Abstract
Type 2 diabetes (T2D), called the burden of the twenty-first century, is growing with an epidemic rate. Here, we explored the differences in metabolite concentrations between T2D patients and healthy volunteers. Metabolomics represents an emerging discipline concerned with comprehensive analysis of small molecule metabolites and provides a powerful approach to discover biomarkers in biological systems. The acquired data were analyzed by ultra-performance liquid chromatography–electrospray ionization/quadrupole time-of-flight high-definition mass spectrometry coupled with pattern recognition approach [principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA)] to identify potential disease-specific biomarkers. PCA showed satisfactory clustering between patients and healthy volunteers. Biomarkers reflected the biochemical events associated with early stages of T2D which were observed in PLS-DA loading plots. These urinary differential metabolites, such as adiponectin, acylcarnitines, citric acid, kynurenic acid, 3-indoxyl sulfate, urate, and glucose, were identified involving several key metabolic pathways such as taurine and hypotaurine metabolism; cysteine and methionine metabolism; valine, leucine, and isoleucine biosynthesis metabolism, etc. Our data suggest that robust metabolomics has the potential as a noninvasive strategy to evaluate the early diagnosis of T2D patients and provides new insight into pathophysiologic mechanisms and may enhance the understanding of its cause of disease.
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Arakaki AK, Skolnick J, McDonald JF (2008) Marker metabolites can be therapeutic targets as well. Nature 456:443
Bremer CM, Sominskaya I, Skrastina D, Pumpens P, El Wahed AA, Beutling U, Frank R, Fritz HJ, Hunsmann G, Gerlich WH, Glebe D (2011) N-terminal myristoylation-dependent masking of neutralizing epitopes in the preS1 attachment site of hepatitis B virus. J Hepatol 55:29–37
Chen J, Wen H, Liu J, Yu C, Zhao X, Shi X, Xu G (2012) Metabonomics study of the acute graft rejection in rat renal transplantation using reversed-phase liquid chromatography and hydrophilic interaction chromatography coupled with mass spectrometry. Mol Biosyst 8:871–878
Connor SC, Hansen MK, Corner A, Smith RF, Ryan TE (2010) Integration of metabolomics and transcriptomics data to aid biomarker discovery in type 2 diabetes. Mol Biosyst 6:909–921
Fabris C, Falleti E, Cussigh A, Bitetto D, Fontanini E, Bignulin S, Cmet S, Fornasiere E, Fumolo E, Fangazio S, Cerutti A, Minisini R, Pirisi M, Toniutto P (2011) IL-28B rs12979860 C/T allele distribution in patients with liver cirrhosis: role in the course of chronic viral hepatitis and the development of HCC. J Hepatol 54:716–722
Fellay J, Thompson AJ, Ge D, Gumbs CE, Urban TJ, Shianna KV, Little LD, Qiu P, Bertelsen AH, Watson M, Warner A, Muir AJ, Brass C, Albrecht J, Sulkowski M, McHutchison JG, Goldstein DB (2010) ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature 464:405–408
Ganter B, Giroux CN (2008) Emerging applications of network and pathway analysis in drug discovery and development. Curr Opin Drug Discov Dev 11:86–94
Hamed EA, Zakary MM, Abdelal RM, Abdel Moneim EM (2011) Vasculopathy in type 2 diabetes mellitus: role of specific angiogenic modulators. J Physiol Biochem 67:339–349
Lee SA, Kim K, Kim H, Kim BJ (2012) Nucleotide change of codon 182 in the surface gene of hepatitis B virus genotype C leading to truncated surface protein is associated with progression of liver diseases. J Hepatol 56:63–69
Li S, Liu H, Jin Y, Lin S, Cai Z, Jiang Y (2011) Metabolomics study of alcohol-induced liver injury and hepatocellular carcinoma xenografts in mice. Chromatogr B Analyt Technol Biomed Life Sci 879:2369–2375
Manna SK, Patterson AD, Yang Q, Krausz KW, Idle JR, Fornace AJ, Gonzalez FJ (2011) UPLC-MS-based urine metabolomics reveals indole-3-lactic acid and phenyllactic acid as conserved biomarkers for alcohol-induced liver disease in the Ppara-null mouse model. J Proteome Res 10:4120–4133
Maher AD, Lindon JC, Nicholson JK (2009) 1H NMR-based metabonomics for investigating diabetes. Futur Med Chem 1:737–747
McMahon MA, Jilek BL, Brennan TP, Shen L, Zhou Y, Wind-Rotolo M, Xing S, Bhat S, Hale B, Hegarty R, Chong CR, Liu JO, Siliciano RF, Thio CL (2007) The HBV drug entecavir—effects on HIV-1 replication and resistance. N Engl J Med 356:2614–2621
Ouattara DA, Prot JM, Bunescu A, Dumas ME, Elena-Herrmann B, Leclerc E, Brochot C (2012) Metabolomics-on-a-chip and metabolic flux analysis for label-free modeling of the internal metabolism of HepG2/C3A cells. Mol Biosyst 8:1908–1920
Ramesh B, Saralakumari D (2012) Antihyperglycemic, hypolipidemic and antioxidant activities of ethanolic extract of Commiphora mukul gum resin in fructose-fed male Wistar rats. J Physiol Biochem 68:573–582
Rodrigues L, Crisóstomo J, Matafome P, Louro T, Nunes E, Seiça R (2011) Dietary restriction improves systemic and muscular oxidative stress in type 2 diabetic Goto-Kakizaki rats. J Physiol Biochem 67:613–619
