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    Biotransformation of 5,7-Methoxyflavones by Selected Entomopathogenic Filamentous Fungi. Łużny Mateusz,Tronina Tomasz,Kozłowska Ewa,Kostrzewa-Susłow Edyta,Janeczko Tomasz Journal of agricultural and food chemistry 5,7-Dimethoxyflavone, a chrysin derivative, occurs in many plants and shows very low toxicity, even at high doses. On the basis of this phenomenon, we biotransformed a series of methoxy-derivatives of chrysin, apigenin, and tricetin obtained by chemical synthesis. We used entomopathogenic fungal strains with the confirmed ability of simultaneous hydroxylation/demethylation and glycosylation of flavonoid compounds. Both the amount and the place of attachment of the methoxy group influenced the biotransformation rate and the product's amount nascent. Based on product and semi-product structures, it can be concluded that they are the result of cascading transformations. Only in the case of 5,7,3',4',5'-pentamethoxyflavone, the strains were able to attach a sugar molecule in place of the methoxy substituent to give 3'--β-d-(4″--methylglucopyranosyl)-5,7,4',5'-tetramethoxyflavone. However, we observed the tested strains' ability to selectively demethylate/hydroxylate the carbon C-3' and C-4' of ring B of the substrates used. The structures of four hydroxyl-derivatives were determined: 4'-hydroxy-5,7-dimethoxyflavone, 3'-hydroxy-5,7-dimethoxyflavone, 3'-hydroxy-5,7,4',5'-tetramethoxyflavone, and 5,7-dimethoxy-3',4'-dihydroxyflavone (5,7-dimethoxy-luteolin). 10.1021/acs.jafc.1c00136
    Chickpea Extract Ameliorates Metabolic Syndrome Symptoms via Restoring Intestinal Ecology and Metabolic Profile in Type 2 Diabetic Rats. Li Pei,Lu Biyu,Gong Jing,Li Lin,Chen Guoping,Zhang Jiaxian,Chen Yongda,Tian Xing,Han Bo,Guo Yake,Xie Zhiyong,Liao Qiongfeng Molecular nutrition & food research SCOPE:Chickpeas have been recognized as a natural Uyghur medicine in Xinjiang (China) for 2500 years. Although the phenotypic effect on obesity or diabetes was authenticated, the mechanism was unclear. This work aims to study the effect of chickpea extract (CE) on metabolic syndrome induced by type 2 diabetes and to reveal its related mechanisms, focusing on intestinal flora and metabolomics. METHODS AND RESULTS:Diabetic rats are induced by a high-fat diet and intraperitoneal injection of streptozotocin. CE supplementation (3 g kg ) for 4 weeks improved the hyperglycemia, inflammatory state, and organ functions of diabetic rats. The metabolic profile trajectories of urine and faeces obtained by NMR have good separations among all groups, and CE significantly increases the contents of SCFAs in the cecum. Moreover, CE relieves intestinal dysbiosis by increasing the abundance of SCFAs-producing bacteria (e.g., Enterococcaceae) but reduces conditional pathogenic bacteria (e.g., Corynebacterium). PICRUSt predicts the functions of gut microbiome from the 16S rRNA gene sequences and metagenome, and finds that CE restored amino acids degradation, bile acids metabolism, and carbohydrate metabolism. CONCLUSION:This study elucidates the role of CE from the perspective of metabolomics and the microbiota, which provides evidence for chickpea as a prebiotic to prevent diabetes. 10.1002/mnfr.202100007
    Probiotics Mediated Modulation of Gut-Flora Might Be a Biotherapeutical Approach for Obesity and Type 2 Diabetes. Yadav Hariom,Jain Shalini,Marotta Francesco Metabolomics : open access 10.4172/2153-0769.1000107e
    Dose-Related Urinary Metabolic Alterations of a Combination of Quercetin and Resveratrol-Treated High-Fat Diet Fed Rats. Zhuang Tongxi,Liu Xinhua,Wang Wen,Song Jing,Zhao Le,Ding Lili,Yang Li,Zhou Mingmei Frontiers in pharmacology Most herbal polyphenols and flavonoids reveals multiple ameliorative benefits for obesity caused by chronic metabolic disorders. Accumulated studies have revealed that preferable therapeutic effects can be obtained through clinical combination of these two kinds of natural compounds for obesity improvement. The typical representative research was the combination of quercetin and resveratrol (CQR), in which the ratio of quercetin and resveratrol is 2:1, demonstrating a synergistic effect in anti-obesity process. Although there exists reports clarifying the mechanism of the combination of two to improve obesity from the perspective of improving adipose tissue inflammation or modulating the composition of intestinal flora, there are few further studies on the mechanism of drug action from the perspective of metabolites transformation. In this research, we mainly focused on the alterations of endogenous metabolites in rats, and analyzed the urine metabolites of obese and intervention model. Therefore, a gas chromatography-mass spectrometry (GC-MS) based metabolomics approach was applied to assess the potential effects and mechanisms of CQR at different dosages (45, 90, and 180 mg/kg) in high fat diet (HFD)-induced obesity rats. Body weight gain and visceral fat weight were reduced by CQR, as well as blood lipid and inflammatory factor levels were increased by CQR in a dose-related manner. Urinary metabolomics revealed 22 differential metabolites related to the HFD-induced obesity, which were reversed in a dose-dependent manner by CQR, of which 8 were reversed in the 45 mg/kg CQR group, 15 were reversed in the 90 mg/kg CQR group, and 18 were reversed in the 180 mg/kg CQR group. Combined with bioinformatics and pattern recognition, the results demonstrated that the key differential metabolites were basically involved in amino acid metabolism, galactose metabolism, pantothenate and CoA biosynthesis, pyruvate metabolism and lysine degradation. In summary, our results showed significant therapeutic action by CQR administration and remarkable metabolomic changes after HFD feeding and CQR intervention. Urinary metabolomic analysis was highlighted on account of providing holistic and comprehensive insights into the pathophysiological mechanisms of the HFD-induced obesity, which also supplied clues for the future mechanism studies of CQR's anti-obesity effects. 10.3389/fphar.2021.655563
    Gut microbiome-derived metabolites characterize a peculiar obese urinary metabotype. Calvani R,Miccheli A,Capuani G,Tomassini Miccheli A,Puccetti C,Delfini M,Iaconelli A,Nanni G,Mingrone G International journal of obesity (2005) Obesity is a complex multifactorial disease involving genetic and environmental factors and influencing several different metabolic pathways. In this regard, metabonomics, that is the study of complex metabolite profiles in biological samples, may provide a systems approach to understand the global metabolic regulation of the organism in relation to this peculiar pathology. In this pilot study, we have applied a nuclear magnetic resonance (NMR)-based metabolomic approach on urinary samples of morbidly obese subjects. Urine samples of 15 morbidly obese insulin-resistant (body mass index>40; homeostasis assessment model of insulin resistance>3) male patients and 10 age-matched controls were collected, frozen and analyzed by high-resolution (1)H-NMR spectroscopy combined with partial least squares-discriminant analysis. Furthermore, two obese patients who underwent bariatric surgery (biliopancreatic diversion and gastric bypass, respectively) were monitored during the first 3 months after surgery and their urinary metabolic profiles were characterized. NMR-based metabolomic analysis allowed us to identify an obesity-associated metabolic phenotype (metabotype) that differs from that of lean controls. Gut flora-derived metabolites such as hippuric acid, trigonelline, 2-hydroxyisobutyrate and xanthine contributed most to the classification model and were responsible for the discrimination. These preliminary results confirmed that in humans the gut microflora metabolism is strongly linked to the obesity phenotype. Moreover, the typical obese metabotype is lost after weight loss induced by bariatric surgery. 10.1038/ijo.2010.44
    Effects of triphenyl phosphate exposure during fetal development on obesity and metabolic dysfunctions in adult mice: Impaired lipid metabolism and intestinal dysbiosis. Wang Dezhen,Yan Sen,Yan Jin,Teng Miaomiao,Meng Zhiyuan,Li Ruisheng,Zhou Zhiqiang,Zhu Wentao Environmental pollution (Barking, Essex : 1987) Previous in vitro studies have implied that triphenyl phosphate (TPHP) may act as an obesogen. However, its specific contributions to the progression of obesity and related metabolic diseases are still unclear in vivo in mice. In this study, we evaluated the effects of in utero and lactational exposure to three doses of TPHP (10, 100, and 1000 μg/kg BW) on obesity and metabolic dysfunctions in adult male mice fed a low-fat diet (LFD) or high-fat diet (HFD), by examining body weight, liver weight, histopathology, blood biochemistry, gene expression, and gut microbiota compositions and metabolic functions. Results showed that TPHP exposure led to increased body weight, liver weight, fat mass, hepatic steatosis, impaired glucose homeostasis, and insulin resistance, and mRNA levels of genes involved in lipid metabolism, especially lipogenesis and lipid accumulation, were significantly altered by TPHP treatment. Gas chromatography-mass spectrometry (GC-MS) analysis further supported the changes in fatty acid composition. Intestinal flora measurements by 16S rRNA gene sequencing and H NMR based fecal metabolomics indicated that TPHP treatment modulated gut microbiome composition and influenced host-gut co-metabolism, especially for bile acids and short chain fatty acids (SCFAs). These results suggest that fetal exposure to TPHP can promote the development of obesity and metabolic dysfunctions in adult mice. 10.1016/j.envpol.2018.12.053
    Targeted metabolomics for the quantitative measurement of 9 gut microbiota-host co-metabolites in rat serum, urine and feces by liquid chromatography-tandem mass spectrometry. Zeng Yifeng,Lin Yixuan,Li Lin,Li Yuan,Zhang Xiaojun,Wang Mengxia,Chen Yongxiong,Luo Liang,Lu Biyu,Xie Zhiyong,Liao Qiongfeng Journal of chromatography. B, Analytical technologies in the biomedical and life sciences Gut microbiota-host co-metabolites play an essential role in maintaining homeostasis, and their concentration changes are closely related to a variety of diseases. Developing a targeted metabolomics analytical platform for these co-metabolites will help to elucidate the relationship between intestinal flora and host. Here we present a simple and sensitive liquid chromatography-tandem mass spectrometry method for the analysis of nine gut microbiota-host co-metabolites in rat serum, urine and feces. The compounds were separated on a reversed-phase C column using gradient elution with a solvent system consisting of methanol and water (containing 0.05% formic acid) and a 7-min run time. All of the calibration curves exhibited good linear relationships (R ≥ 0.9984, Percent Residual Accuracy ≥93.27%). The intra- and interday precision, expressed as relative standard deviation (RSD), was ≤ 14.84%. The accuracy was within 100 ± 13.16% for all analytes. The recovery of the nine compounds in biological samples was ≥ 85.80% with an appropriate RSD (≤12.04%). The validated method was successfully applied to monitor the global changes of these metabolites in obesity. Taken together, these results demonstrate that the method can simultaneously determine the nine co-metabolites in multiple biological matrices and is an essential part of the targeted metabolomics analytical platform, which may become an approach to evaluate the occurrence, development and therapeutic effects of metabolic diseases. 10.1016/j.jchromb.2019.02.019
    Modeling Longitudinal Metabonomics and Microbiota Interactions in C57BL/6 Mice Fed a High Fat Diet. Montoliu Ivan,Cominetti Ornella,Boulangé Claire L,Berger Bernard,Siddharth Jay,Nicholson Jeremy,Martin François-Pierre J Analytical chemistry Longitudinal studies aim typically at following populations of subjects over time and are important to understand the global evolution of biological processes. When it comes to longitudinal omics data, it will often depend on the overall objective of the study, and constraints imposed by the data, to define the appropriate modeling tools. Here, we report the use of multilevel simultaneous component analysis (MSCA), orthogonal projection on latent structures (OPLS), and regularized canonical correlation analysis (rCCA) to study associations between specific longitudinal urine metabonomics data and microbiome data in a diet-induced obesity model using C57BL/6 mice. (1)H NMR urine metabolic profiling was performed on samples collected weekly over a period of 13 weeks, and stool microbial composition was assessed using 16S rRNA gene sequencing at three specific time periods (baseline, first week response, end of study). MSCA and OPLS allowed us to explore longitudinal urine metabonomics data in relation to the dietary groups, as well as dietary effects on body weight. In addition, we report a data integration strategy based on regularized CCA and correlation analyses of urine metabonomics data and 16S rRNA gene sequencing data to investigate the functional relationships between metabolites and gut microbial composition. Thanks to this workflow enabling the breakdown of this data set complexity, the most relevant patterns could be extracted to further explore physiological processes at an anthropometric, cellular, and molecular level. 10.1021/acs.analchem.6b01343
    Sex and puberty-related differences in metabolomic profiles associated with adiposity measures in youth with obesity. Saner Christoph,Harcourt Brooke E,Pandey Ahwan,Ellul Susan,McCallum Zoe,Kao Kung-Ting,Twindyakirana Celia,Pons Anke,Alexander Erin J,Saffery Richard,Burgner David P,Juonala Markus,Sabin Matthew A Metabolomics : Official journal of the Metabolomic Society BACKGROUND:Specific patterns of metabolomic profiles relating to cardiometabolic disease are associated with increased weight in adults. In youth with obesity, metabolomic data are sparse and associations with adiposity measures unknown. OBJECTIVES:Primary, to determine associations between adiposity measures and metabolomic profiles with increased cardiometabolic risks in youth with obesity. Secondary, to stratify associations by sex and puberty. METHODS:Participants were from COBRA (Childhood Overweight BioRepository of Australia; a paediatric cohort with obesity). Adiposity measures (BMI, BMI z-score, %truncal and %whole body fat, waist circumference and waist/height ratio), puberty staging and NMR metabolomic profiles from serum were assessed. Statistics included multivariate analysis (principal component analysis, PCA) and multiple linear regression models with false discovery rate adjustment. RESULTS:214 participants had metabolomic profiles analyzed, mean age 11.9 years (SD ± 3.1), mean BMI z-score 2.49 (SD ± 0.24), 53% females. Unsupervised PCA identified no separable clusters of individuals. Positive associations included BMI z-score and phenylalanine, total body fat % and lipids in medium HDL, and waist circumference and tyrosine; negative associations included total body fat % and the ratio of docosahexaenoic acid/total fatty acids and histidine. Stratifying by sex and puberty, patterns of associations with BMI z-score in post-pubertal males included positive associations with lipid-, cholesterol- and triglyceride-content in VLDL lipoproteins; total fatty acids; total triglycerides; isoleucine, leucine and glycoprotein acetyls. CONCLUSION:In a paediatric cohort with obesity, increased adiposity measures, especially in post-pubertal males, were associated with distinct patterns in metabolomic profiles. 10.1007/s11306-019-1537-y
    Application of NMR-based metabolomics to the study of gut microbiota in obesity. Calvani Riccardo,Brasili Elisa,Praticò Giulia,Sciubba Fabio,Roselli Marianna,Finamore Alberto,Marini Federico,Marzetti Emanuele,Miccheli Alfredo Journal of clinical gastroenterology Lifestyle habits, host gene repertoire, and alterations in the intestinal microbiota concur to the development of obesity. A great deal of research has recently been focused on investigating the role gut microbiota plays in the pathogenesis of metabolic dysfunctions and increased adiposity. Altered microbiota can affect host physiology through several pathways, including enhanced energy harvest, and perturbations in immunity, metabolic signaling, and inflammatory pathways. A broad range of "omics" technologies is now available to help decipher the interactions between the host and the gut microbiota at detailed genetic and functional levels. In particular, metabolomics--the comprehensive analysis of metabolite composition of biological fluids and tissues--could provide breakthrough insights into the links among the gut microbiota, host genetic repertoire, and diet during the development and progression of obesity. Here, we briefly review the most insightful findings on the involvement of gut microbiota in the pathogenesis of obesity. We also discuss how metabolomic approaches based on nuclear magnetic resonance spectroscopy could help understand the activity of gut microbiota in relation to obesity, and assess the effects of gut microbiota modulation in the treatment of this condition. 10.1097/MCG.0000000000000236
    Power of metabolomics in biomarker discovery and mining mechanisms of obesity. Zhang A,Sun H,Wang X Obesity reviews : an official journal of the International Association for the Study of Obesity Obesity, the prevalence of which is increasing rapidly worldwide, is recognized as a risk factor for diabetes, cardiovascular disease, liver disease and renal disease. Unfortunately, the mechanisms underlying it have not been well characterized. Fortunately, metabolomics - the systematic study of metabolites, which are small molecules generated by the process of metabolism - has been important in elucidating the pathways underlying obesity. Small-molecule metabolites have an important role in biological system and represent attractive candidates to understand obesity phenotypes. Metabolomic analysis is a valid and powerful tool with which to further define the mechanisms. Recent attention has focused on identifying biomarkers that would propose a better non-invasive way to detect or visualize obesity and prevent its events. The discovery of the biomarkers has become a key breakthrough towards a better molecular understanding of obesity. Thus, this review covers how recent metabolomic studies have advanced biomarker discovery and the elucidation of mechanisms underlying obesity and its comorbidities. The importance of identifying metabolic markers and pathways of disease-associated intermediate phenotypes is also emphasized. These biomarkers would be applicable as diagnostic tools in a personalized healthcare setting and may also open door to biomarker discovery, disease diagnosis and novel therapeutic avenues. 10.1111/obr.12011
