contribute to the renoprotective properties of dapagliflozin.
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Leptin-Mediated Changes in the Human Metabolome.
Lawler, K, Huang-Doran, I, Sonoyama, T, Collet, TH, Keogh, JM, Henning, E, O'Rahilly, S, Bottolo, L, Farooqi, IS
The Journal of clinical endocrinology and metabolism. 2020;(8):2541-52
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CONTEXT While severe obesity due to congenital leptin deficiency is rare, studies in patients before and after treatment with leptin can provide unique insights into the role that leptin plays in metabolic and endocrine function. OBJECTIVE The aim of this study was to characterize changes in peripheral metabolism in people with congenital leptin deficiency undergoing leptin replacement therapy, and to investigate the extent to which these changes are explained by reduced caloric intake. DESIGN Ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) was used to measure 661 metabolites in 6 severely obese people with congenital leptin deficiency before, and within 1 month after, treatment with recombinant leptin. Data were analyzed using unsupervised and hypothesis-driven computational approaches and compared with data from a study of acute caloric restriction in healthy volunteers. RESULTS Leptin replacement was associated with class-wide increased levels of fatty acids and acylcarnitines and decreased phospholipids, consistent with enhanced lipolysis and fatty acid oxidation. Primary and secondary bile acids increased after leptin treatment. Comparable changes were observed after acute caloric restriction. Branched-chain amino acids and steroid metabolites decreased after leptin, but not after acute caloric restriction. Individuals with severe obesity due to leptin deficiency and other genetic obesity syndromes shared a metabolomic signature associated with increased BMI. CONCLUSION Leptin replacement was associated with changes in lipolysis and substrate utilization that were consistent with negative energy balance. However, leptin's effects on branched-chain amino acids and steroid metabolites were independent of reduced caloric intake and require further exploration.
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Compositional and Functional Adaptations of Intestinal Microbiota and Related Metabolites in CKD Patients Receiving Dietary Protein Restriction.
Wu, IW, Lee, CC, Hsu, HJ, Sun, CY, Chen, YC, Yang, KJ, Yang, CW, Chung, WH, Lai, HC, Chang, LC, et al
Nutrients. 2020;(9)
Abstract
The relationship between change of gut microbiota and host serum metabolomics associated with low protein diet (LPD) has been unraveled incompletely in CKD patients. Fecal 16S rRNA gene sequencing and serum metabolomics profiling were performed. We reported significant changes in the β-diversity of gut microbiota in CKD patients having LPD (CKD-LPD, n = 16). We identified 19 genera and 12 species with significant differences in their relative abundance among CKD-LPD patients compared to patients receiving normal protein diet (CKD-NPD, n = 27) or non-CKD controls (n = 34), respectively. CKD-LPD had a significant decrease in the abundance of many butyrate-producing bacteria (family Lachnospiraceae and Bacteroidaceae) associated with enrichment of functional module of butanoate metabolism, leading to concomitant reduction in serum levels of SCFA (acetic, heptanoic and nonanoic acid). A secondary bile acid, glyco λ-muricholic acid, was significantly increased in CKD-LPD patients. Serum levels of indoxyl sulfate and p-cresyl sulfate did not differ among groups. The relationship between abundances of microbes and metabolites remained significant in subset of resampling subjects of comparable characteristics. Enrichment of bacterial gene markers related to D-alanine, ketone bodies and glutathione metabolism was noted in CKD-LPD patients. Our analyses reveal signatures and functions of gut microbiota to adapt dietary protein restriction in renal patients.
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Metabolomic effects of androgen deprivation therapy treatment for prostate cancer.