Sun H, Zhang A, Yan G, Piao C, Li W, Sun C, Wu X, Li X, Chen Y, Wang X (2013) Metabolomic analysis of key regulatory metabolites in hepatitis C virus-infected tree shrews. Mol Cell Proteomics 12:710–719
Wang X, Yang B, Zhang A, Sun H, Yan G (2012) Potential drug targets on insomnia and intervention effects of jujuboside A through metabolic pathway analysis as revealed by UPLC/ESI-SYNAPT-HDMS coupled with pattern recognition approach. J Proteomics 75:1411–1427
Wang X, Zhang A, Han Y, Wang P, Sun H, Song G, Dong T, Yuan Y, Yuan X, Zhang M, Xie N, Zhang H, Dong H, Dong W (2012) Urine metabolomics analysis for biomarker discovery and detection of jaundice syndrome in patients with liver disease. Mol Cell Proteomics 11:370–380
Wang X, Wang Q, Zhang A, Zhang F, Zhang H, Sun H, Cao H, Zhang H (2013) Metabolomics study of intervention effects of Wen-Xin-Formula using ultra high-performance liquid chromatography/mass spectrometry coupled with pattern recognition approach. J Pharm Biomed Anal 74:22–30
Wang X, Yang B, Sun H, Zhang A (2012) Pattern recognition approaches and computational systems tools for ultra performance liquid chromatography-mass spectrometry-based comprehensive metabolomic profiling and pathways analysis of biological data sets. Anal Chem 84:428–439
Wang X, Zhang A, Sun H (2012) Future perspectives of Chinese medical formulae: chinmedomics as an effector. OMICS 16:414–421
Wang X, Zhang A, Sun H (2013) Power of metabolomics in diagnosis and biomarker discovery of hepatocellular carcinoma. Hepatology 57:2072–2077
Wang X, Zhang A, Wang P, Sun H, Wu G, Sun W, Lv H, Jiao G, Xu H, Yuan Y, Liu L, Zou D, Wu Z, Han Y, Yan G, Dong W, Wu F, Dong T, Yu Y, Zhang S, Wu X, Tong X, Meng X (2013) Metabolomics coupled with proteomics advancing drug discovery toward more agile development of targeted combination therapies. Mol Cell Proteomics 12:1226–1238
Wedemeyer H, Yurdaydìn C, Dalekos GN, Erhardt A, Çakaloğlu Y, Değertekin H, Gürel S, Zeuzem S, Zachou K, Bozkaya H, Koch A, Bock T, Dienes HP, Manns MP, HIDIT Study Group (2011) Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med 364:322–331
Wong VW, Wong GL, Chu WC, Chim AM, Ong A, Yeung DK, Yiu KK, Chu SH, Chan HY, Woo J, Chan FK, Chan HL (2012) Hepatitis B virus infection and fatty liver in the general population. J Hepatol 56:533–540
Zhang A, Sun H, Wang P, Han Y, Wang X (2012) Recent and potential developments of biofluid analyses in metabolomics. J Proteomics 75:1079–1088
Zhang A, Sun H, Han Y, Yuan Y, Wang P, Song G, Yuan X, Zhang M, Xie N, Wang X (2012) Exploratory urinary metabolic biomarkers and pathways using UPLC-Q-TOF-HDMS coupled with pattern recognition approach. Analyst 137:4200–4208
Zhang AH, Sun H, Qiu S, Wang XJ (2013) Metabolomics in noninvasive breast cancer. Clin Chim Acta 424C:3–7
Zhang A, Sun H, Yan G, Han Y, Ye Y, Wang X (2013) Urinary metabolic profiling identifies a key role for glycocholic acid in human liver cancer by ultra-performance liquid-chromatography coupled with high-definition mass spectrometry. Clin Chim Acta 418:86–90
Zhang AH, Sun H, Qiu S, Wang XJ (2013) NMR-based metabolomics coupled with pattern recognition methods in biomarker discovery and disease diagnosis. Magn Reson Chem 51(9):549–556. doi:10.1002/mrc.3985
Zhang H, Jia J, Cheng J, Ye F, Li X, Gao H (2012) 1H NMR-based metabonomics study on serum of renal interstitial fibrosis rats induced by unilateral ureteral obstruction. Mol Biosyst 8:595–601
Zhang A, Sun H, Wang X (2012) Power of metabolomics in biomarker discovery and mining mechanisms of obesity. Obes Rev 14(4):344–349. doi:10.1111/obr.12011
Zhang A, Sun H, Han Y, Yan G, Wang X (2013) Urinary metabolic biomarker and pathway study of hepatitis B virus infected patients based on UPLC-MS system. PLoS One 8:e64381
Acknowledgments
This work was supported by grants from the Key Program of Natural Science Foundation of State (grant nos. 90709019, 81173500, 81302905 and 81202639), the National Key Technology Research and Development Program of the Ministry of Science and Technology of China (grant nos. 2011BAI03B03, 2011BAI03B06, and 2011BAI03B08), the Key Science and Technology Program of Heilongjiang Province, China (grant nos. GC06C501, GA08C303, and GA06C30101), the National Specific Program on the Subject of Public Welfare (grant no. 200807014), the National Key Subject of Drug Innovation (grant no. 2009ZX09502-005), the Foundation of Heilongjiang University of Chinese Medicine (grant no. 201209), and the Key Project of Chinese Ministry of Education (grant no. 212044). We thank Gao-chen Song, Xiao-xia Yuan, Liu Li, and Ning Xie for their assistance in the experiment.
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Zhang, Ah., Sun, H., Yan, Gl. et al. Metabolomics study of type 2 diabetes using ultra-performance LC-ESI/quadrupole-TOF high-definition MS coupled with pattern recognition methods. J Physiol Biochem 70, 117–128 (2014). https://doi.org/10.1007/s13105-013-0286-z
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DOI: https://doi.org/10.1007/s13105-013-0286-z