    An individual participant data meta-analysis on metabolomics profiles for obesity and insulin resistance in European children. Hellmuth Christian,Kirchberg Franca F,Brandt Stephanie,Moß Anja,Walter Viola,Rothenbacher Dietrich,Brenner Hermann,Grote Veit,Gruszfeld Dariusz,Socha Piotr,Closa-Monasterolo Ricardo,Escribano Joaquin,Luque Veronica,Verduci Elvira,Mariani Benedetta,Langhendries Jean-Paul,Poncelet Pascale,Heinrich Joachim,Lehmann Irina,Standl Marie,Uhl Olaf,Koletzko Berthold,Thiering Elisabeth,Wabitsch Martin Scientific reports Childhood obesity prevalence is rising in countries worldwide. A variety of etiologic factors contribute to childhood obesity but little is known about underlying biochemical mechanisms. We performed an individual participant meta-analysis including 1,020 pre-pubertal children from three European studies and investigated the associations of 285 metabolites measured by LC/MS-MS with BMI z-score, height, weight, HOMA, and lipoprotein concentrations. Seventeen metabolites were significantly associated with BMI z-score. Sphingomyelin (SM) 32:2 showed the strongest association with BMI z-score (P = 4.68 × 10) and was also closely related to weight, and less strongly to height and LDL, but not to HOMA. Mass spectrometric analyses identified SM 32:2 as myristic acid containing SM d18:2/14:0. Thirty-five metabolites were significantly associated to HOMA index. Alanine showed the strongest positive association with HOMA (P = 9.77 × 10), while acylcarnitines and non-esterified fatty acids were negatively associated with HOMA. SM d18:2/14:0 is a powerful marker for molecular changes in childhood obesity. Tracing back the origin of SM 32:2 to dietary source in combination with genetic predisposition will path the way for early intervention programs. Metabolic profiling might facilitate risk prediction and personalized interventions in overweight children. 10.1038/s41598-019-41449-x
    Targeted High Performance Liquid Chromatography Tandem Mass Spectrometry-based Metabolomics differentiates metabolic syndrome from obesity. Zhong Fanyi,Xu Mengyang,Bruno Richard S,Ballard Kevin D,Zhu Jiangjiang Experimental biology and medicine (Maywood, N.J.) Both obesity and the metabolic syndrome are risk factors for type 2 diabetes and cardiovascular disease. Identification of novel biomarkers are needed to distinguish metabolic syndrome from equally obese individuals in order to direct them to early interventions that reduce their risk of developing further health problems. We utilized mass spectrometry-based targeted metabolic profiling of 221 metabolites to evaluate the associations between metabolite profiles and established metabolic syndrome criteria (i.e. elevated waist circumference, hypertension, elevated fasting glucose, elevated triglycerides, and low high-density lipoprotein cholesterol) in plasma samples from obese men ( n = 29; BMI = 35.5 ± 5.2 kg/m) and women ( n = 40; 34.9 ± 6.7 kg/m), of which 26 met the criteria for metabolic syndrome (17 men and 9 women). Compared to obese individuals without metabolic syndrome, univariate statistical analysis and partial least squares discriminant analysis showed that a specific group of metabolites from multiple metabolic pathways (i.e. purine metabolism, valine, leucine and isoleucine degradation, and tryptophan metabolism) were associated with the presence of metabolic syndrome. Receiver operating characteristic curves generated based on the PLS-DA models showed excellent areas under the curve (0.85 and 0.96, for metabolites only model and enhanced metabolites model, respectively), high specificities (0.86 and 0.93), and good sensitivities (0.71 and 0.91). Moreover, principal component analysis revealed that metabolic profiles can be used to further differentiate metabolic syndrome with 3 versus 4-5 metabolic syndrome criteria. Collectively, these findings support targeted metabolomics approaches to distinguish metabolic syndrome from obesity alone, and to stratify metabolic syndrome status based on the number of criteria met. Impact statement We utilized mass spectrometry-based targeted metabolic profiling of 221 metabolites to evaluate the associations between metabolite profiles and established MetS criteria. To our best knowledge, the findings of this study provide the first evidence that metabolic profiles can be used to differentiate participants with MetS from similarly obese individuals who do not meet established criteria of MetS. Furthermore, the study demonstrated that within MetS participants, their unique metabolic profiles correlated to the number of criteria used for MetS determination. Taken together, this metabolic profiling approach can potentially serve as a novel tool for MetS detection and monitoring, and provide useful metabolic information for future interventions targeting obesity and MetS. 10.1177/1535370217694098
    Serum Metabolomics of Activity Energy Expenditure and its Relation to Metabolic Syndrome and Obesity. Palmnäs Marie S A,Kopciuk Karen A,Shaykhutdinov Rustem A,Robson Paula J,Mignault Diane,Rabasa-Lhoret Rémi,Vogel Hans J,Csizmadi Ilona Scientific reports Modifiable lifestyle factors, including exercise and activity energy expenditure (AEE), may attenuate the unfavorable health effects of obesity, such as risk factors of metabolic syndrome (MetS). However, the underlying mechanisms are not clear. In this study we sought to investigate whether the metabolite profiles of MetS and adiposity assessed by body mass index (BMI) and central obesity are inversely correlated with AEE and physical activity. We studied 35 men and 47 women, aged 30-60 years, using doubly labeled water to derive AEE and the Sedentary Time and Activity Reporting Questionnaire (STAR-Q) to determine the time spent in moderate and vigorous physical activity. Proton nuclear magnetic resonance spectroscopy was used for serum metabolomics analysis. Serine and glycine were found in lower concentrations in participants with more MetS risk factors and greater adiposity. However, serine and glycine concentrations were higher with increasing activity measures. Metabolic pathway analysis and recent literature suggests that the lower serine and glycine concentrations in the overweight/obese state could be a consequence of serine entering de novo sphingolipid synthesis. Taken together, higher levels of AEE and physical activity may play a crucial part in improving metabolic health in men and women with and without MetS risk factors. 10.1038/s41598-018-21585-6
    Undaria pinnatifida improves obesity-related outcomes in association with gut microbiota and metabolomics modulation in high-fat diet-fed mice. Li Lili,Wang Yuting,Yuan Jingyi,Liu Zhengyi,Ye Changqing,Qin Song Applied microbiology and biotechnology Dietary fiber has beneficial effects on obesity-related diseases and gut microbiota, contributing a key role in the interaction between dietary metabolism and host metabolism. Our objective was to investigate the cause of the improvement in multiple types of physiological states with seaweed Undaria pinnatifida treatment on high-fat diet-fed mice and to evaluate whether its consequent anti-adiposity and anti-hyperlipidemic effects are associated with gut microbiota and its metabolomics regulation. U. pinnatifida administration in our experiment was shown to significantly decrease high-fat diet-induced body weight gain, as well as epididymal and abdominal adiposity. U. pinnatifida intake also significantly reduced liver weight and serum triacylglycerol accumulation. We also found that improving effects of U. pinnatifida on high-fat diet-induced metabolic dysfunctions were associated with significant increase in specific bacteria, such as Bacteroides acidifaciens and Bacteroides ovatus, as well as metabolites, including short-chain fatty acids and tricarboxylic acid cycle intermediates. Our result provides a cheap dietary strategy to host metabolism improvement and obesity management. KEY POINTS: • U. pinnatifida improved adipose accumulation and lipid metabolism. • B. acidifaciens and B. ovatus contributed to the beneficial effects of U. pinnatifida. • SCFAs and TCA cycle intermediates were critical to the metabolic outcomes. • Our study provides a cheap dietary strategy for obesity management. 10.1007/s00253-020-10954-9
    Plasma High-Resolution Metabolomics Differentiates Adults with Normal Weight Obesity from Lean Individuals. Bellissimo Moriah P,Cai Qingpo,Ziegler Thomas R,Liu Ken H,Tran Phong H,Vos Miriam B,Martin Greg S,Jones Dean P,Yu Tianwei,Alvarez Jessica A Obesity (Silver Spring, Md.) OBJECTIVE:This study explored underlying metabolism-related dysfunction by examining metabolomic profiles in adults categorized as lean, as having normal weight obesity (NWO), or as having overweight/obesity. METHODS:Participants (N = 179) had fasting plasma analyzed by liquid chromatography and high-resolution mass spectrometry for high-resolution metabolomics. Body composition was assessed by dual-energy x-ray absorptiometry. NWO was defined as BMI < 25 and body fat > 30% for women and > 23% for men. Differentiating metabolomic features were determined by using linear regression models and likelihood ratio tests with false discovery rate correction. Mummichog was used for pathway and network analyses. RESULTS:A total of 222 metabolites significantly differed between the groups at a false discovery rate of q = 0.2. Linoleic acid, β-alanine, histidine, and aspartate/asparagine metabolism pathways were significantly enriched (all P < 0.01) by metabolites that were similarly upregulated in the NWO and overweight/obesity groups compared with the lean group. A module analysis linked branched-chain amino acids and amino acid metabolites as elevated in the NWO and overweight/obesity groups compared with the lean group (all P < 0.05). CONCLUSIONS:Metabolomic profiles of individuals with NWO reflected similar metabolic disruption as those of individuals with overweight/obesity. High-resolution metabolomics may help identify people at risk for developing obesity-related disease, despite normal BMI. 10.1002/oby.22654
    Metabolite Variation in Lean and Obese Streptozotocin (STZ)-Induced Diabetic Rats via H NMR-Based Metabolomics Approach. Abu Bakar Sajak Azliana,Mediani Ahmed,Maulidiani ,Ismail Amin,Abas Faridah Applied biochemistry and biotechnology Diabetes mellitus (DM) is considered as a complex metabolic disease because it affects the metabolism of glucose and other metabolites. Although many diabetes studies have been conducted in animal models throughout the years, the pathogenesis of this disease, especially between lean diabetes (ND + STZ) and obese diabetes (OB + STZ), is still not fully understood. In this study, the urine from ND + STZ, OB + STZ, lean/control (ND), and OB + STZ rats were collected and compared by using H NMR metabolomics. The results from multivariate data analysis (MVDA) showed that the diabetic groups (ND + STZ and OB + STZ) have similarities and dissimilarities for a certain level of metabolites. Differences between ND + STZ and OB + STZ were particularly noticeable in the synthesis of ketone bodies, branched-chain amino acid (BCAA), and sensitivity towards the oral T2DM diabetes drug metformin. This finding suggests that the ND + STZ group was more similar to the T1DM model and OB + STZ to the T2DM model. In addition, we also managed to identify several pathways and metabolism aspects shared by obese (OB) and OB + STZ. The results from this study are useful in developing drug target-based research as they can increase understanding regarding the cause and effect of DM. 10.1007/s12010-016-2352-9
    Indolepropionic acid and novel lipid metabolites are associated with a lower risk of type 2 diabetes in the Finnish Diabetes Prevention Study. de Mello Vanessa D,Paananen Jussi,Lindström Jaana,Lankinen Maria A,Shi Lin,Kuusisto Johanna,Pihlajamäki Jussi,Auriola Seppo,Lehtonen Marko,Rolandsson Olov,Bergdahl Ingvar A,Nordin Elise,Ilanne-Parikka Pirjo,Keinänen-Kiukaanniemi Sirkka,Landberg Rikard,Eriksson Johan G,Tuomilehto Jaakko,Hanhineva Kati,Uusitupa Matti Scientific reports Wide-scale profiling technologies including metabolomics broaden the possibility of novel discoveries related to the pathogenesis of type 2 diabetes (T2D). By applying non-targeted metabolomics approach, we investigated here whether serum metabolite profile predicts T2D in a well-characterized study population with impaired glucose tolerance by examining two groups of individuals who took part in the Finnish Diabetes Prevention Study (DPS); those who either early developed T2D (n = 96) or did not convert to T2D within the 15-year follow-up (n = 104). Several novel metabolites were associated with lower likelihood of developing T2D, including indole and lipid related metabolites. Higher indolepropionic acid was associated with reduced likelihood of T2D in the DPS. Interestingly, in those who remained free of T2D, indolepropionic acid and various lipid species were associated with better insulin secretion and sensitivity, respectively. Furthermore, these metabolites were negatively correlated with low-grade inflammation. We replicated the association between indolepropionic acid and T2D risk in one Finnish and one Swedish population. We suggest that indolepropionic acid, a gut microbiota-produced metabolite, is a potential biomarker for the development of T2D that may mediate its protective effect by preservation of β-cell function. Novel lipid metabolites associated with T2D may exert their effects partly through enhancing insulin sensitivity. 10.1038/srep46337
    Biomarkers of Morbid Obesity and Prediabetes by Metabolomic Profiling of Human Discordant Phenotypes. Tulipani Sara,Palau-Rodriguez Magali,Miñarro Alonso Antonio,Cardona Fernando,Marco-Ramell Anna,Zonja Bozo,Lopez de Alda Miren,Muñoz-Garach Araceli,Sanchez-Pla Alejandro,Tinahones Francisco J,Andres-Lacueva Cristina Clinica chimica acta; international journal of clinical chemistry Metabolomic studies aimed to dissect the connection between the development of type 2 diabetes and obesity are still scarce. In the present study, fasting serum from sixty-four adult individuals classified into four sex-matched groups by their BMI [non-obese versus morbid obese] and the increased risk of developing diabetes [prediabetic insulin resistant state versus non-prediabetic non-insulin resistant] was analyzed by LC- and FIA-ESI-MS/MS-driven metabolomic approaches. Altered levels of [lyso]glycerophospholipids was the most specific metabolic trait associated to morbid obesity, particularly lysophosphatidylcholines acylated with margaric, oleic and linoleic acids [lysoPC C17:0: R=-0.56, p=0.0003; lysoPC C18:1: R=-0.61, p=0.0001; lysoPC C18:2 R=-0.64, p<0.0001]. Several amino acids were biomarkers of risk of diabetes onset associated to obesity. For instance, glutamate significantly associated with fasting insulin [R=0.5, p=0.0019] and HOMA-IR [R=0.46, p=0.0072], while glycine showed negative associations [fasting insulin: R=-0.51, p=0.0017; HOMA-IR: R=-0.49, p=0.0033], and the branched chain amino acid valine associated to prediabetes and insulin resistance in a BMI-independent manner [fasting insulin: R=0.37, p=0.0479; HOMA-IR: R=0.37, p=0.0468]. Minority sphingolipids including specific [dihydro]ceramides and sphingomyelins also associated with the prediabetic insulin resistant state, hence deserving attention as potential targets for early diagnosis or therapeutic intervention. 10.1016/j.cca.2016.10.005
    Urine metabolomics of high-fat diet induced obesity using UHPLC-Q-TOF-MS. Men Lihui,Pi Zifeng,Zhou Yuan,Wei Mengying,Liu Yuanyuan,Song Fengrui,Liu Zhongying Journal of pharmaceutical and biomedical analysis Obesity has become a global epidemic and public health challenge which associates with serious health issues including diabetes, cardiovascular disease, stroke, arthritis, and some types of cancer. To better understand obesity and obesity-related dysfunction, a high-fat diet (HFD) induced obese model was developed on Sprague-Dawley rats. Metabolomics based on ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was untilized to identify and analyze obesity related metabolites in rat urine samples. Multivariate analyses were applied to differentiate metabolite patterns between HFD group and normal group. The study successfully identified 20 altered urine metabolites that correlated with obesity. These metabolites are mainly involved in tryptophan metabolism, phenylalanine and tyrosine metabolism, gut microbiota metabolism and insulin resistance related metabolism. They could serve as potential biomarkers to diagnose the development of obesity. 10.1016/j.jpba.2016.10.012
    Blood Metabolic Signatures of Body Mass Index: A Targeted Metabolomics Study in the EPIC Cohort. Carayol Marion,Leitzmann Michael F,Ferrari Pietro,Zamora-Ros Raul,Achaintre David,Stepien Magdalena,Schmidt Julie A,Travis Ruth C,Overvad Kim,Tjønneland Anne,Hansen Louise,Kaaks Rudolf,Kühn Tilman,Boeing Heiner,Bachlechner Ursula,Trichopoulou Antonia,Bamia Christina,Palli Domenico,Agnoli Claudia,Tumino Rosario,Vineis Paolo,Panico Salvatore,Quirós J Ramón,Sánchez-Cantalejo Emilio,Huerta José María,Ardanaz Eva,Arriola Larraitz,Agudo Antonio,Nilsson Jan,Melander Olle,Bueno-de-Mesquita Bas,Peeters Petra H,Wareham Nick,Khaw Kay-Tee,Jenab Mazda,Key Timothy J,Scalbert Augustin,Rinaldi Sabina Journal of proteome research Metabolomics is now widely used to characterize metabolic phenotypes associated with lifestyle risk factors such as obesity. The objective of the present study was to explore the associations of body mass index (BMI) with 145 metabolites measured in blood samples in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolites were measured in blood from 392 men from the Oxford (UK) cohort (EPIC-Oxford) and in 327 control subjects who were part of a nested case-control study on hepatobiliary carcinomas (EPIC-Hepatobiliary). Measured metabolites included amino acids, acylcarnitines, hexoses, biogenic amines, phosphatidylcholines, and sphingomyelins. Linear regression models controlled for potential confounders and multiple testing were run to evaluate the associations of metabolite concentrations with BMI. 40 and 45 individual metabolites showed significant differences according to BMI variations, in the EPIC-Oxford and EPIC-Hepatobiliary subcohorts, respectively. Twenty two individual metabolites (kynurenine, one sphingomyelin, glutamate and 19 phosphatidylcholines) were associated with BMI in both subcohorts. The present findings provide additional knowledge on blood metabolic signatures of BMI in European adults, which may help identify mechanisms mediating the relationship of BMI with obesity-related diseases. 10.1021/acs.jproteome.6b01062