Chi, JT, Lin, PH, Tolstikov, V, Oyekunle, T, Chen, EY, Bussberg, V, Greenwood, B, Sarangarajan, R, Narain, NR, Kiebish, MA, et al
Cancer medicine. 2020;(11):3691-3702
Abstract
Androgen deprivation therapy (ADT) is the main treatment strategy for men with metastatic prostate cancer (PC). However, ADT is associated with various metabolic disturbances, including impaired glucose tolerance, insulin resistance and weight gain, increasing risk of diabetes and cardiovascular death. Much remains unknown about the metabolic pathways and disturbances altered by ADT and the mechanisms. We assessed the metabolomic effects of ADT in the serum of 20 men receiving ADT. Sera collected before (baseline), 3 and 6 months after initiation of ADT was used for the metabolomics and lipidomics analyses. The ADT-associated metabolic changes were identified by univariable and multivariable statistical analysis, ANOVA, and Pearson correlation. We found multiple key changes. First, ADT treatments reduced the steroid synthesis as reflected by the lower androgen sulfate and other steroid hormones. Greater androgen reduction was correlated with higher serum glucose levels, supporting the diabetogenic role of ADT. Second, ADT consistently decreased the 3-hydroxybutyric acid and ketogenesis. Third, many acyl-carnitines were reduced, indicating the effects on the fatty acid metabolism. Fourth, ADT was associated with a corresponding reduction in 3-formyl indole (a.k.a. indole-3-carboxaldehyde), a microbiota-derived metabolite from the dietary tryptophan. Indole-3-carboxaldehyde is an agonist for the aryl hydrocarbon receptor and regulates the mucosal reactivity and inflammation. Together, these ADT-associated metabolomic analyses identified reduction in steroid synthesis and ketogenesis as prominent features, suggesting therapeutic potential of restricted ketogenic diets, though this requires formal testing. ADT may also impact the microbial production of indoles related to the immune pathways. Future research is needed to determine the functional impact and underlying mechanisms to prevent ADT-linked comorbidities and diabetes risk.
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Metabolomic signature of exposure and response to citalopram/escitalopram in depressed outpatients.
Bhattacharyya, S, Ahmed, AT, Arnold, M, Liu, D, Luo, C, Zhu, H, Mahmoudiandehkordi, S, Neavin, D, Louie, G, Dunlop, BW, et al
Translational psychiatry. 2019;(1):173
Abstract
Metabolomics provides valuable tools for the study of drug effects, unraveling the mechanism of action and variation in response due to treatment. In this study we used electrochemistry-based targeted metabolomics to gain insights into the mechanisms of action of escitalopram/citalopram focusing on a set of 31 metabolites from neurotransmitter-related pathways. Overall, 290 unipolar patients with major depressive disorder were profiled at baseline, after 4 and 8 weeks of drug treatment. The 17-item Hamilton Depression Rating Scale (HRSD17) scores gauged depressive symptom severity. More significant metabolic changes were found after 8 weeks than 4 weeks post baseline. Within the tryptophan pathway, we noted significant reductions in serotonin (5HT) and increases in indoles that are known to be influenced by human gut microbial cometabolism. 5HT, 5-hydroxyindoleacetate (5HIAA), and the ratio of 5HIAA/5HT showed significant correlations to temporal changes in HRSD17 scores. In the tyrosine pathway, changes were observed in the end products of the catecholamines, 3-methoxy-4-hydroxyphenylethyleneglycol and vinylmandelic acid. Furthermore, two phenolic acids, 4-hydroxyphenylacetic acid and 4-hydroxybenzoic acid, produced through noncanconical pathways, were increased with drug exposure. In the purine pathway, significant reductions in hypoxanthine and xanthine levels were observed. Examination of metabolite interactions through differential partial correlation networks revealed changes in guanosine-homogentisic acid and methionine-tyrosine interactions associated with HRSD17. Genetic association studies using the ratios of these interacting pairs of metabolites highlighted two genetic loci harboring genes previously linked to depression, neurotransmission, or neurodegeneration. Overall, exposure to escitalopram/citalopram results in shifts in metabolism through noncanonical pathways, which suggest possible roles for the gut microbiome, oxidative stress, and inflammation-related mechanisms.