    Twenty-four-hour rhythmicity of circulating metabolites: effect of body mass and type 2 diabetes. Isherwood Cheryl M,Van der Veen Daan R,Johnston Jonathan D,Skene Debra J FASEB journal : official publication of the Federation of American Societies for Experimental Biology Metabolic profiling of individuals with type 2 diabetes mellitus (T2DM) has previously been limited to single-time-point samples, ignoring time-of-day variation. Here, we tested our hypothesis that body mass and T2DM affect daily rhythmicity and concentrations of circulating metabolites across a 24-h day in 3 age-matched, male groups-lean, overweight/obese (OW/OB), and OW/OB with T2DM-in controlled laboratory conditions, which were not confounded by large meals. By using targeted liquid chromatography/mass spectrometry metabolomics, we quantified 130 plasma metabolites every 2 h over 24 h, and we show that average metabolite concentrations were significantly altered by increased body mass (90 of 130) and T2DM (56 of 130). Thirty-eight percent of metabolites exhibited daily rhythms in at least 1 study group, and where a metabolite was rhythmic in >1 group, its peak time was comparable. The optimal time of day was assessed to provide discriminating biomarkers. This differed between metabolite classes and study groups-for example, phospholipids showed maximal difference at 5:00 AM (lean OW/OB) and at 5:00 PM (OW/OB T2DM). Metabolites that were identified with both robust 24-h rhythms and significant concentration differences between study groups emphasize the importance of controlling the time of day for diagnosis and biomarker discovery, offering a significant improvement over current single sampling.-Isherwood, C. M., Van der Veen, D. R., Johnston, J. D., Skene, D. J. Twenty-four-hour rhythmicity of circulating metabolites: effect of body mass and type 2 diabetes. 10.1096/fj.201700323R
    The role of gut microbiota (GM) and GM-related metabolites in diabetes and obesity. A review of analytical methods used to measure GM-related metabolites in fecal samples with a focus on metabolites' derivatization step. Mojsak Patrycja,Rey-Stolle Fernanda,Parfieniuk Ewa,Kretowski Adam,Ciborowski Michal Journal of pharmaceutical and biomedical analysis Disruption of gut microbiota (GM) composition is increasingly related to the pathogenesis of various metabolic diseases. Additionally, GM is responsible for the production and transformation of metabolites involved in the development of metabolic disorders, such as obesity and type 2 diabetes mellitus (T2DM). The current state of knowledge regarding the composition of GM and GM-related metabolites in relation to the progress and development of obesity and T2DM is presented in this review. To understand the relationships between GM-related metabolites and the development of metabolic disorders, their accurate qualitative and quantitative measurement in biological samples is needed. Feces represent a valuable biological matrix which composition may reflect the health status of the lower gastrointestinal tract and the whole organism. Mass spectrometry (MS), mainly in combination with gas chromatography (GC) or liquid chromatography (LC), is commonly used to measure fecal metabolites. However, profiling metabolites in such a complex matrix as feces is challenging from both analytical chemistry and biochemistry standpoints. Chemical derivatization is one of the most effective methods used to overcome these problems. In this review, we provide a comprehensive summary of the derivatization methods of GM-related metabolites prior to GC-MS or LC-MS analysis, which have been published in the last five years (2015-2020). Additionally, analytical methods used for the analysis of GM-related metabolites without the derivatization step are also presented. 10.1016/j.jpba.2020.113617
    Plasma Lipidome and Prediction of Type 2 Diabetes in the Population-Based Malmö Diet and Cancer Cohort. Fernandez Céline,Surma Michal A,Klose Christian,Gerl Mathias J,Ottosson Filip,Ericson Ulrika,Oskolkov Nikolay,Ohro-Melander Marju,Simons Kai,Melander Olle Diabetes care OBJECTIVE:Type 2 diabetes mellitus (T2DM) is associated with dyslipidemia, but the detailed alterations in lipid species preceding the disease are largely unknown. We aimed to identify plasma lipids associated with development of T2DM and investigate their associations with lifestyle. RESEARCH DESIGN AND METHODS:At baseline, 178 lipids were measured by mass spectrometry in 3,668 participants without diabetes from the Malmö Diet and Cancer Study. The population was randomly split into discovery ( = 1,868, including 257 incident cases) and replication ( = 1,800, including 249 incident cases) sets. We used orthogonal projections to latent structures discriminant analyses, extracted a predictive component for T2DM incidence (lipid-PC), and assessed its association with T2DM incidence using Cox regression and lifestyle factors using general linear models. RESULTS:A T2DM-predictive lipid-PC derived from the discovery set was independently associated with T2DM incidence in the replication set, with hazard ratio (HR) among subjects in the fifth versus first quintile of lipid-PC of 3.7 (95% CI 2.2-6.5). In comparison, the HR of T2DM among obese versus normal weight subjects was 1.8 (95% CI 1.2-2.6). Clinical lipids did not improve T2DM risk prediction, but adding the lipid-PC to all conventional T2DM risk factors increased the area under the receiver operating characteristics curve by 3%. The lipid-PC was also associated with a dietary risk score for T2DM incidence and lower level of physical activity. CONCLUSIONS:A lifestyle-related lipidomic profile strongly predicts T2DM development beyond current risk factors. Further studies are warranted to test if lifestyle interventions modifying this lipidomic profile can prevent T2DM. 10.2337/dc19-1199
    Lipidomics-Reshaping the Analysis and Perception of Type 2 Diabetes. Markgraf Daniel F,Al-Hasani Hadi,Lehr Stefan International journal of molecular sciences As a consequence of a sedentary lifestyle as well as changed nutritional behavior, today's societies are challenged by the rapid propagation of metabolic disorders. A common feature of diseases, such as obesity and type 2 diabetes (T2D), is the dysregulation of lipid metabolism. Our understanding of the mechanisms underlying these diseases is hampered by the complexity of lipid metabolic pathways on a cellular level. Furthermore, overall lipid homeostasis in higher eukaryotic organisms needs to be maintained by a highly regulated interplay between tissues, such as adipose tissue, liver and muscle. Unraveling pathological mechanisms underlying metabolic disorders therefore requires a diversified approach, integrating basic cellular research with clinical research, ultimately relying on the analytical power of mass spectrometry-based techniques. Here, we discuss recent progress in the development of lipidomics approaches to resolve the pathological mechanisms of metabolic diseases and to identify suitable biomarkers for clinical application. Due to its growing impact worldwide, we focus on T2D to highlight the key role of lipidomics in our current understanding of this disease, discuss remaining questions and suggest future strategies to address them. 10.3390/ijms17111841
    Metabolic and biochemical changes in streptozotocin induced obese-diabetic rats treated with Phyllanthus niruri extract. Mediani Ahmed,Abas Faridah,Maulidiani M,Khatib Alfi,Tan Chin Ping,Ismail Intan Safinar,Shaari Khozirah,Ismail Amin,Lajis N H Journal of pharmaceutical and biomedical analysis Herbal medicine has been proven to be an effective therapy offering a variety of benefits, such as moderate reduction in hypoglycemia, in the treatment and prevention of obesity and diabetes. Phyllanthus niruri has been used as a treatment for diabetes mellitus. Herein, the induction of type 2 diabetes in Sprague-Dawley rats was achieved by a low dose of streptozotocin (STZ) (25mg/kgbw). Here, we evaluated the in vivo antidiabetic properties of two concentrations (250 and 500mg/kg bw) of P. niruri via metabolomics approach. The administration of 500mg/kgbw of P. niruri extract caused the metabolic disorders of obese diabetic rats to be improved towards the normal state. The extract also clearly decreased the serum glucose level and improved the lipid profile in obese diabetic rats. The results of this study may contribute towards better understanding the molecular mechanism of this medicinal plant in managing diabetes mellitus. 10.1016/j.jpba.2016.06.003
    Metabolic alteration in obese diabetes rats upon treatment with Centella asiatica extract. Maulidiani ,Abas F,Khatib A,Perumal V,Suppaiah V,Ismail A,Hamid M,Shaari K,Lajis N H Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:'Pegaga' is a traditional Malay remedy for a wide range of complaints. Among the 'pegaga', Centella asiatica has been used as a remedy for diabetes mellitus. Thus, we decided to validate this claim by evaluating the in vivo antidiabetic property of C. asiatica (CA) on T2DM rat model using the holistic (1)H NMR-based metabolomics approach. METHOD:In this study, an obese diabetic (mimic of T2DM condition) animal model was developed using Sprague-Dawley rats fed with a high-fat diet and induced into diabetic condition by the treatment of a low dose of streptozotocin (STZ). The effect of C. asiatica extract on the experimental animals was followed based on the changes observed in the urinary and serum metabolites, measured by (1)H NMR of urine and blood samples collected over the test period. RESULTS:A long-term treatment of obese diabetic rats with CA extract could reverse the glucose and lipid levels, as well as the tricarboxylic acid cycle and amino acid metabolic disorders, back towards normal states. Biochemical analysis also showed an increase of insulin production in diabetic rats upon treatment of CA extract. CONCLUSION:This study has provided evidence that clearly supported the traditional use of CA as a remedy for diabetes. NMR-based metabolomics was successfully applied to show that CA produced both anti-hyperglycemic and anti-hyperlipidemic effects on a rat model. In addition to increasing the insulin secretion, the CA extract also ameliorates the metabolic pathways affected in the induced diabetic rats. This study further revealed the potential usage of CA extract in managing diabetes mellitus and the results of this work may contribute towards the further understanding of the underlying molecular mechanism of this herbal remedy. 10.1016/j.jep.2016.01.001
    Fecal microbiota transplantation alters the susceptibility of obese rats to type 2 diabetes mellitus. Zhang Lijing,Zhou Wen,Zhan Libin,Hou Shenglin,Zhao Chunyan,Bi Tingting,Lu Xiaoguang Aging Obesity is one of the susceptibility factors for type 2 diabetes (T2DM), both of which could accelerate the aging of the body and bring many hazards. A causal relationship is present between intestinal microbiota and body metabolism, but how the microbiota play a role in the progression of obesity to T2DM has not been elucidated. In this study, we transplanted healthy or obese-T2DM intestinal microbiota to ZDF and LZ rats, and used 16S rRNA and targeted metabonomics to evaluate the directional effect of the microbiota on the susceptibility of obese rats to T2DM. The glycolipid metabolism phenotype could be changed bidirectionally in obese rats instead of in lean ones. One possible mechanism is that the microbiota and metabolites alter the structure of the intestinal tract, and improve insulin and leptin resistance through JAK2 / IRS / Akt pathway. It is worth noting that 7 genera, such as , and can regulate 15 metabolites, such as 3-indolpropionic acid, acetic acid and docosahexaenoic acid, and have a significant improvement on glycolipid metabolism phenotype. Attention to intestinal homeostasis may be the key to controlling obesity and preventing T2DM. 10.18632/aging.103756
    Metabolite profiling paradoxically reveals favorable levels of lipids, markers of oxidative stress and unsaturated fatty acids in a diabetes susceptible group of Middle Eastern immigrants. Al-Majdoub Mahmoud,Spégel Peter,Bennet Louise Acta diabetologica AIMS:The population of immigrants from the Middle East in Sweden show a higher prevalence of type 2 diabetes (T2D) compared to native Swedes. The exact reason for this is unknown. Here, we have performed metabolite profiling to investigate these differences. METHODS:Metabolite profiling was conducted in Iraqi immigrants (n = 93) and native Swedes (n = 77) using two complementary mass spectrometry-based platforms. Differences in metabolite levels were compared after adjustment for confounding anthropometric, diet and clinical variables. RESULTS:The Iraqi immigrant population were more obese (44.1 vs 24.7%, p < 0.05), but had a lower prevalence of hypertension (32.3 vs 54.8%, p < 0.01) than the native Swedish population. We detected 140 metabolites, 26 of which showed different levels between populations (q < 0.05,) after adjustment for age, sex, BMI, T2D and use of metformin. Twenty-two metabolites remained significant after further adjustment for HOMA-IR, HOMA-beta or insulin sensitivity index. Levels of polyunsaturated acylcarnitines (14:2 and 18:2) and fatty acid (18:2) were higher, whereas those of saturated and monounsaturated acylcarnitines (14:0, 18:1, and 8:1), fatty acids (12:0, 14:0, 16:0, and 18:1), uremic solutes (urate and quinate) and ketone bodies (beta-hydroxybutyrate) were lower in Iraqi immigrants. Further, levels of phospholipids were generally lower in the Iraqi immigrant population. CONCLUSIONS:Our result suggests an overall beneficial lipid profile in Iraqi immigrants, despite a higher risk to develop T2D. Higher levels of polyunsaturated fatty acids may suggest differences in dietary pattern, which in turn may reduce the risk of hypertension. 10.1007/s00592-019-01464-w
    Bile acid signaling in lipid metabolism: metabolomic and lipidomic analysis of lipid and bile acid markers linked to anti-obesity and anti-diabetes in mice. Qi Yunpeng,Jiang Changtao,Cheng Jie,Krausz Kristopher W,Li Tiangang,Ferrell Jessica M,Gonzalez Frank J,Chiang John Y L Biochimica et biophysica acta Bile acid synthesis is the major pathway for catabolism of cholesterol. Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting enzyme in the bile acid biosynthetic pathway in the liver and plays an important role in regulating lipid, glucose and energy metabolism. Transgenic mice overexpressing CYP7A1 (CYP7A1-tg mice) were resistant to high-fat diet (HFD)-induced obesity, fatty liver, and diabetes. However the mechanism of resistance to HFD-induced obesity of CYP7A1-tg mice has not been determined. In this study, metabolomic and lipidomic profiles of CYP7A1-tg mice were analyzed to explore the metabolic alterations in CYP7A1-tg mice that govern the protection against obesity and insulin resistance by using ultra-performance liquid chromatography-coupled with electrospray ionization quadrupole time-of-flight mass spectrometry combined with multivariate analyses. Lipidomics analysis identified seven lipid markers including lysophosphatidylcholines, phosphatidylcholines, sphingomyelins and ceramides that were significantly decreased in serum of HFD-fed CYP7A1-tg mice. Metabolomics analysis identified 13 metabolites in bile acid synthesis including taurochenodeoxycholic acid, taurodeoxycholic acid, tauroursodeoxycholic acid, taurocholic acid, and tauro-β-muricholic acid (T-β-MCA) that differed between CYP7A1-tg and wild-type mice. Notably, T-β-MCA, an antagonist of the farnesoid X receptor (FXR) was significantly increased in intestine of CYP7A1-tg mice. This study suggests that reducing 12α-hydroxylated bile acids and increasing intestinal T-β-MCA may reduce high fat diet-induced increase of phospholipids, sphingomyelins and ceramides, and ameliorate diabetes and obesity. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. 10.1016/j.bbalip.2014.04.008
    Metabolite profiling in plasma and tissues of ob/ob and db/db mice identifies novel markers of obesity and type 2 diabetes. Giesbertz Pieter,Padberg Inken,Rein Dietrich,Ecker Josef,Höfle Anja S,Spanier Britta,Daniel Hannelore Diabetologia AIMS/HYPOTHESIS:Metabolomics approaches in humans have identified around 40 plasma metabolites associated with insulin resistance (IR) and type 2 diabetes, which often coincide with those for obesity. We aimed to separate diabetes-associated from obesity-associated metabolite alterations in plasma and study the impact of metabolically important tissues on plasma metabolite concentrations. METHODS:Two obese mouse models were studied; one exclusively with obesity (ob/ob) and another with type 2 diabetes (db/db). Both models have impaired leptin signalling as a cause for obesity, but the different genetic backgrounds determine the susceptibility to diabetes. In these mice, we profiled plasma, liver, skeletal muscle and adipose tissue via semi-quantitative GC-MS and quantitative liquid chromatography (LC)-MS/MS for a wide range of metabolites. RESULTS:Metabolite profiling identified 24 metabolites specifically associated with diabetes but not with obesity. Among these are known markers such as 1,5-anhydro-D-sorbitol, 3-hydroxybutyrate and the recently reported marker glyoxylate. New metabolites in the diabetic model were lysine, O-phosphotyrosine and branched-chain fatty acids. We also identified 33 metabolites that were similarly altered in both models, represented by branched-chain amino acids (BCAA) as well as glycine, serine, trans-4-hydroxyproline, and various lipid species and derivatives. Correlation analyses showed stronger associations for plasma amino acids with adipose tissue metabolites in db/db mice compared with ob/ob mice, suggesting a prominent contribution of adipose tissue to changes in plasma in a diabetic state. CONCLUSIONS/INTERPRETATION:By studying mice with metabolite signatures that resemble obesity and diabetes in humans, we have found new metabolite entities for validation in appropriate human cohorts and revealed their possible tissue of origin. 10.1007/s00125-015-3656-y
    and : Three Potential Biomarkers of Gut Microbiota That Affect Progression and Complications of Obesity-Induced Type 2 Diabetes Mellitus. Wang Yuxin,Ouyang Meishuo,Gao Xibao,Wang Shuai,Fu Chunyang,Zeng Jiayi,He Xiaodong Diabetes, metabolic syndrome and obesity : targets and therapy Purpose:The purpose of this study was to explore the difference and association between intestinal microbiota and plasma metabolomics between type 2 diabetes mellitus (T2DM) and normal group and to identify potential microbiota biomarkers that contribute the most to the difference in metabolites. Methods:Six male ZDF model (fa/fa) rats were fed by a Purina #5008 Lab Diet (crude protein 23.5%, crude fat 6.5%) for 3 weeks and their age-matched 6 ZDF control (fa/+) rats were fed by normal rodent diet. Their stool and blood samples were collected at 12 weeks. To analyze the microbial populations in these samples, we used a 16S rRNA gene sequencing approach. Liquid chromatography-mass spectrometry (LC-MS) followed by multivariate statistical analysis was applied to the plasma metabolites profiling. Correlation analysis of them was calculated by Pearson statistical method. Results:Twelve potential biomarkers of intestinal microbial flora and 357 differential metabolites were found in ZDF fa/fa rats, among which there are three flora that contributed the most to the perturbation of metabolites, including genus and species . Conclusion:Our study demonstrates the alterations of the abundance and diversity of the intestinal microbiota and the perturbation of metabolites in ZDF rats (fa/fa). We found three potential biomarkers of intestinal microbiota that may lead to perturbation in plasma metabolites. This may prompt new pathogenesis of obesity-related T2DM, but we also need to study further about the causal relationship between intestinal microbe and T2DM, so as to find the target of T2DM treatment or preventive measures. 10.2147/DMSO.S240728
    Short-term high-fat diet exacerbates insulin resistance and glycolipid metabolism disorders in young obese men with hyperlipidemia, as determined by metabolomics analysis using ultra-HPLC-quadrupole time-of-flight mass spectrometry. Feng Rennan,Sun Guozhang,Zhang Yunbo,Sun Qintong,Ju Liyan,Sun Changhao,Wang Cheng Journal of diabetes BACKGROUND:The prevalence of obesity is increasing rapidly worldwide, and dietary intake is strongly associated with obesity-related chronic diseases. However, key metabolic perturbations in obese young men with hyperlipidemia after high-fat diet (HFD) intervention are not yet clear, and remain to be determined. The aim of this study was to investigate the effects of a short-term HFD on glycolipid metabolism, insulin resistance (IR), and urinary metabolomic profiling in young obese men with hyperlipidemia. METHODS:Sixty young men (19-25 years; 30 normal weight, 30 obese with hyperlipidemia) were enrolled in the study. Differences in metabolomic profiling of urine between normal-weight and obese young men before and after 3 days intake of the HFD were investigated using ultra-HPLC-quadrupole time-of-flight mass spectrometry. RESULTS:After the HFD intervention, total cholesterol (TC), low-density lipoprotein cholesterol, fasting plasma glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were significantly increased and high-density lipoprotein cholesterol was significantly decreased in obese men, but only TC was significantly increased in normal-weight subjects. Based on metabolic differences, normal-weight and obese men, and obese men before and after the HFD intervention could be separated into distinct clusters. Seventeen major metabolites were identified that were associated with type 2 diabetes mellitus, glycolipid metabolism and IR; the changes in these metabolites suggest metabolic changes in young obese males after short-term HFD intake. CONCLUSIONS:The findings of this study may contribute to increased understanding of the early biological adaptations of obesity with hyperlipidemia to HFD for the early prevention and control of diabetes and IR. 10.1111/1753-0407.12828
    Genomics and Metabolomics in Obesity and Type 2 Diabetes. Kretowski Adam,Ruperez Francisco J,Ciborowski Michal Journal of diabetes research 10.1155/2016/9415645
    The effects of liraglutide in mice with diet-induced obesity studied by metabolomics. Bugáňová Martina,Pelantová Helena,Holubová Martina,Šedivá Blanka,Maletínská Lenka,Železná Blanka,Kuneš Jaroslav,Kačer Petr,Kuzma Marek,Haluzík Martin The Journal of endocrinology Liraglutide is the glucagon-like peptide-1 receptor agonist widely used for the treatment of type 2 diabetes mellitus. Recently, it has been demonstrated to decrease cardiovascular morbidity and mortality in patients with type 2 diabetes and high cardiovascular risk. Although the major modes of liraglutide action are well-known, its detailed action at the metabolic level has not been studied. To this end, we explored the effect of 2-week liraglutide treatment in C57BL/6 male mice with obesity and diabetes induced by 13 weeks of high-fat diet using NMR spectroscopy to capture the changes in urine metabolic profile induced by the therapy. The liraglutide treatment decreased body and fat pads weight along with blood glucose and triglyceride levels. NMR spectroscopy identified 11 metabolites significantly affected by liraglutide treatment as compared to high-fat diet-fed control group. These metabolites included ones involved in nicotinamide adenine dinucleotide metabolism, β-oxidation of fatty acids and microbiome changes. Although majority of the metabolites changed after liraglutide treatment were similar as the ones previously identified after vildagliptin administration in a similar mouse model, the changes in creatinine, taurine and trigonelline were specific for liraglutide administration. The significance of these changes and its possible use in the personalization of antidiabetic therapy in humans requires further research. 10.1530/JOE-16-0478
    Metabolomics in diabetes, a review. Pallares-Méndez Rigoberto,Aguilar-Salinas Carlos A,Cruz-Bautista Ivette,Del Bosque-Plata Laura Annals of medicine Metabolomics is a promising approach for the identification of chemical compounds that serve for early detection, diagnosis, prediction of therapeutic response and prognosis of disease. Moreover, metabolomics has shown to increase the diagnostic threshold and prediction of type 2 diabetes. Evidence suggests that branched-chain amino acids, acylcarnitines and aromatic amino acids may play an early role on insulin resistance, exposing defects on amino acid metabolism, β-oxidation, and tricarboxylic acid cycle. This review aims to provide a panoramic view of the metabolic shifts that antecede or follow type 2 diabetes. Key messages BCAAs, AAAs and acylcarnitines are strongly associated with early insulin resistance. Diabetes risk prediction has been improved when adding metabolomic markers of dysglycemia to standard clinical and biochemical factors. 10.3109/07853890.2015.1137630
    Identification of pathognomonic purine synthesis biomarkers by metabolomic profiling of adolescents with obesity and type 2 diabetes. Concepcion Jennifer,Chen Katherine,Saito Rintaro,Gangoiti Jon,Mendez Eric,Nikita Maria Eleni,Barshop Bruce A,Natarajan Loki,Sharma Kumar,Kim Jane J PloS one The incidence of type 2 diabetes is increasing more rapidly in adolescents than in any other age group. We identified and compared metabolite signatures in obese children with type 2 diabetes (T2D), obese children without diabetes (OB), and healthy, age- and gender-matched normal weight controls (NW) by measuring 273 analytes in fasting plasma and 24-hour urine samples from 90 subjects by targeted LC-MS/MS. Diabetic subjects were within 2 years of diagnosis in an attempt to capture early-stage disease prior to declining renal function. We found 22 urine metabolites that were uniquely associated with T2D when compared to OB and NW groups. The metabolites most significantly elevated in T2D youth included members of the betaine pathway, nucleic acid metabolism, and branched-chain amino acids (BCAAs) and their catabolites. Notably, the metabolite pattern in OB and T2D groups differed between urine and plasma, suggesting that urinary BCAAs and their intermediates behaved as a more specific biomarker for T2D, while plasma BCAAs associated with the obese, insulin resistant state independent of diabetes status. Correlative analysis of metabolites in the T2D signature indicated that betaine metabolites, BCAAs, and aromatic amino acids were associated with hyperglycemia, but BCAA acylglycine derivatives and nucleic acid metabolites were linked to insulin resistance. Of major interest, we found that urine levels of succinylaminoimidazole carboxamide riboside (SAICA-riboside) were increased in diabetic youth, identifying urine SAICA-riboside as a potential biomarker for T2D. 10.1371/journal.pone.0234970
    A Metabolomic Approach to Understanding the Metabolic Link between Obesity and Diabetes. Park Seokjae,Sadanala Krishna Chaitanya,Kim Eun-Kyoung Molecules and cells Obesity and diabetes arise from an intricate interplay between both genetic and environmental factors. It is well recognized that obesity plays an important role in the development of insulin resistance and diabetes. Yet, the exact mechanism of the connection between obesity and diabetes is still not completely understood. Metabolomics is an analytical approach that aims to detect and quantify small metabolites. Recently, there has been an increased interest in the application of metabolomics to the identification of disease biomarkers, with a number of well-known biomarkers identified. Metabolomics is a potent approach to unravel the intricate relationships between metabolism, obesity and progression to diabetes and, at the same time, has potential as a clinical tool for risk evaluation and monitoring of disease. Moreover, metabolomics applications have revealed alterations in the levels of metabolites related to obesity-associated diabetes. This review focuses on the part that metabolomics has played in elucidating the roles of metabolites in the regulation of systemic metabolism relevant to obesity and diabetes. It also explains the possible metabolic relation and association between the two diseases. The metabolites with altered profiles in individual disorders and those that are specifically and similarly altered in both disorders are classified, categorized and summarized. 10.14348/molcells.2015.0126
    Are we close to defining a metabolomic signature of human obesity? A systematic review of metabolomics studies. Rangel-Huerta Oscar Daniel,Pastor-Villaescusa Belén,Gil Angel Metabolomics : Official journal of the Metabolomic Society INTRODUCTION:Obesity is a disorder characterized by a disproportionate increase in body weight in relation to height, mainly due to the accumulation of fat, and is considered a pandemic of the present century by many international health institutions. It is associated with several non-communicable chronic diseases, namely, metabolic syndrome, type 2 diabetes mellitus (T2DM), cardiovascular diseases (CVD), and cancer. Metabolomics is a useful tool to evaluate changes in metabolites due to being overweight and obesity at the body fluid and cellular levels and to ascertain metabolic changes in metabolically unhealthy overweight and obese individuals (MUHO) compared to metabolically healthy individuals (MHO). OBJECTIVES:We aimed to conduct a systematic review (SR) of human studies focused on identifying metabolomic signatures in obese individuals and obesity-related metabolic alterations, such as inflammation or oxidative stress. METHODS:We reviewed the literature to identify studies investigating the metabolomics profile of human obesity and that were published up to May 7th, 2019 in SCOPUS and PubMed through an SR. The quality of reporting was evaluated using an adapted of QUADOMICS. RESULTS:Thirty-three articles were included and classified according to four types of approaches. (i) studying the metabolic signature of obesity, (ii) studying the differential responses of obese and non-obese subjects to dietary challenges (iii) studies that used metabolomics to predict weight loss and aimed to assess the effects of weight loss interventions on the metabolomics profiles of overweight or obese human subjects (iv) articles that studied the effects of specific dietary patterns or dietary compounds on obesity-related metabolic alterations in humans. CONCLUSION:The present SR provides state-of-the-art information about the use of metabolomics as an approach to understanding the dynamics of metabolic processes involved in human obesity and emphasizes metabolic signatures related to obesity phenotypes. 10.1007/s11306-019-1553-y
    Metabolomics - the complementary field in systems biology: a review on obesity and type 2 diabetes. Abu Bakar Mohamad Hafizi,Sarmidi Mohamad Roji,Cheng Kian-Kai,Ali Khan Abid,Suan Chua Lee,Zaman Huri Hasniza,Yaakob Harisun Molecular bioSystems Metabolomic studies on obesity and type 2 diabetes mellitus have led to a number of mechanistic insights into biomarker discovery and comprehension of disease progression at metabolic levels. This article reviews a series of metabolomic studies carried out in previous and recent years on obesity and type 2 diabetes, which have shown potential metabolic biomarkers for further evaluation of the diseases. Literature including journals and books from Web of Science, Pubmed and related databases reporting on the metabolomics in these particular disorders are reviewed. We herein discuss the potential of reported metabolic biomarkers for a novel understanding of disease processes. These biomarkers include fatty acids, TCA cycle intermediates, carbohydrates, amino acids, choline and bile acids. The biological activities and aetiological pathways of metabolites of interest in driving these intricate processes are explained. The data from various publications supported metabolomics as an effective strategy in the identification of novel biomarkers for obesity and type 2 diabetes. Accelerating interest in the perspective of metabolomics to complement other fields in systems biology towards the in-depth understanding of the molecular mechanisms underlying the diseases is also well appreciated. In conclusion, metabolomics can be used as one of the alternative approaches in biomarker discovery and the novel understanding of pathophysiological mechanisms in obesity and type 2 diabetes. It can be foreseen that there will be an increasing research interest to combine metabolomics with other omics platforms towards the establishment of detailed mechanistic evidence associated with the disease processes. 10.1039/c5mb00158g
    Pre-diagnostic biomarkers of type 2 diabetes identified in the UAE's obese national population using targeted metabolomics. Fikri Asma M,Smyth Rosemary,Kumar Vijay,Al-Abadla Zainab,Abusnana Salahedeen,Munday Michael R Scientific reports Currently, type 2 diabetes mellitus (T2DM) and obesity are major global public health issues, and their prevalence in the United Arab Emirates (UAE) are among the highest in the world. In 2019, The UAE diabetes national prevalence was 15.4%. In recent years there has been a considerable investigation of predictive biomarkers associated with these conditions. This study analysed fasting (8 h) blood samples from an obese, normoglycemic cohort and an obese, T2DM cohort of UAE nationals, employing clinical chemistry analysis, 1D H NMR and mass spectroscopy (FIA-MS/MS and LC-MS/MS) techniques. The novel findings reported for the first time in a UAE population revealed significant differences in a number of metabolites in the T2DM cohort. Metabolic fingerprints identified by NMR included BCAAs, trimethylamine N-oxide, β-hydroxybutyrate, trimethyl uric acid, and alanine. A targeted MS approach showed significant differences in lysophosphatidylcholines, phosphatidylcholines, acylcarnitine, amino acids and sphingomyelins; Lyso.PC.a.C18.0, PC.ae.C34.2, C3.DC..C4.OH, glutamine and SM.C16.1, being the most significant metabolites. Pearson's correlation studies showed associations between these metabolites and the clinical chemistry parameters across both cohorts. This report identified differences in metabolites in response to T2DM in agreement with many published population studies. This contributes to the global search for a bank of metabolite biomarkers that can predict the advent of T2DM and give insight to its pathogenic mechanisms. 10.1038/s41598-020-73384-7
    Metabolic signature of obesity-associated insulin resistance and type 2 diabetes. Al-Sulaiti Haya,Diboun Ilhame,Agha Maha V,Mohamed Fatima F S,Atkin Stephen,Dömling Alex S,Elrayess Mohamed A,Mazloum Nayef A Journal of translational medicine BACKGROUND:Obesity is associated with an increased risk of insulin resistance and type 2 diabetes mellitus (T2DM). However, some obese individuals maintain their insulin sensitivity and exhibit a lower risk of associated comorbidities. The underlying metabolic pathways differentiating obese insulin sensitive (OIS) and obese insulin resistant (OIR) individuals remain unclear. METHODS:In this study, 107 subjects underwent untargeted metabolomics of serum samples using the Metabolon platform. Thirty-two subjects were lean controls whilst 75 subjects were obese including 20 OIS, 41 OIR, and 14 T2DM individuals. RESULTS:Our results showed that phospholipid metabolites including choline, glycerophosphoethanolamine and glycerophosphorylcholine were significantly altered from OIS when compared with OIR and T2DM individuals. Furthermore, our data confirmed changes in metabolic markers of liver disease, vascular disease and T2DM, such as 3-hydroxymyristate, dimethylarginine and 1,5-anhydroglucitol, respectively. CONCLUSION:This pilot data has identified phospholipid metabolites as potential novel biomarkers of obesity-associated insulin sensitivity and confirmed the association of known metabolites with increased risk of obesity-associated insulin resistance, with possible diagnostic and therapeutic applications. Further studies are warranted to confirm these associations in prospective cohorts and to investigate their functionality. 10.1186/s12967-019-2096-8
    Visceral Adipose Tissue Displays Unique Metabolomic Fingerprints in Obesity, Pre-Diabetes and Type 2 Diabetes. Morais Tiago,Seabra Alexandre L,Patrício Bárbara G,Guimarães Marta,Nora Mário,Oliveira Pedro F,Alves Marco G,Monteiro Mariana P International journal of molecular sciences Visceral adipose tissue (VAT) metabolic profiling harbors the potential to disentangle molecular changes underlying obesity-related dysglycemia. In this study, the VAT exometabolome of subjects with obesity and different glycemic statuses are analyzed. The subjects ( = 19) are divided into groups according to body mass index and glycemic status: subjects with obesity and euglycemia (Ob+NGT, = 5), subjects with obesity and pre-diabetes (Ob+Pre-T2D, = 5), subjects with obesity and type 2 diabetes under metformin treatment (Ob+T2D, = 5) and subjects without obesity and with euglycemia (Non-Ob, = 4), used as controls. VATs are incubated in culture media and extracellular metabolite content is determined by proton nuclear magnetic resonance (H-NMR). Glucose consumption is not different between the groups. Pyruvate and pyroglutamate consumption are significantly lower in all groups of subjects with obesity compared to Non-Ob, and significantly lower in Ob+Pre-T2D as compared to Ob+NGT. In contrast, isoleucine consumption is significantly higher in all groups of subjects with obesity, particularly in Ob+Pre-T2D, compared to Non-Ob. Acetate production is also significantly lower in Ob+Pre-T2D compared to Non-Ob. In sum, the VAT metabolic fingerprint is associated with pre-diabetes and characterized by higher isoleucine consumption, accompanied by lower acetate production and pyruvate and pyroglutamate consumption. We propose that glucose metabolism follows different fates within the VAT, depending on the individuals' health status. 10.3390/ijms22115695