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The plasma metabolome of women in early pregnancy differs from that of non-pregnant women.
Handelman, SK, Romero, R, Tarca, AL, Pacora, P, Ingram, B, Maymon, E, Chaiworapongsa, T, Hassan, SS, Erez, O
PloS one. 2019;(11):e0224682
Abstract
BACKGROUND In comparison to the non-pregnant state, the first trimester of pregnancy is characterized by systemic adaptation of the mother. The extent to which these adaptive processes are reflected in the maternal blood metabolome is not well characterized. OBJECTIVE To determine the differences between the plasma metabolome of non-pregnant and pregnant women before 16 weeks gestation. STUDY DESIGN This study included plasma samples from 21 non-pregnant women and 50 women with a normal pregnancy (8-16 weeks of gestation). Combined measurements by ultrahigh performance liquid chromatography/tandem mass spectrometry and by gas chromatography/mass spectrometry generated molecular abundance measurements for each sample. Molecular species detected in at least 10 samples were included in the analysis. Differential abundance was inferred based on false discovery adjusted p-values (FDR) from Mann-Whitney-Wilcoxon U tests <0.1 and a minimum median abundance ratio (fold change) of 1.5. Alternatively, metabolic data were quantile normalized to remove sample-to-sample differences in the overall metabolite abundance (adjusted analysis). RESULTS Overall, 637 small molecules met the inclusion criteria and were tested for association with pregnancy; 44% (281/637) of small molecules had significantly different abundance, of which 81% (229/281) were less abundant in pregnant than in non-pregnant women. Eight percent (14/169) of the metabolites that remained significant in the adjusted analysis also changed as a function of gestational age. A pathway analysis revealed enrichment in steroid metabolites related to sex hormones, caffeine metabolites, lysolipids, dipeptides, and polypeptide bradykinin derivatives (all, FDR < 0.1). CONCLUSIONS This high-throughput mass spectrometry study identified: 1) differences between pregnant vs. non-pregnant women in the abundance of 44% of the profiled plasma metabolites, including known and novel molecules and pathways; and 2) specific metabolites that changed with gestational age.
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Metabolomic change due to combined treatment with myo-inositol, D-chiro-inositol and glucomannan in polycystic ovarian syndrome patients: a pilot study.
Troisi, J, Cinque, C, Giugliano, L, Symes, S, Richards, S, Adair, D, Cavallo, P, Sarno, L, Scala, G, Caiazza, M, et al
Journal of ovarian research. 2019;(1):25
Abstract
BACKGROUND Polycystic ovarian syndrome (PCOS) is a highly variable syndrome and one of the most common female endocrine disorders. Although the association inositols-glucomannan may represent a good therapeutic strategy in the treatment of PCOS women with insulin resistance, the effect of inositols on the metabolomic profile of these women has not been described yet. RESULTS Fifteen PCOS-patients and 15 controls were enrolled. Patients were treated with myo-inositol (1.75 g/day), D-chiro-inositol (0.25 g/day) and glucomannan (4 g/day) for 3 months. Blood concentrations of glucose, insulin, triglycerides and cholesterol, and ovary volumes and antral follicles count, as well as metabolomic profiles, were evaluated for control subjects and for cases before and after treatment. PCOS-patients had higher BMI compared with Controls, BMI decreased significantly after 3 months of treatment although it remained significantly higher compared to controls. 3-methyl-1-hydroxybutyl-thiamine-diphosphate, valine, phenylalanine, ketoisocapric, linoleic, lactic, glyceric, citric and palmitic acid, glucose, glutamine, creatinine, arginine, choline and tocopherol emerged as the most relevant metabolites for distinguishing cases from controls. CONCLUSION Our pilot study has identified a complex network of serum molecules that appear to be correlated with PCOS, and with a combined treatment with inositols and glucomannan. TRIAL REGISTRATION ClinicalTial.gov, NCT03608813 . Registered 1st August 2018 - Retrospectively registered, .