    Urinary metabolomic profiling in mice with diet-induced obesity and type 2 diabetes mellitus after treatment with metformin, vildagliptin and their combination. Pelantová Helena,Bugáňová Martina,Holubová Martina,Šedivá Blanka,Zemenová Jana,Sýkora David,Kaválková Petra,Haluzík Martin,Železná Blanka,Maletínská Lenka,Kuneš Jaroslav,Kuzma Marek Molecular and cellular endocrinology Metformin, vildagliptin and their combination are widely used for the treatment of diabetes, but little is known about the metabolic responses to these treatments. In the present study, NMR-based metabolomics was applied to detect changes in the urinary metabolomic profile of a mouse model of diet-induced obesity in response to these treatments. Additionally, standard biochemical parameters and the expression of enzymes involved in glucose and fat metabolism were monitored. Significant correlations were observed between several metabolites (e.g., N-carbamoyl-β-alanine, N1-methyl-4-pyridone-3-carboxamide, N1-methyl-2-pyridone-5-carboxamide, glucose, 3-indoxyl sulfate, dimethylglycine and several acylglycines) and the area under the curve of glucose concentrations during the oral glucose tolerance test. The present study is the first to present N-carbamoyl-β-alanine as a potential marker of type 2 diabetes mellitus and consequently to demonstrate the efficacies of the applied antidiabetic interventions. Moreover, the elevated acetate level observed after vildagliptin administration might reflect increased fatty acid oxidation. 10.1016/j.mce.2016.05.003
    Progress in Metabonomics of Type 2 Diabetes Mellitus. Ma Quantao,Li Yaqi,Wang Min,Tang Ziyan,Wang Ting,Liu Chenyue,Wang Chunguo,Zhao Baosheng Molecules (Basel, Switzerland) With the improvement of living standards and a change in lifestyle, the incidence of type 2 diabetes mellitus (T2DM) is increasing. Its etiology is too complex to be completely understand yet. Metabonomics techniques are used to study the changes of metabolites and metabolic pathways before and after the onset of diabetes and make it more possible to further understand the pathogenesis of T2DM and improve its prediction, early diagnosis, and treatment. In this review, we summarized the metabonomics study of T2DM in recent years and provided a theoretical basis for the study of pathogenesis and the effective prevention and treatment of T2DM. 10.3390/molecules23071834
    Based on Plasma Metabonomics and Network Pharmacology Exploring the Therapeutic Mechanism of on Type 2 Diabetes. Guo Wenjing,Ouyang Hui,Liu Mi,Wu Jiahui,He Xiao,Yang Shilin,He Mingzhen,Feng Yulin Frontiers in pharmacology (GP) is a perennial herbal medicine and food homologous plant, which has been reported to have a good hypoglycemic effect. However, its active components and underlying mechanism of action are not clear. Here, we aimed to confirm the effects of GP on type 2 diabetes (T2DM) from several different aspects. We used UPLC/Q-TOF MS to analyze the metabolic patterns, which included blood samples of clinical subjects and / mice to screen for serum metabolic markers and metabolic pathways. We also used network pharmacology to study GP targets in the treatment of T2DM. Data from endogenous metabolites in plasma showed that two common pathways, including glycerol phosphate metabolism and retinol metabolism, were identified in plasma samples of the groups. Finally, Western blot analysis was used to verify the expression of proteins in the PI3K/AKT and AGE-RAGE signaling pathways. The protein expression of AKT, eNOS, iNS, and MAPK was significantly upregulated, and the expression of caspase-8 and caspase-3 was significantly downregulated. Thus, our findings indicated that GP could alleviate insulin resistance by regulating biometabolic markers and key proteins in the PI3K/AKT and AGE-RAGE signaling pathways to treat T2DM. 10.3389/fphar.2021.674379
    Metabolomic analysis and biochemical changes in the urine and serum of streptozotocin-induced normal- and obese-diabetic rats. Mediani Ahmed,Abas Faridah,Maulidiani M,Abu Bakar Sajak Azliana,Khatib Alfi,Tan Chin Ping,Ismail Intan Safinar,Shaari Khozirah,Ismail Amin,Lajis N H Journal of physiology and biochemistry Diabetes mellitus (DM) is a chronic disease that can affect metabolism of glucose and other metabolites. In this study, the normal- and obese-diabetic rats were compared to understand the diabetes disorders of type 1 and 2 diabetes mellitus. This was done by evaluating their urine metabolites using proton nuclear magnetic resonance (H NMR)-based metabolomics and comparing with controls at different time points, considering the induction periods of obesity and diabetes. The biochemical parameters of the serum were also investigated. The obese-diabetic model was developed by feeding the rats a high-fat diet and inducing diabetic conditions with a low dose of streptozotocin (STZ) (25 mg/kg bw). However, the normal rats were induced by a high dose of STZ (55 mg/kg bw). A partial least squares discriminant analysis (PLS-DA) model showed the biomarkers of both DM types compared to control. The synthesis and degradation of ketone bodies, tricarboxylic (TCA) cycles, and amino acid pathways were the ones most involved in the variation with the highest impact. The diabetic groups also exhibited a noticeable increase in the plasma glucose level and lipid profile disorders compared to the control. There was also an increase in the plasma cholesterol and low-density lipoprotein (LDL) levels and a decline in the high-density lipoprotein (HDL) of diabetic rats. The normal-diabetic rats exhibited the highest effect of all parameters compared to the obese-diabetic rats in the advancement of the DM period. This finding can build a platform to understand the metabolic and biochemical complications of both types of DM and can generate ideas for finding targeted drugs. 10.1007/s13105-018-0631-3
    UPLC-Q-TOF/MS based fecal metabolomics reveals the potential anti-diabetic effect of Xiexin Decoction on T2DM rats. Zhang Zhi-Miao,Chen Meng-Jun,Zou Jun-Feng,Jiang Shu,Shang Er-Xin,Qian Da-Wei,Duan Jin-Ao Journal of chromatography. B, Analytical technologies in the biomedical and life sciences Xiexin Decoction (XXD), a traditional Chinese medicine prescription composed of Rhei rhizome (RR), Scutellaria radix (SR) and Coptidis rhizome (CR), has been used to cure diabetes in clinical practices for thousands of years, but its mechanism is not clear. Our previous study indicated that XXD could significantly ameliorate the symptom of type 2 diabetes mellitus (T2DM) rats by shifting the composition of gut microbiota. However, the effect of XXD on the metabolic activity of gut microbiota is not clarified. In this study, the underlying mechanism of XXD on the amelioration of T2DM was explored by fecal metabolic profiling analysis based on ultra performance liquid chromatography coupled with quadrupole time-of-fight mass spectrometry (UPLC-Q-TOF/MS). The disordered metabolic profiles in T2DM rats were notably improved by XXD. Ten potential biomarkers, which were mainly involved in arachidonic acid metabolism, amino acid metabolism, bile acid metabolism, glycolysis and gluconeogenesis, were identified. Furthermore, these metabolites were closely related to SCFAs-producing and anti-inflammatory gut microflora. After XXD intervention, these biomarkers restored to the normal level at some extent. This study not only revealed potential biomarkers and related pathways in T2DM rats affected by XXD, but also provided a novel insight to uncover how traditional herb medicines worked from fecal metabolomics. 10.1016/j.jchromb.2021.122683
    Metabolomics Based on MS in Mice with Diet-Induced Obesity and Type 2 Diabetes Mellitus: the Effect of Vildagliptin, Metformin, and Their Combination. Tomášová Petra,Bugáňová Martina,Pelantová Helena,Holubová Martina,Šedivá Blanka,Železná Blanka,Haluzík Martin,Maletínská Lenka,Kuneš Jaroslav,Kuzma Marek Applied biochemistry and biotechnology Type 2 diabetes mellitus (T2DM) is a major epidemiological problem. Metformin and vildagliptin are well-established antidiabetic drugs. The aim of the study was to evaluate the changes of plasma metabolic profile induced by a high-fat diet (HFD) and subsequent oral administration of metformin, vildagliptin, and their combination in a mouse model of diet-induced obesity (DIO)/T2DM analyzed using quadrupole-time-of-flight mass spectrometry (qTOF-MS). Metformin treatment increased the levels of butyrylcarnitine and acylcarnitine C18:1 concentrations and decreased the levels of isoleucine concentrations compared to untreated HFD mice. Vildagliptin treatment increased levels of butyrylcarnitine and acetylcarnitine. In summary, our metabolomics study revealed multiple differences between obese diabetic HFD mice and lean standard chow diet (SCD) mice, which were partially modifiable by subsequent metformin and vildagliptin treatment. 10.1007/s12010-018-2899-8
    UPLC-Q/TOF-MS-Based Serum Metabolomics Reveals Hypoglycemic Effects of , and Their Combination on High-Fat-Diet-Induced Diabetes in KK-Ay Mice. Qin Zhenxian,Wang Wei,Liao Dengqun,Wu Xiaoying,Li Xian'en International journal of molecular sciences Diabetes is a worldwide severe health issue which causes various complications. This study aimed to evaluate the hypoglycemic effects of (RG), (CC) alone and their combination on high-fat-diet-induced diabetes in mice via biochemical assays and UPLC-Q/TOF-MS-based serum metabolomic analysis. Diabetic KK-Ay mice were induced by high-fat diet and treated for eight weeks, separately with RG, CC and their combination and the positive control drug metformin. Administration of RG and CC alone, and their combination could decrease the fasting blood glucose level, ameliorate the tolerance of glucose, and recover the levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in sera of diabetic mice. Orthogonal partial least squares discriminant analysis (OPLS-DA) on serum metabolomes revealed that 79 ESI⁺ and 76 ESI metabolites were changed by diabetes mellitus (DM) compared to the normal control. Heatmaps on these diabetes-related metabolites showed that CC and RG/CC were clustered closer with the normal control, indicating that they had the better antidiabetic effects at the metabolite level. Fifteen of the differential metabolites in DM serum were annotated and their related metabolic pathways were lipid metabolism. These data suggested that RG and CC alone and in combination treatment had the antidiabetic activity in lowering glycemia and improving lipid metabolism. UPLC-Q/TOF-MS-based metabolomics shed light on the differential metabolite effects of RG and CC in DM treatment. However, it should be noted that some differential metabolites were possibly generated or not detected due to our groupwise run order, which possibly contributed to or covered the group difference in our experiment. They need to be further discriminated in the future work. 10.3390/ijms19123984
    Untargeted metabolomics analysis on Cicer arietinium L.-Induced Amelioration in T2D rats by UPLC-Q-TOF-MS/MS. Lin Lei,Zhang Shaobao,Lin Yixuan,Liu Wen,Zou Baorong,Cai Ying,Liu Deliang,Sun Yangwen,Zhong Yuping,Xiao Dan,Liao Qiongfeng,Xie Zhiyong Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Cicer arietinium L., which belongs to Cicer genus, was not only a kind of traditional Chinese medicines (TCM) recorded in Pharmacopoeia of the People's Republic of China (version 2015), but also a kind of Uighur antidiabetic medicines. It has been used as an adjuvant drug or functional food for thousand years in Xinjiang province, China. However, the mechanisms of C. arietinium treatment in T2D have not been fully understood especially on the perspective of metabolomics. AIM OF THE STUDY:To clarify the potential mechanisms of C. arietinium treatment in T2D from the perspective of metabolomics since T2D is indeed a kind of metabolic syndromes. MATERIALS AND METHODS:T2D rat model was built by HFD for 4 weeks, combining with STZ administration. T2D rats were administrated C. arietinium extraction or metformin (positive control) for 4 weeks. UPLC-Q-TOF-MS was applied to screen and identify differential metabolites among groups. RESULTS:After 4 weeks of treatments, IR and inflammation were greatly ameliorated in C. arietinium group. And the therapeutic efficiency of C. arietinium treatment was comparable to metformin treatment. Differential metabolites related to C. arietinium treatment, including acylcarnitines, amino acid related metabolites and organic acids, were further used to indicate relevant pathways in T2D rats, including glyoxylate and dicarboxylate metabolism, tricarboxylic acid cycle, vitamin B6 metabolism and energy metabolism. CONCLUSIONS:In summary, C. arietinium treatment could effectively alleviate diabetic symptoms and regulate metabolic disorders in T2D rats. 10.1016/j.jep.2020.113013
    Urinary Metabolomics and Biochemical Analysis of Antihyperglycemic Effect of Ficus deltoidea Jack Varieties in Streptozotocin-Nicotinamide-Induced Diabetic Rats. Mohammad Noor Halimatul Saadiah,Ismail Nor Hadiani,Kasim Noraini,Mediani Ahmed,Mohd Zohdi Rozaini,Ali Abdul Manaf,Mat Nashriyah,Al-Mekhlafi Nabil Ali Applied biochemistry and biotechnology Patients are turning into herbs for the management of diabetes, which cause increasing in the demand of plant-based alternative medicines. Ficus deltoidea or locally known as "Mas Cotek" in Malaysia is a famous herbal plant. However, many varieties of F. deltoidea existed with varied antidiabetic activities inspire us to evaluate in vivo antidiabetic activity of the most available varieties of F. deltoidea. Therefore, antihyperglycemic effect of different varieties of F. deltoidea at dose 250 mg/kg was evaluated on streptozotocin-nicotinamide-induced diabetic rats and further assessed their urinary metabolites using proton nuclear magnetic resonance (H-NMR). The hyperglycemic blood level improved towards normoglycemic state after 30 days of treatment with standardized extracts of F. deltoidea var. trengganuensis, var. kunstleri, and var. intermedia. The extracts also significantly managed the biochemical parameters in diabetic rats. Metabolomics results showed these varieties were able to manage the altered metabolites of diabetic rats by shifting some of the metabolites back to their normal state. This knowledge might be very important in suggesting the use of these herbs in long-term treatment for diabetes. The most potential variety can be recommended, which may be useful for further pharmacological studies and herbal authentication processes. 10.1007/s12010-020-03304-y
    Untargeted serum metabolomics reveals Fu-Zhu-Jiang-Tang tablet and its optimal combination improve an impaired glucose and lipid metabolism in type II diabetic rats. Tao Yi,Chen Xi,Cai Hao,Li Weidong,Cai Baochang,Chai Chuan,Di Liuqing,Shi Liyun,Hu Lihong Journal of chromatography. B, Analytical technologies in the biomedical and life sciences Fu-Zhu-Jiang-Tang tablet, a six-herb preparation, was proved to show beneficial effects on type II diabetes patients in clinical. This study aims to optimize the component proportion of the six-herb preparation and explore the serum metabolic signatures of type II diabetes rats after treatment with Fu-Zhu-Jiang-Tang tablet and its optimal combination. The component proportion of the preparation was optimized using uniform experimental design and machine learning techniques. Untargeted GC-MS metabolomic experiments were carried out with serum samples from model group and treatment groups. Data were normalized, multivariate and univariate statistical analysis performed and metabolites of interest putatively identified. 23 metabolites were significantly changed by Fu-Zhu-Jiang-Tang tablet treatment and the majority of these were decreased, including various carbohydrates (glucose, mannose, fructose, allose and gluconic acid), unsaturated fatty acids (palmitic acid, 9-octadecenoic acid, oleic acid, arachidonic acid), alanine, valine, propanoic acid, 3-hydroxybutyrate, along with pyrimidine and cholesterol. Increased concentrations of oxalic acid, leucine, glycine, serine, threonine, proline, lysine and citrate were observed. In the optimal combination-fed group, 21 metabolites were significantly affected and strikingly, the magnitudes of changes here were generally much greater than that of Fu-Zhu-Jiang-Tang tablet treated rats. 18 metabolites affected in both groups included various carbohydrates (mannose, glucose, allose, fructose and gluconic acid), unsaturated fatty acids (palmitic acid, 9-octadecenoic acid, oleic acid and arachidonic acid), short-chain fatty acids (oxalic acid, 3-hydroxybutyrate), and amino acids (alanine, valine, leucine, glycine, proline and lysine), as well as pyrimidine. Metabolites exclusively affected in optimal combination treated rat included succinic acid, cysteine and phenylalanine, whilst four metabolites (propanoic acid, citrate, serine and threonine) were only altered in Fu-Zhu-Jiang-Tang tablet treated rat. Our investigation demonstrated Fu-Zhu-Jiang-Tang tablet and its optimal combination treatments were able to ameliorate impaired glucose and lipid metabolism, down- regulate the high level of glucose to a lower level and reverse abnormal levels of metabolites in serum of type II diabetes rats. However, the optimal combination treatment was able to maximize the magnitudes of changes in some metabolites. These findings may be helpful in clarifying the anti-diabetic mechanism of FZJT tablet and its optimal combination. 10.1016/j.jchromb.2016.11.012
    A Novel Approach Based on Metabolomics Coupled With Intestinal Flora Analysis and Network Pharmacology to Explain the Mechanisms of Action of Bekhogainsam Decoction in the Improvement of Symptoms of Streptozotocin-Induced Diabetic Nephropathy in Mice. Meng Xianglong,Ma Junnan,Kang An Na,Kang Seok Yong,Jung Hyo Won,Park Yong-Ki Frontiers in pharmacology Bekhogainsam decoction (BHID), a representative prescription for the treatment of diabetes mellitus (DM) and diabetic complications in both traditional Korean and Chinese medicine, was examined for its ability to ameliorate diabetic nephropathy (DN), and its mechanism of action was evaluated by metabolomics, gut microbiota, and network pharmacology. In this study, male specific pathogen-free C57BL/6 mice were intraperitoneally injected with streptozotocin (STZ, 100 mg/kg) once per day for 3 days consecutively, and were then orally administered BHID at 100 and 500 mg/kg, and metformin at 250 mg/kg once per day for 4 weeks. Our results showed that the administration of BHID to mice with STZ-induced DN prevented physiological and serological changes, structural damage, and kidney dysfunction. Based on a metabolomics test with serum, the profoundly altered metabolites in the BHID treatment group were identified. Thirty-six BHID-related proteins and four signaling pathways, including valine, leucine, and isoleucine biosynthesis, nicotinate and nicotinamide metabolism, tryptophan metabolism, and alanine, aspartate, and glutamate metabolism pathways, were explored. Principal coordinates analysis (PCoA) of the gut microbiota revealed that BHID treatment significantly affected the flora composition. In addition, the network pharmacology analysis revealed that BHID acted through phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) and MAPK-related protein targets. Our findings on the anti-DN effects of BHID and its mechanism of action, from the perspective of systems biology, have provided scientific evidence to support the clinical treatment of patients with diabetes, and implied that BHID has the potential to prevent the progression of DN. 10.3389/fphar.2020.00633
    Mechanism of YLTZ on glycolipid metabolism based on UPLC/TOF/MS metabolomics. Zhuo Jun-Cheng,Cai Da-Ke,Xie Kai-Feng,Gan Hai-Ning,Li Sha-Sha,Huang Xue-Jun,Huang Dane,Zhang Cheng-Zhe,Li Ru-Yue,Chen Yu-Xing,Zeng Xiao-Hui Journal of chromatography. B, Analytical technologies in the biomedical and life sciences Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by dysfunction of glycolipid metabolism. YLTZ is used to treat hyperlipidemia, yet its hypolipidemic and hypoglycemic mechanism on T2DM are unknown. Thus, UPLC/TOF/MS was applied in this study to identify the potential bio-markers, and deduce the possible metabolic pathways. According to bio-indexes, the increased blood lipid levels, including TC, TG, LDL and FA, and the decreased HDL, the elevated glucose, reduced insulin level and impaired OGTT were observed in diabetic rat model. While YLTZ can decrease the lipid levels and glucose content, as well as increased insulin standards and improve OGTT. After data from UPLC/TOF/MS processed, 17 metabolites were obtained, including phospholipids (LPCs, PCs and PGP (18:1)), beta-oxidation production (HAA, VAG and CNE) and precursors (THA), bile acid (CA, CDCA and IDCA), hydrolysate of TG (MG (22:4)), glycometabolism (G6P), cholesterol-driven synthetics (ADO) and production of arachidonate acid (THETA). As a result, YLTZ was able to reduce LPCs, PCs, PGP (18:1), HAA, VAG, CNE, CA, ADO and THETA, as well as enhance MG (22:4) and G6P. After analyzing results, several metabolic pathways were deduced, which containing, cholesterol synthesis and elimination, FA beta-oxidation, TG hydrolysis, phospholipids synthesis, glycolysis, gluconeogenesis and inflammation. Consequently, YLTZ performed to prohibit the FA beta-oxidation, synthesis of cholesterol and phospholipids, gluconeogenesis and inflammation level, as well as promote TG hydrolysis, glycolysis and blood circulation. Hence, applying metabonomics in TCM research can uncover its pharmacological edges, elucidating comprehensively that YLTZ has capacity of hypolipidemic, hypoglycemic and promoting blood circulation, matching the effect of removing blood stasis, eliminating phlegm and dampness. 10.1016/j.jchromb.2018.08.023
    CMap analysis identifies Atractyloside as a potential drug candidate for type 2 diabetes based on integration of metabolomics and transcriptomics. Li Hailong,Shi Xiaodong,Jiang Hua,Kang Junren,Yu Miao,Li Qifei,Yu Kang,Chen Zhengju,Pan Hui,Chen Wei Journal of cellular and molecular medicine BACKGROUND:This research aimed at exploring the mechanisms of alterations of metabolites and pathways in T2D from the perspective of metabolomics and transcriptomics, as well as uncovering novel drug candidate for T2D treatment. METHODS:Metabolites in human plasma from 42 T2D patients and 45 non-diabetic volunteers were detected by liquid chromatography-mass spectrometer (LC-MS). Microarray dataset of the transcriptome was obtained from Gene Expression Omnibus (GEO) database. Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used to conduct pathway enrichment analysis. Connectivity Map (CMap) was employed to select potential drugs for T2D therapy. In vivo assay was performed to verify above findings. The protein expression levels of ME1, ME2 and MDH1 were detected by Western blot to determine the status of NAD/NADH cofactor system. RESULTS:In our study, differentially expressed metabolites were selected out between healthy samples and T2D samples with selection criteria P value < .05, |Fold Change| > 2, including N-acetylglutamate and Malate. Genes set enrichment analysis (GSEA) revealed that 34 pathways were significantly enriched in T2D. Based on CMap analysis and animal experiments, Atractyloside was identified as a potential novel drug for T2D treatment via targeting ME1, ME2 and MDH1 and regulating the NAD/NADH cofactor system. CONCLUSION:The present research revealed differentially expressed metabolites and genes, as well as significantly altered pathways in T2D via an integration of metabolomics, transcriptomics and CMap analysis. It was also demonstrated that comprehensive analysis based on metabolomics and transcriptomics was an effective approach for identification and verification of metabolic biomarkers and alternated pathways. 10.1111/jcmm.15357
    H NMR-based metabolomics reveals sub-lethal toxicity of a mixture of diabetic and lipid-regulating pharmaceuticals on amphibian larvae. Melvin Steven D,Habener Leesa J,Leusch Frederic D L,Carroll Anthony R Aquatic toxicology (Amsterdam, Netherlands) Pharmaceuticals are widely used for the treatment of various physical and psychological ailments. Due to incomplete removal during sewage treatment many pharmaceuticals are frequently detected in aquatic waterways at trace concentrations. The diversity of pharmaceutical contaminants and potential for complex mixtures to occur makes it very difficult to predict the toxicity of these compounds on wildlife, and robust methods are therefore needed to explore sub-lethal effects. Metabolic syndrome is one of the most widespread health concerns currently facing the human population, and various drugs, including anti-diabetic medications and lipid- and cholesterol-lowering fibrates and statins, are widely prescribed as treatment. In this study, we exposed striped marsh frog (Limnodynastes peronii) tadpoles to a mixture of the drugs metformin, atorvastatin and bezafibrate at 0.5, 5, 50 and 500μg/L to explore possible effects on growth and development, energy reserves (triglycerides and cholesterol), and profiles of small polar metabolites extracted from hepatic tissues. It was hypothesised that exposure would result in a general reduction in energy reserves, and that this would subsequently correspond with reduced growth and development. Responses differed from expected outcomes based on the known mechanisms of these compounds in humans, with no changes to hepatic triglycerides or cholesterol and a general increase in mass and condition with increasing exposure concentration. Deviation from the expected response patterns may be explained by differences in the receptivity or uptake of the compounds in non-mammalian species. Proton nuclear magnetic resonance (H NMR) spectroscopy revealed evidence of broad metabolic dysregulation in exposed animals, and possible interaction between the solvent and mixture. Specifically, increased lactic acid and branched-chain amino acids were observed, with responses tending to follow a non-monotonic pattern. Overall, results demonstrate that a mixture of drugs commonly prescribed to treat human metabolic syndrome is capable of eliciting physiological and developmental effects on larval amphibians. Importantly, outcomes further suggest that it may not be possible to predict toxicological effects in non-target wildlife based on our knowledge of how these compounds act in humans. 10.1016/j.aquatox.2017.01.012
    Complementary NMR- and MS-based metabolomics approaches reveal the correlations of phytochemicals and biological activities in Phyllanthus acidus leaf extracts. Abd Ghafar Siti Zulaikha,Mediani Ahmed,Maulidiani M,Rudiyanto R,Mohd Ghazali Hasanah,Ramli Nurul Shazini,Abas Faridah Food research international (Ottawa, Ont.) Proton nuclear magnetic resonance (H NMR)- and ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS)-based analytical tools are frequently used in metabolomics studies. These complementary metabolomics platforms were applied to identify and quantify the metabolites in Phyllanthus acidus extracted with different ethanol concentrations. In total, 38 metabolites were tentatively identified by H NMR and 39 via UHPLC-MS, including 30 compounds are reported for the first time from this plant. The partial least square analysis (PLS) revealed the metabolites that contributed to α-glucosidase and nitric oxide (NO) inhibitory activities, including kaempferol, quercetin, myricetin, phyllanthusol A, phyllanthusol B, chlorogenic, catechin, cinnamic coumaric, caffeic, quinic, citric, ellagic and malic acids. This study shows the significance of combining H NMR- and UHPLC-MS-based metabolomics as the best strategies in identifying metabolites in P. acidus extracts and establishing an extract with potent antioxidant, anti-diabetic, and anti-inflammatory properties. 10.1016/j.foodres.2020.109312
    NMR-based metabolomics reveals brain region-specific metabolic alterations in streptozotocin-induced diabetic rats with cognitive dysfunction. Zheng Hong,Lin Qiuting,Wang Dan,Xu Pengtao,Zhao Liangcai,Hu Wenyi,Bai Guanghui,Yan Zhihan,Gao Hongchang Metabolic brain disease Diabetes mellitus (DM) can result in cognitive dysfunction, but its potential metabolic mechanisms remain unclear. In the present study, we analyzed the metabolite profiling in eight different brain regions of the normal rats and the streptozotocin (STZ)-induced diabetic rats accompanied by cognitive dysfunction using a H NMR-based metabolomic approach. A mixed linear model analysis was performed to assess the effects of DM, brain region and their interaction on metabolic changes. We found that different brain regions in rats displayed significant metabolic differences. In addition, the hippocampus was more susceptible to DM compared with other brain regions in rats. More interestingly, significant interaction effects of DM and brain region were observed on alanine, creatine/creatine-phosphate, lactate, succinate, aspartate, glutamate, glutamine, γ-aminobutyric acid, glycine, choline, N-acetylaspartate, myo-inositol and taurine. Based on metabolic pathway analysis, we speculate that cognitive dysfunction in the STZ-induced diabetic rats may be associated with brain region-specific metabolic alterations involving energy metabolism, neurotransmitters, membrane metabolism and osmoregulation. 10.1007/s11011-016-9949-0
    Metabolic Effect of 1-Deoxynojirimycin from Mulberry Leaves on db/db Diabetic Mice Using Liquid Chromatography-Mass Spectrometry Based Metabolomics. Hu Xue-Qin,Thakur Kiran,Chen Gui-Hai,Hu Fei,Zhang Jian-Guo,Zhang Hong-Bin,Wei Zhao-Jun Journal of agricultural and food chemistry Metabolomics was applied to the liquid chromatography-mass spectrometry urinary metabolic profile of type 2 diabetes (T2DM) mice treated with mulberry 1-deoxynojirimycin (DNJ). The serum biochemical indicators related to T2DM like blood glucose, insulin, triglyceride, total cholesterol, nitrogen, malondialdehyde, and creatinine decreased significantly in the treated group. The histopathological changes in liver cells were marked by deformations and disruptions in central area of nuclei in DM mice, whereas DNJ treatment recovered regular liver cells with normal nuclei. Most of the metabolites of T2DM were significantly different from healthy controls in the bulk data generated. The level of 16 metabolites showed that the diabetic group was closer to the healthy group as the DNJ treatment time prolonged. Moreover, DNJ inhibited the activity of glucosidase on glucose, lipid, and amino acid metabolism. Our results showed the mechanism of DNJ treatment of T2DM and could fetch deep insights into the potent metabolite markers of the applied antidiabetic interventions. 10.1021/acs.jafc.7b01766
    H NMR-Based Metabolomics Coupled With Molecular Docking Reveal the Anti-Diabetic Effects and Potential Active Components of on Type 2 Diabetic Rats. Li Qi,Zhao Chengcheng,Zhang Yunsen,Du Huan,Xu Tong,Xu Xinmei,Zhang Jing,Kuang Tingting,Lai Xianrong,Fan Gang,Zhang Yi Frontiers in pharmacology The dried stem bark of C.K.Schneid., known as "Xiao-bo-pi" in Chinese, is a representative anti-diabetic herb in traditional Tibetan medical system. However, its anti-diabetic mechanisms and active components remain unclear. In this study, H NMR-based metabolomics, biochemistry assay, molecular docking, and network analysis were integrated to evaluate the anti-diabetic effects of extract on type 2 diabetic rats, and to explore its active components and underlying mechanisms. Diabetes was induced by high-fat diet and streptozotocin. After 30 days of treatment, extract significantly decreased the serum levels of fasting blood glucose, insulin, insulin resistance index, glycated serum protein, TNF-α, IL-1β, and IL-6, whereas significantly increased the serum levels of insulin sensitivity index in type 2 diabetic rats. A total of 28 endogenous metabolites were identified by H NMR-based metabolomics, of which 9 metabolites that were changed by diabetes were significantly reversed by extract. The constructed compound-protein-metabolite-disease (CPMD) interaction network revealed the correlation between chemical constituents, target proteins, differential metabolites, and type 2 diabetes. Ferulic acid 4---D-glucopyranoside, bufotenidine, jatrorrhizine, and berberine showed good hit rates for both the 30 disease-related proteins and 14 differential metabolites-related proteins, indicating that these four compounds might be the active ingredients of against type 2 diabetes. Moreover, pathway analysis revealed that the anti-diabetic mechanisms of might be related to its regulation of several metabolic pathways (e.g., butanoate metabolism) and disease-related signal pathways (e.g., adipocytokine signaling pathway). In summary, exerts a significant anti-diabetic effect and has potential as a drug candidate for the treatment of type 2 diabetes. 10.3389/fphar.2020.00932
    Identification of chemotypes in bitter melon by metabolomics: a plant with potential benefit for management of diabetes in traditional Chinese medicine. Zhou Shuaizhen,Allard Pierre-Marie,Wolfrum Christian,Ke Changqiang,Tang Chunping,Ye Yang,Wolfender Jean-Luc Metabolomics : Official journal of the Metabolomic Society INTRODUCTION:Bitter melon (Momordica charantia, Cucurbitaceae) is a popular edible medicinal plant, which has been used as a botanical dietary supplement for the treatment of diabetes and obesity in Chinese folk medicine. Previously, our team has proved that cucurbitanes triterpenoid were involved in bitter melon's anti-diabetic effects as well as on increasing energy expenditure. The triterpenoids composition can however be influenced by changes of varieties or habitats. OBJECTIVES:To clarify the significance of bioactive metabolites diversity among different bitter melons and to provide a guideline for selection of bitter melon varieties, an exploratory study was carried out using a UHPLC-HRMS based metabolomic study to identify chemotypes. METHODS:Metabolites of 55 seed samples of bitter melon collected in different parts of China were profiled by UHPLC-HRMS. The profiling data were analysed with multivariate (MVA) statistical methods. Principle component analysis (PCA) and hierarchical cluster analysis (HCA) were applied for sample differentiation. Marker compounds were identified by comparing spectroscopic data with isolated compounds, and additional triterpenes were putatively identified by propagating annotations through a molecular network (MN) generated from UHPLC-HRMS & MS/MS metabolite profiling. RESULTS:PCA and HCA provided a good discrimination between bitter melon samples from various origins in China. This study revealed for the first time the existence of two chemotypes of bitter melon. Marker compounds of those two chemotypes were identified at different MSI levels. The combined results of MN and MVA demonstrated that the two chemotypes mainly differ in their richness in cucurbitane versus oleanane triterpenoid glycosides (CTGs vs. OTGs). CONCLUSION:Our finding revealed a clear chemotype distribution of bioactive components across bitter melon varieties. While bioactivities of individual CTGs and OTGs still need to be investigated in more depth, our results could help in future the selection of bitter melon varieties with optimised metabolites profile for an improved management of diabetes with this popular edible Chinese folk medicine. 10.1007/s11306-019-1565-7
    UHPLC/QTOF-MS-based metabolomics reveal the effect of extract in type 2 diabetic rats. Weng Jingyu,Zhou Jingkai,Liang Liqing,Li Li Pharmaceutical biology Lour. (Melastomataceae) is a traditional Chinese medicine. This is the first study to report a protective effect of the ethanol extract from (MDE) in type 2 diabetic (T2DM) rats. To investigate the therapeutic mechanism of MDE in T2DM rats. Sprague-Dawley rats were fed a high-fat diet for 6 consecutive weeks, followed by intraperitoneal injection of streptozotocin (STZ) (30 mg/kg) to induce diabetes. T2DM rats were divided into untreated diabetic, metformin-treated and MDE-treated groups. Additionally, normal rats without treatment served as the control group ( = 6). Metformin (250 mg/kg) and MDE (600 mg/kg) were intragastrically administered to T2DM rats for 5 consecutive weeks. Serum samples were evaluated via ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC/QTOF-MS), followed by principal components analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). The 17 identified potential biomarkers were mainly involved in lipid, amino acid, arachidonic acid, taurine and nicotinic acid metabolism. MDE also significantly reduced the level of fasting blood glucose (FBG), oral glucose tolerance, insulin, total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), malondialdehyde (MDA), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and urea nitrogen (BUN) in T2DM rats. The high-density lipoprotein (HDL), serum creatinine (Scr), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) levels were elevated in MDE-treated group. MDE possesses substantial antidiabetic activity, especially in lipid disorder regulation. This suggests that the use of MDE can be generalized to broader pharmacological studies, such as obesity and hyperlipidaemia. 10.1080/13880209.2019.1693605