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Chronic kidney disease attenuates the plasma metabolome response to insulin.
Roshanravan, B, Zelnick, LR, Djucovic, D, Gu, H, Alvarez, JA, Ziegler, TR, Gamboa, JL, Utzschneider, K, Kestenbaum, B, Himmelfarb, J, et al
JCI insight. 2018;(16)
Abstract
Chronic kidney disease (CKD) leads to decreased sensitivity to the metabolic effects of insulin, contributing to protein energy wasting and muscle atrophy. Targeted metabolomics profiling during hyperinsulinemic-euglycemic insulin clamp testing may help identify aberrant metabolic pathways contributing to insulin resistance in CKD. Using targeted metabolomics profiling, we examined the plasma metabolome in 95 adults without diabetes in the fasted state (58 with CKD, 37 with normal glomerular filtration rate [GFR]) who underwent hyperinsulinemic-euglycemic clamp. We assessed heterogeneity in fasting metabolites and the response to insulin to identify potential metabolic pathways linking CKD with insulin resistance. Baseline differences and effect modification by CKD status on changes with insulin clamp testing were adjusted for confounders. Mean GFR among participants with CKD was 37.3 compared with 89.3 ml/min per 1.73 m2 among controls. Fasted-state differences between CKD and controls included abnormalities in tryptophan metabolism, ubiquinone biosynthesis, and the TCA cycle. Insulin infusion markedly decreased metabolite levels, predominantly amino acids and their metabolites. CKD was associated with attenuated insulin-induced changes in nicotinamide, arachidonic acid, and glutamine/glutamate metabolic pathways. Metabolomics profiling suggests disruption in amino acid metabolism and mitochondrial function as putative manifestations or mechanisms of the impaired anabolic effects of insulin in CKD.
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Statin Effects on Metabolic Profiles: Data From the PREVEND IT (Prevention of Renal and Vascular End-stage Disease Intervention Trial).
Kofink, D, Eppinga, RN, van Gilst, WH, Bakker, SJL, Dullaart, RPF, van der Harst, P, Asselbergs, FW
Circulation. Cardiovascular genetics. 2017;(6)
Abstract
BACKGROUND Statins lower cholesterol by inhibiting HMG-CoA reductase, the rate-limiting enzyme of the metabolic pathway that produces cholesterol and other isoprenoids. Little is known about their effects on metabolite and lipoprotein subclass profiles. We, therefore, investigated the molecular changes associated with pravastatin treatment compared with placebo administration using a nuclear magnetic resonance-based metabolomics platform. METHODS AND RESULTS We performed metabolic profiling of 231 lipoprotein and metabolite measures in the PREVEND IT (Prevention of Renal and Vascular End-stage Disease Intervention Trial) study, a placebo-controlled randomized clinical trial designed to test the effects of pravastatin (40 mg once daily) on cardiovascular risk. Metabolic profiles were assessed at baseline and after 3 months of treatment. Pravastatin lowered low-density lipoprotein cholesterol (change in SD units [95% confidence interval]: -1.01 [-1.14, -0.88]), remnant cholesterol (change in SD units [95% confidence interval]: -1.03 [-1.17, -0.89]), and apolipoprotein B (change in SD units [95% confidence interval]: -0.98 [-1.11, -0.86]) with similar effect magnitudes. In addition, pravastatin globally lowered levels of lipoprotein subclasses, with the exception of high-density lipoprotein subclasses, which displayed a more heterogeneous response pattern. The lipid-lowering effect of pravastatin was accompanied by selective changes in lipid composition, particularly in the cholesterol content of very-low-density lipoproteinparticles. In addition, pravastatin reduced levels of several fatty acids but had limited effects on fatty acid ratios. CONCLUSIONS These randomized clinical trial data demonstrate the widespread effects of pravastatin treatment on lipoprotein subclass profiles and fatty acids. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT03073018.