    Metabolomics and Lipidomics Profiling Reveals Hypocholesterolemic and Hypolipidemic Effects of Arabinoxylan on Type 2 Diabetic Rats. Nie Qixing,Xing Mengmeng,Chen Haihong,Hu Jielun,Nie Shaoping Journal of agricultural and food chemistry Type 2 diabetes (T2D) is a pandemic disease chiefly characterized by hyperglycemia. In this study, the combination of serum lipidomic and metabolomic approach was employed to investigate the effect of arabinoxylan on type 2 diabetic rats and identify the critical biomarkers of T2D. Metabolomics analysis revealed that branched-chain amino acids, 12α-hydroxylated bile acids, ketone bodies, and several short- and long-chain acylcarnitines were significantly increased in T2D, whereas lysophosphatidylcholines (LPCs) were significantly decreased. Lipidomics analysis indicated T2D-related dyslipidemia was mainly associated with the increased levels of acetylcarnitine, free fatty acids (FFA), diacylglycerols, triacylglycerols, and cholesteryl esters and the decreased levels of some unsaturated phosphatidylcholines (less than 22 carbons). These variations indicated the disturbed amino acid and lipid metabolism in T2D, and the accumulation of incompletely oxidized lipid species might eventually contribute to impaired insulin action and glucose homeostasis. Arabinoxylan treatment decreased the concentrations of 12α-hydroxylated bile acids, carnitines, and FFAs and increased the levels of LPCs. The improved bile acid and lipid metabolism by arabinoxylan might be involved in the alleviation of hypercholesterolemia and hyperlipidemia in T2D. 10.1021/acs.jafc.9b03430
    Effect of 20(S)-ginsenoside Rg3 on streptozotocin-induced experimental type 2 diabetic rats: a urinary metabonomics study by rapid-resolution liquid chromatography/mass spectrometry. Niu Jun,Pi Zi-Feng,Yue Hao,Yang Hongmei,Wang Yang,Yu Qing,Liu Shu-Ying Rapid communications in mass spectrometry : RCM RATIONALE:20(S)-ginsenoside Rg3 is an active component of Panax ginseng. It is known that 20(S)-ginsenoside Rg3 has a protective effect against hyperglycemia, obesity and diabetes in vivo, but the precise mechanisms of these actions have not yet been entirely elucidated. METHODS:A urinary metabonomics method based on rapid-resolution liquid chromatography/mass spectrometry (RRLC/MS) was developed to investigate the effect of 20(S)-ginsenoside Rg3 on type 2 diabetic rats. RESULTS:With multivariate statistical analysis, a clear separation between type 2 diabetic rats and those treated with 20(S)-ginsenoside Rg3 was achieved. Six potential biomarkers were found and identified. CONCLUSIONS:This work shows that the mechanism of the effect of 20(S)-ginsenoside Rg3 on type 2 diabetes may be involved with the regulation of nucleic acid metabolism, energy metabolism and gut flora metabolism. 10.1002/rcm.6392
    Intervention of resistant starch 3 on type 2 diabetes mellitus and its mechanism based on urine metabonomics by liquid chromatography-tandem mass spectrometry. Zhang Caijuan,Dong Ling,Wu Jiahui,Qiao Sanyang,Xu Wenjuan,Ma Shuangshuang,Zhao Baosheng,Wang Xueyong Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie As a severe metabolic disease, type 2 diabetes mellitus (T2DM) has aroused increasing public attentions. Resistant starch 3 (RS3), as a starch resistant to enzymatic hydrolysis owing to its special structure, has a good effect on improving insulin resistance and reducing blood sugar in T2DM patients. However, the possible mechanisms were barely interpreted yet. In our research, we aimed to evaluate the effects and the possible mechanisms of RS3 on the treatment of T2DM. ICR mice treated with high-fat diet (HFD) for eight weeks, and then injected with streptozotocin (STZ) (100 mg/kg) to establish the T2DM. We choose the mice with the fast blood glucose (FBG) more than 11 mmol/L as T2DM. After treated for 11 weeks the relevant data was analyzed. According to the results, the FBG was dramatically reduced (p < 0.05), which also downregulated triglyceride (p < 0.01) and total cholesterol (p < 0.01). Additionally, the insulin resistance indexes were significantly reduced (p < 0.01), the homeostasis model assessment-β and insulin-sensitive index were significantly improved (p < 0.01) in RS3 group. Meanwhile, the metabolic profiles of urine were analyzed and 29 potential biomarkers were screened out, including amino acids and lipids. In conclusion, we speculated that the tricarboxylic acid cycle, amino acid metabolism and lipid metabolism played roles in the therapeutic mechanisms of RS3 on T2DM. 10.1016/j.biopha.2020.110350
    NMR metabolomics identifies over 60 biomarkers associated with Type II Diabetes impairment in db/db mice. Mora-Ortiz Marina,Nuñez Ramos Patricia,Oregioni Alain,Claus Sandrine P Metabolomics : Official journal of the Metabolomic Society INTRODUCTION:The rapid expansion of Type 2 Diabetes (T2D), that currently affects 90% of people suffering from diabetes, urges us to develop a better understanding of the metabolic processes involved in the disease process in order to develop better therapies. The most commonly used model for T2D research is the db/db (BKS.Cg-Dock7 < m > +/+ Lepr < db >/J) mouse model. Yet, a systematic H NMR based metabolomics characterisation of most tissues in this animal model has not been published. Here, we provide a systematic organ-specific metabolomics analysis of this widely employed model using NMR spectroscopy. OBJECTIVES:The aim of this study was to characterise the metabolic modulations associated with T2D in db/db mice in 18 relevant biological matrices. METHODS:High-resolution H-NMR and 2D-NMR spectroscopy were applied to 18 biological matrices of 12 db/db mice (WT control n = 6, db/db = 6) aged 22 weeks, when diabetes is fully established. RESULTS:61 metabolites associated with T2D were identified. Kidney, spleen, eye and plasma were the biological matrices carrying the largest metabolomics modulations observed in established T2D, based on the total number of metabolites that showed a statistical difference between the diabetic and control group in each tissue (16 in each case) and the strength of the O-PLS DA model for each tissue. Glucose and glutamate were the most commonly associated metabolites found significantly increased in nine biological matrices. Investigated sections where no increase of glucose was associated with T2D include all intestinal segments (i.e. duodenum, jejunum, ileum and colon). Microbial co-metabolites such as acetate and butyrate, used as carbon sources by the host, were identified in excess in the colonic tissues of diabetic individuals. CONCLUSIONS:The metabolic biomarkers identified using H NMR-based metabolomics will represent a useful resource to explore metabolic pathways involved in T2D in the db/db mouse model. 10.1007/s11306-019-1548-8
    [Quality evaluation of different Berberidis Cortex species based on ~1H-NMR metabolomics and anti-diabetic activity]. Gang Fan,Qi L I,Xin-Mei X U,Huan D U,Tong X U,Xian-Rong Lai,Lei-Lei D U Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica To evaluate the quality differences of four mainstream species of Berberidis Cortex,~1H-NMR metabolomics was applied to detect its primary and secondary metabolites, and the partial least squares discriminant analysis and analysis of variance were integrated to screen differential metabolites between species. Furthermore, diabetic rat model was established by high fat diet and streptozotocin to assess differences in antidiabetic activities among the four species. Sixteen compounds were simultaneously detected and identified, including alkaloids, organic acids, carbohydrates and amino acids. Interspecific difference markers were revealed as magnoflorine, jateorhi-zine, bufotenidine and saccharose for the first time. Berberis vernae and B. kansuensis presented superior activities on reducing blood glucose level, improving insulin resistance, increasing insulin sensibility and anti-inflammation. B. dictyophylla showed moderate antidiabe-tic effect, while B. diaphana rendered inferior antidiabetic capacity. Based on the contents of four differential markers and the results of antidiabetic activity evaluation, the quality of four Berberidis Cortex species was ranked as B.vernae≈B.kansuensis&gt;B. dictyophylla&gt;B. diaphana. These results provided references for species collation, quality standard establishment and exploitation of Berberidis Cortex. The antidiabetic activities of B. vernae and B. kansuensis as well as their mechanisms of action merit further study in the future. 10.19540/j.cnki.cjcmm.20200620.201
    Therapeutic Effectiveness of on Type 2 Diabetic Rats: Mass Spectrometry-Based Metabolomics Approach. Wang Lu,Yang Chen,Song Fengrui,Liu Zhiqiang,Liu Shu Journal of agricultural and food chemistry fruits, a kind of traditional Chinese medicine (TCM), have shown prospects in the prevention of diabetes and its complications. However, due to their chemical diversity and multiple biological targets, the effective mechanism remains largely unknown. In this study, mass spectrometry-based metabolomics was applied to uncover the underlying therapeutic mechanism of on type 2 diabetes (T2D) and its clinical complications. We established a T2D rat model using high-fat diet and identified 45 urinary endogenous metabolites as potential diagnostic biomarkers for T2D rats. After treatment with , pathologic symptoms of T2D rats were significantly improved and some of the diagnostic biomarkers were significantly regulated. Bioinformatics analysis demonstrated that these therapeutic biomarkers were involved in bile acid biosynthesis, amino acid metabolism, vitamin B metabolism, taurine metabolism, etc., which indicated potential therapeutic mechanisms of on T2D and its complications. 10.1021/acs.jafc.0c02873
    Effects of Qijian mixture on type 2 diabetes assessed by metabonomics, gut microbiota and network pharmacology. Gao Kuo,Yang Ran,Zhang Jian,Wang Zhiyong,Jia Caixia,Zhang Feilong,Li Shaojing,Wang Jinping,Murtaza Ghulam,Xie Hua,Zhao Huihui,Wang Wei,Chen Jianxin Pharmacological research Qijian mixture, a new traditional Chinese medicine (TCM) formula comprising of Astragalus membranaceus, Ramulus euonymi, Coptis chinensis and Pueraria lobata, was designed to ameliorate the type 2 diabetes (T2D), and its safety and efficacy were evaluated in the research by metabonomics, gut microbiota and system pharmacology. To study the hypoglycemic effect of Qijian mixture, male KKay mice (28-30 g, 8-9 week) and C57/BL6 mice (18-19 g, 8-9 week) were used. Thirty KKay diabetic mice were randomly distributed into 5 groups, abbreviated as Model group (Model), Low Qijian Mixture group (QJM(L)), High Qijian Mixture group (QJM(H)), Chinese Medicine (Gegen Qinlian Decoction) Positive group (GGQL), and Western Medicine (Metformin hydrochloride) Positive group (Metformin). C57/BL6 was considered as the healthy control group (Control). Moreover, a system pharmacology approach was utilized to assess the physiological targets involved in the action of Qijian mixture. There was no adverse drug reaction of Qijian mixture in the acute toxicity study and HE result, and, compared with Model group, Qijian mixture could modulate blood glycemic level safely and effectively. Qijian Mixture was lesser effective than metformin hydrochloride; however, both showed similar hypoglycemic trend. Based on H NMR based metabonomics study, the profoundly altered metabolites in Qijian mixture treatment group were identified. Qijian mixture-related 55 proteins and 4 signaling pathways, including galactose metabolism, valine, leucine and isoleucine degradation metabolism, aminoacyl-tRNA biosynthesis metabolism and alanine, aspartate and glutamate metabolism pathways, were explored. The PCoA analysis of gut microbiota revealed that Qijian mixture treatment profoundly enriched bacteroidetes. In addition, the system pharmacology paradigm revealed that Qijian mixture acted through TP53, AKT1 and PPARA proteins. It was concluded that Qijian mixture effectively alleviated T2D, and this effect was linked with the altered features of the metabolite profiles and the gut microbiota. 10.1016/j.phrs.2018.01.011
    Metabolomics Study of Type 2 Diabetes Mellitus and the AntiDiabetic Effect of Berberine in Zucker Diabetic Fatty Rats Using Uplc-ESI-Hdms. Dong Yu,Chen Yi-Tao,Yang Yuan-Xiao,Zhou Xiao-Jie,Dai Shi-Jie,Tong Jun-Feng,Shou Dan,Li Changyu Phytotherapy research : PTR The present study aimed to evaluate the pathogenesis of type 2 diabetes mellitus (T2DM) and the anti-diabetic effect of berberine in Zucker diabetic fatty (ZDF) rats. A urinary metabolomics analysis was performed with ultra-performance liquid chromatography/electrospray ionization synapt high-definition mass spectrometry. Pattern recognition approaches were integrated to discover differentiating metabolites. We identified 29 ions (13 in negative mode and 16 in positive mode) as 'differentiating metabolites' with this metabolomic approach. A functional pathway analysis revealed that the alterations were mainly associated with glyoxylate and dicarboxylate metabolism, pentose and glucuronate interconversions and sphingolipid metabolism. These results indicated that the dysfunctions of glycometabolism and lipometabolism are involved in the pathological process of T2DM. Berberine could decrease the serum levels of glycosylated hemoglobin, total cholesterol and triglyceride and increase the secretion of insulin. The urinary metabolomics analysis showed that berberine could reduce the concentrations of citric acid, tetrahydrocortisol, ribothymidine and sphinganine to a near-normal state. These results suggested that the anti-diabetic effect of berberine occurred mainly via its regulation of glycometabolism and lipometabolism and activation of adenosine 5'-monophosphate-activated protein kinase. Our work not only provides a better understanding of the anti-diabetic effect of berberine in ZDF rats but also supplies a useful database for further study in humans and for investigating the pharmacological actions of drugs. Copyright © 2016 John Wiley & Sons, Ltd. 10.1002/ptr.5587
    Systemic perturbations of key metabolites in diabetic rats during the evolution of diabetes studied by urine metabonomics. Guan Mimi,Xie Liyun,Diao Chengfeng,Wang Na,Hu Wenyi,Zheng Yongquan,Jin Litai,Yan Zhihan,Gao Hongchang PloS one BACKGROUND:Elucidation of metabolic profiles during diabetes progression helps understand the pathogenesis of diabetes mellitus. In this study, urine metabonomics was used to identify time-related metabolic changes that occur during the development of diabetes mellitus and characterize the biochemical process of diabetes on a systemic, metabolic level. METHODOLOGY/PRINCIPAL FINDINGS:Urine samples were collected from diabetic rats and age-matched controls at different time points: 1, 5, 10, and 15 weeks after diabetes modeling. (1)H nuclear magnetic resonance ((1)H NMR) spectra of the urine samples were obtained and analyzed by multivariate data analysis and quantitative statistical analysis. The metabolic patterns of diabetic groups are separated from the controls at each time point, suggesting that the metabolic profiles of diabetic rats were markedly different from the controls. Moreover, the samples from the diabetic 1-wk group are closely associated, whereas those of the diabetic 15-wk group are scattered, suggesting that the presence of various of complications contributes significantly to the pathogenesis of diabetes. Quantitative analysis indicated that urinary metabolites related to energy metabolism, tricarboxylic acid (TCA) cycle, and methylamine metabolism are involved in the evolution of diabetes. CONCLUSIONS/SIGNIFICANCE:The results highlighted that the numbers of metabolic changes were related to diabetes progression, and the perturbed metabolites represent potential metabolic biomarkers and provide clues that can elucidate the mechanisms underlying the generation and development of diabetes as well as its complication. 10.1371/journal.pone.0060409
    Metabolomics-based evidence of the hypoglycemic effect of Ge-Gen-Jiao-Tai-Wan in type 2 diabetic rats via UHPLC-QTOF/MS analysis. Wang Wenbo,Zhao Linlin,He Zhenyu,Wu Ning,Li Qiuxia,Qiu Xinjian,Zhou Lu,Wang Dongsheng Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Ge-Gen-Jiao-Tai-Wan (GGJTW) formula, derived from traditional Chinese herbal medicine, is composed of Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep (Ge-Gen in Chinese), Coptis chinensis Franch (Huang-Lian), and Cinnamomum cassia (L.) J. Presl (Rou-Gui). GGJTW is used for treatment of diabetes in China, reflecting the potent hypoglycemic effect of its ingredients. However, little is known of the hypoglycemic effect of GGJTW and the underlying metabolic mechanism. AIM OF THE STUDY:This study aimed to investigate the hypoglycemic effect of GGJTW in type 2 diabetic rats and the metabolic mechanism of action. MATERIALS AND METHODS:Ultra high-performance liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry (UHPLC-QTOF/MS)-based metabolomics approach was used for monitoring hyperglycaemia induced by high-sugar high-fat fodder and streptozotocin (STZ), and the protective effect of GGJTW. Dynamic fasting blood glucose (FBG) levels, body weight, and biochemical parameters, including lipid levels, hepatic-renal function, and hepatic histopathology were used to confirm the hyperglycaemic toxicity and attenuation effects. An orthogonal partial least squared-discriminant analysis (OPLS-DA) approach highlighted significant differences in the metabolome of the healthy control, diabetic, and drug-treated rats. The metabolomics pathway analysis (MetPA) and Kyoto encyclopedia of genes and genomes (KEGG) database were used to investigate the underlying metabolic pathways. RESULTS:Metabolic profiling revealed 37 metabolites as the most potential biomarker metabolites distinguishing GGJTW-treated rats from model rats. Most of the metabolites were primarily associated with bile acid metabolism and lipid metabolism. The most critical pathway was primary bile acid biosynthesis pathway involving the up-regulation of the levels of cholic acid (CA), chenodeoxycholic acid (CDCA), taurocholic acid (TCA), glycocholic acid (GCA), taurochenodesoxycholic acid (TCDCA), and taurine. CONCLUSIONS:The significantly-altered metabolite levels indicated the hypoglycemic effect of GGJTW on diabetic rats and the underlying metabolic mechanism. This study will be meaningful for the clinical application of GGJTW and valuable for further exploration of the mechanism. 10.1016/j.jep.2018.03.026
    Berberine combined with stachyose induces better glycometabolism than berberine alone through modulating gut microbiota and fecal metabolomics in diabetic mice. Li Cai-Na,Wang Xing,Lei Lei,Liu Min-Zhi,Li Rong-Cui,Sun Su-Juan,Liu Shuai-Nan,Huan Yi,Zhou Tian,Liu Quan,Cao Hui,Bai Guo-Liang,Han Yu-Wei,Shen Zhu-Fang Phytotherapy research : PTR Berberine (BBR), a small alkaloid, is used as a hypoglycemic agent in China. Stachyose (Sta), a Rehmannia glutinosa oligosaccharide, acts as a prebiotic. This study aimed to evaluate whether BBR combined with Sta produced better glycometabolism than BBR alone, and explored the effects on gut microbiota and metabolomics. Type-2 diabetic db/db mice were administered BBR (100 mg/kg), Sta (200 mg/kg), or both by gavage once daily. Glucose metabolism, the balance of α- and β-cells, and mucin-2 expression were ameliorated by combined treatment of BBR and Sta, with stronger effects than upon treatment with BBR alone. The microbial diversity and richness were altered after combined treatment and after treatment with BBR alone. The abundance of Akkermansia muciniphila was increased by combined treatment compared to treatment with BBR alone, while the levels of the metabolite all-trans-heptaprenyl diphosphate were decreased and the levels of fumaric acid were increased, which both showed a strong correlation with A. muciniphila. In summary, BBR combined with Sta produced better glycometabolism than BBR alone through modulating gut microbiota and fecal metabolomics, and may aid in the development of a novel pharmaceutical strategy for treating Type 2 diabetes mellitus. 10.1002/ptr.6588
    H NMR Metabolomics and Full-Length RNA-Seq Reveal Effects of Acylated and Nonacylated Anthocyanins on Hepatic Metabolites and Gene Expression in Zucker Diabetic Fatty Rats. Chen Kang,Wei Xuetao,Pariyani Raghunath,Kortesniemi Maaria,Zhang Yumei,Yang Baoru Journal of agricultural and food chemistry Anthocyanins have been reported to possess antidiabetic effects. Recent studies indicate acylated anthocyanins have better stability and antioxidative activity compared to their nonacylated counterparts. This study compared the effects of nonacylated and acylated anthocyanins on hepatic gene expression and metabolic profile in diabetic rats, using full-length transcriptomics and H NMR metabolomics. Zucker diabetic fatty (ZDF) rats were fed with nonacylated anthocyanin extract from bilberries (NAAB) or acylated anthocyanin extract from purple potatoes (AAPP) at daily doses of 25 and 50 mg/kg body weight for 8 weeks. Both anthocyanin extracts restored the levels of multiple metabolites (glucose, lactate, alanine, and pyruvate) and expression of genes (, , , and ) involved in glycolysis and gluconeogenesis. AAPP decreased the hepatic glutamine level. NAAB regulated the expression of , , and , whereas AAPP modified the expression of , , , and . This study indicated different effects of AAPP and NAAB on the hepatic transcriptomic and metabolic profiles of diabetic rats. 10.1021/acs.jafc.1c00130
    Modulation of metabolic alterations of obese diabetic rats upon treatment with Salacca zalacca fruits extract using H NMR-based metabolomics. Saleh Mohammed S M,Siddiqui Mohammad Jamshed,Mediani Ahmed,Ahmed Qamar Uddin,Mat So'ad Siti Zaiton,Saidi-Besbes Salima,Elnaem Mohamed Hassan,Othman Hairol Azrin,Ismail Nor Hadiani Food research international (Ottawa, Ont.) Fruit of salak (Salacca zalacca) is traditionally used and commercialized as an antidiabetic agent. However, the scientific evidence to prove this traditional use is lacking. This research was aimed to evaluate the metabolic changes of obese-diabetic (OBDC) rats treated with S. zalacca fruit extract using proton-nuclear magnetic resonance (H NMR)-based metabolomics approach. This research presents the first report on the in vitro antidiabetic effect of S. zalacca fruits extract using this approach. The obtained results indicated that the administration of 400 mg/kg bw of 60% ethanolic S. zalacca extract for 6 weeks significantly decreased the blood glucose level and normalized the blood lipid profile of the OBDC rats. The potential biomarkers in urine were 2-oxoglutarate, alanine, leucine, succinate 3-hydroxybutyrate, taurine, betaine, allantoin, acetate, dimethylamine, creatine, creatinine, glucose, phenyl-acetylglycine, and hippurate. Based on the data obtained, the 60% ethanolic extract could not fully improved the metabolic complications of diabetic rats. The extract of S. zalacca fruit was able to decrease the ketones bodies as 3-hydroxybutyrate and acetoacetate. It also improved energy metabolism, involving glucose, acetate, lactate, 2-hydroxybutyrate, 2-oxoglutarate, citrate, and succinate. Moreover, it decreased metabolites from gut microflora, including choline. This extract had significant effect on amino acid metabolism, metabolites from gut microflora, bile acid metabolism and creatine. The result can further support the traditional claims of S. zalacca fruits in management of diabetes. This finding might be valuable in understanding the molecular mechanism and pharmacological properties of this medicinal plant for managing diabetes mellitus. 10.1016/j.foodres.2020.109547
    Revealing hypoglycemic and hypolipidemic mechanism of Xiaokeyinshui extract combination on streptozotocin-induced diabetic mice in high sucrose/high fat diet by metabolomics and lipidomics. Xiang Zhinan,Xie Haifei,Tong Qilin,Pan Jun,Wan Luosheng,Fang Jinbo,Chen Jiachun Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Type 2 diabetic mellitus (T2DM), often accompanied by disorders of glucose and lipid metabolism, has troubled hundreds of millions of people. Xiaokeyinshui extract combination (XEC), derived from traditional Chinese medicines formula, has exerted hypoglycemic effects against T2DM. However, its mechanism of metabolic level is still unclear. In this study, a T2DM mice model, induced by a high sucrose/high fat diet combined with low-dose streptozotocin (STZ) injections, was adopted. The biochemical index was determined and a combination of metabolomics and lipidomics analyses of plasma were performed. The results showed that XEC increased secretion of insulin and level of HDL-C, decreased levels of FBG, HbA1c, TC, TG, LDL-C and repaired islet structure in diabetic mice. In addition, the metabolic profiles of plasma were analyzed and 54 potential biomarkers were screened out, mainly including carbohydrates, lipids and amino acids. These potential biomarkers were found to be correlated with the following pathways: galactose metabolism, fructose and mannose metabolism, TCA cycle, arachidonic acid metabolism, glycerolipid metabolism, glycerophospholipid metabolism, sphingolipid metabolism and amino acid metabolism. In conclusion, we speculated that carbohydrate metabolism, lipid metabolism and amino acid metabolism played roles in the therapeutic mechanisms of XEC on T2DM. 10.1016/j.biopha.2021.111219
    Study on Hypoglycemic Effect of the Drug Pair of Astragalus Radix and Dioscoreae Rhizoma in T2DM Rats by Network Pharmacology and Metabonomics. Guo Qian,Niu Wanlin,Li Xuejia,Guo Hongru,Zhang Na,Wang Xiufeng,Wu Lirong Molecules (Basel, Switzerland) Type 2 diabetes mellitus (T2DM) is a metabolic disease accompanied by a series of diseases such as diabetic nephropathy. The drug pair (HS) of Astragalus Radix (HQ) and Dioscoreae Rhizoma (SY) was designed by Dr. Shi Jinmo to improve the treatment of T2DM. However, the exact mechanism involved requires further clarification. In this work, H-NMR-based metabonomics and network pharmacology were adopted. Metabolic profiling indicated that the metabolic perturbation was reduced after HS treatment. The results found 21 biomarkers. According to the network pharmacology, we found that the regulation of T2DM was primarily associated with 18 active compounds in HS. These active compounds mainly had an effect on 135 targets. Subsequently, combining network pharmacology and metabonomics, we found four target proteins, which indicated that HS has potential hypoglycemic effects through regulating monoamine oxidases B (MAOB), acetyl-CoA carboxylase 1 (ACACA), carbonic anhydrase 2 (CA2), and catalase (CAT). In conclusion, the result showed that these four targets might be the most relevant targets for the treatment of T2DM with HS. This study clarified the mechanism of HS in the treatment of T2DM and also confirmed the feasibility of combining metabonomics and network pharmacology to study the mechanisms of traditional Chinese medicine (TCM). In the future, this approach may be a potentially powerful tool to discovery active components of traditional Chinese medicines and elucidate their mechanisms. 10.3390/molecules24224050
    Explore of the beneficial effects of Huang-Lian-Jie-Du Decoction on diabetic encephalopathy in db/db mice by UPLC-Q-Orbitrap HRMS/MS based untargeted metabolomics analysis. He Wen-Jiao,Cao Dong-Min,Chen Yun-Bo,Shi Jing-Jing,Hu Tian,Zhang Zhi-Tong,Lan Tian,Tang Dan,Wang Shu-Mei Journal of pharmaceutical and biomedical analysis Diabetic encephalopathy (DE) is a severe diabetic complication with cognitive dysfunction. Huang-Lian-Jie-Du Decoction (HLJDD), a famous traditional Chinese formula, is effective for the treatment of diabetes mellitus and Alzheimer's disease in clinical practices, however, the therapeutic effects and the underlying mechanisms of HLJDD on DE is unclear yet. With this purpose, behavior test, brain histological and biochemical analysis were estimated to assess the beneficial effects of HLJDD on DE. Plasma samples were collected for metabolomics analysis based on UPLC-Q-Orbitrap HRMS/MS and chemometric analysis. As a result, morris water maze test revealed that HLJDD could effectively improve the learning and memory abilities in db/db mice. Brain histological and biochemical analysis indicated that HLJDD could protect against neurodegeneration and oxidative stress in db/db mice. Meanwhile, a total of 21 potential biomarkers with significant differences were identified between Model group and Control group using untargeted metabolomics strategy. Among them, 11 metabolites showed a trend towards the normal levels after HLJDD intervention. These metabolites principally involved in glycerophospholipid metabolism, fatty acid β-oxidation, linoleic acid metabolism, glucose metabolism and glutathione metabolism based on the metabolic pathway analysis, which were regulated in DE model mice after HLJDD intervention. Generally, the results demonstrated that HLJDD had beneficial effects on DE, which could be mediated via ameliorating the metabolic disorders. 10.1016/j.jpba.2020.113652
    The application of metabolomics in investigating anti-diabetic activity of medicinal plants. Hasanpour Maede,Iranshahy Milad,Iranshahi Mehrdad Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Diabetes mellitus is the most prevalent endocrine disease in the world and is likely to be the major epidemic in human history. In current years, many modern anti-diabetic medicines have been produced and introduced into the markets, however, long-term treatment of diabetes using synthetic drugs is limited. Medicinal plants play a great role in the treatment of diabetes. Many medicinal plants and their related traditional treatments for diabetes are used throughout the world and represent promising alternatives for the management of diabetes treatment. Metabolomics researches on diabetes have contributed to many aspects of exploring biomarkers and understanding the progression of the disease at metabolic levels. In addition, in the last decade, a number of metabolomics studies have focused on investigating the action mechanism of various herbal medicines. This paper aims to highlight and review a series of metabolomics studies that carried out on the role of herbal medicines on obesity and diabetes, finding potential biomarkers and also characterizing the metabolic disturbances associated with diabetes development. The findings showed that the metabolism of glycolysis/gluconeogenesis (glucose, pyruvate, lactate), TCA cycle (succinate, citrate, β-hydroxybutyrate, 2-oxoglutarate), lipid metabolism (acetoacetate, acetate) and amino acid metabolic pathways (valine, leucine, and isoleucine, hippurate, creatine) were more significantly disturbed metabolic pathways and biomarkers in diabetic models and herbal medicines affect these metabolic pathways by different mechanisms. 10.1016/j.biopha.2020.110263
    Fecal Metabolomics of Type 2 Diabetic Rats and Treatment with Gardenia jasminoides Ellis Based on Mass Spectrometry Technique. Zhou Yuan,Men Lihui,Pi Zifeng,Wei Mengying,Song Fengrui,Zhao Chunfang,Liu Zhiqiang Journal of agricultural and food chemistry Modern studies have indicated Gardenia jasminoides Ellis (G. jasminoides) showed positive effect in treating type 2 diabetes mellitus (T2DM). In this study, 60 streptozotocin-induced T2DM rats were divided into four groups: type 2 diabetes control group, geniposide-treated group, total iridoid glycosides-treated group, and crude extraction of gardenlae fructus-treated group. The other ten healthy rats were the healthy control group. During 12 weeks of treatment, rat's feces samples were collected for the metabolomics study based on mass spectrometry technique. On the basis of the fecal metabolomics method, 19 potential biomarkers were screened and their relative intensities in each group were compared. The results revealed G. jasminoides mainly regulated dysfunctions in phenylalanine metabolism, tryptophan metabolism, and secondary bile acid biosynthesis pathways induced by diabetes. The current study provides new insight for metabonomics methodology toward T2DM, and the results show that feces can preferably reflect the liver and intestines disorders. 10.1021/acs.jafc.7b06082
    Metabolomics window into diabetic complications. Wu Tao,Qiao Shuxuan,Shi Chenze,Wang Shuya,Ji Guang Journal of diabetes investigation Diabetes has become a major global health problem. The elucidation of characteristic metabolic alterations during the diabetic progression is critical for better understanding its pathogenesis, and identifying potential biomarkers and drug targets. Metabolomics is a promising tool to reveal the metabolic changes and the underlying mechanism involved in the pathogenesis of diabetic complications. The present review provides an update on the application of metabolomics in diabetic complications, including diabetic coronary artery disease, diabetic nephropathy, diabetic retinopathy and diabetic neuropathy, and this review provides notes on the prevention and prediction of diabetic complications. 10.1111/jdi.12723
    Urinary metabolomics analysis reveals the anti-diabetic effect of stachyose in high-fat diet/streptozotocin-induced type 2 diabetic rats. Liang Li,Liu Guimei,Yu Guoyong,Zhang Fuming,Linhardt Robert J,Li Quanhong Carbohydrate polymers As a new platform of systems biology, metabolomics provides a powerful approach to discover therapeutic biomarkers and mechanism of metabolic disease. Type 2 diabetes mellitus (T2DM) is a global metabolic disease, thus, a urinary metabolomics profiling was analyzed to study the anti-diabetic effects and mechanism of stachyose (ST) on high-fat diet- and low dose streptozotocinc-induced T2DM rats. The results showed that ST treatment regulated the level of insulin, low-density lipoprotein cholesterol, and triglycerides, which demonstrates improvement in T2DM on ST treatment. Urinary samples from the ST and T2DM group were enrolled in metabolomics study, 21 differential metabolites were identified from urinary metabolomics analysis, indicating that the ST treatment partly exerted the anti-diabetes activity by regulating energy metabolism, gut microbiota changes and inflammation. A metabolomics strategy is both suitable and reliable for exploring the anti-diabetes effects and understanding the mechanisms of ST treatment against T2DM. 10.1016/j.carbpol.2019.115534
    Anti-Diabetic Effects of Berberis kansuensis Extract on Type 2 Diabetic Rats Revealed by H-NMR-Based Metabolomics and Biochemistry Analysis. Du Huan,Li Qi,Yi Huan,Xu Tong,Xu Xin-Mei,Kuang Ting-Ting,Zhang Jing,Huang An-Qing,Fan Gang Chemistry & biodiversity The dried stem bark of Berberis kansuensis C.K.Schneid. (Berberidaceae) was widely used to treat diabetes in traditional Tibetan medicine system. However, its anti-diabetic mechanisms have not been elucidated. In this study, H-NMR-based metabolomics combined with biochemistry assay was applied to investigate the anti-diabetic activities as well as underlying mechanisms of B. kansuensis extract on type 2 diabetic rats. The results showed that after 30 days treatment with B. kansuensis extract, the levels of FBG, GSP, INS, TNF-α, IL-1β and IL-6 were significantly decreased in B. kansuensis group compared with the model group. Besides, a total of 28 metabolites were identified in rat serum by H-NMR-based metabolomics method, 16 of which were significantly different in the normal group compared with the model group, and eight of them were significantly reversed after B. kansuensis intervention. Further analysis of metabolic pathways indicated that therapeutic effect of B. kansuensis might be predominantly related to their ability to improve glycolysis and gluconeogenesis, citric acid cycle, lipid metabolism, amino acid metabolism and choline metabolism. The results of both metabolomics and biochemical analysis indicated that B. kansuensis extract has a potential anti-diabetic effect on type 2 diabetic rats. Its therapeutic effect may be based on the ability of anti-inflammation, alleviating insulin resistance and restoring several disturbed metabolic pathways. 10.1002/cbdv.202000413
    Urine Metabonomics Reveals Early Biomarkers in Diabetic Cognitive Dysfunction. Song Lili,Zhuang Pengwei,Lin Mengya,Kang Mingqin,Liu Hongyue,Zhang Yuping,Yang Zhen,Chen Yunlong,Zhang Yanjun Journal of proteome research Recently, increasing attention has been paid to diabetic encephalopathy, which is a frequent diabetic complication and affects nearly 30% of diabetics. Because cognitive dysfunction from diabetic encephalopathy might develop into irreversible dementia, early diagnosis and detection of this disease is of great significance for its prevention and treatment. This study is to investigate the early specific metabolites biomarkers in urine prior to the onset of diabetic cognitive dysfunction (DCD) by using metabolomics technology. An ultra-high performance liquid-chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-Q/TOF-MS) platform was used to analyze the urine samples from diabetic mice that were associated with mild cognitive impairment (MCI) and nonassociated with MCI in the stage of diabetes (prior to the onset of DCD). We then screened and validated the early biomarkers using OPLS-DA model and support vector machine (SVM) method. Following multivariate statistical and integration analysis, we found that seven metabolites could be accepted as early biomarkers of DCD, and the SVM results showed that the prediction accuracy is as high as 91.66%. The identities of four biomarkers were determined by mass spectrometry. The identified biomarkers were largely involved in nicotinate and nicotinamide metabolism, glutathione metabolism, tryptophan metabolism, and sphingolipid metabolism. The present study first revealed reliable biomarkers for early diagnosis of DCD. It provides new insight and strategy for the early diagnosis and treatment of DCD. 10.1021/acs.jproteome.7b00168