, 15:156 | Cite as

Clinical and metabolomics analysis of hepatocellular carcinoma patients with diabetes mellitus

  • Hongping XiaEmail author
  • Jianxiang Chen
  • Karthik Sekar
  • Ming Shi
  • Tian Xie
  • Kam M. HuiEmail author
Original Article



Diabetes and cancer are among the most frequent causes of death worldwide. Recent epidemiological findings have indicated a link between diabetes and cancer in several organs, particularly the liver. A number of epidemiological studies have demonstrated that diabetes is an established independent risk factor for hepatocellular carcinoma (HCC). However, the metabolites connecting diabetes and HCC remains less well understood.


The study aimed to identify clinical and metabolomics differences of HCC from patients with/without diabetes using comprehensive global metabolomics analysis.


Metabolite profiling was conducted with the Metabolon platform for 120 human diabetes/non-diabetes HCC tumor/normal tissues. Standard statistical analyses were performed using the Partek Genomics Suite on log-transformed data. Principal component analysis (PCA) was conducted using all and dysregulated metabolites.


We identified a group of metabolites that are differentially expressed in the tumor tissues of diabetes HCC compared to non-diabetes HCC patients. Meanwhile, we also identified a group of metabolites that are differentially expressed in the matched normal liver tissues of diabetes HCC compared to non-diabetes HCC patients. Some metabolites are consistently dysregulated in the tumor or matched normal tissues of HCC with or without diabetes. However, some metabolites, including 2-hydroxystearate, were only overexpressed in the tumor tissues of HCC with diabetes and associated with the glucose level.


Metabolic profiling identifies distinct dysregulated metabolites in HCC patients with/without diabetes.


Diabetes Hepatocellular carcinoma Metabolites Principal component analysis Metabolomics 



Hepatocellular carcinoma


Principal component analysis


Chronic hepatitis B


Hepatitis B virus


Gas chromatography coupled to mass spectrometry


Leukotriene B4


Type 2 diabetes mellitus


Ultra performance liquid chromatography–tandem mass spectrometer



This work was supported by grants from the National Medical Research Council of Singapore, the National Young 1000 Talents Program of China, the Jiangsu Province Education Department, the Jiangsu Province “Innovative and the Entrepreneurial Team” and “Innovative and Entrepreneurial Talent.”.

Author contributions

HX and KMH conceived, designed and HX performed the experiments, HX, KS and JC analyzed the data and wrote the manuscript; MS provide the clinical samples and clinical data; KMH and TX sourced funding, KMH supervised the work and contributed to writing the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest concerning the work described.

Ethical approval

This study was approved by the research ethics committee of the Sun Yat-sen University Cancer Center (Guangzhou, China). All tissue samples were collected in accordance with the protocols approved by the Institutional Review Board of the Sun Yat-sen University Cancer Center, and informed consent was obtained from all patients before tissue samples were collected.

Supplementary material

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  1. Bijlsma, M. F., Sadanandam, A., Tan, P., & Vermeulen, L. (2017). Molecular subtypes in cancers of the gastrointestinal tract. Nature Reviews Gastroenterology and Hepatology, 14, 333.CrossRefGoogle Scholar
  2. Chiba, K., et al. (2017). Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism. Science, eaao0535.Google Scholar
  3. Farmer, H., et al. (2005). Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature, 434, 917.CrossRefGoogle Scholar
  4. Gan, H. K., et al. (2015). Phase I study of ABT-414 mono- or combination therapy with temozolomide (TMZ) in recurrent glioblastoma (GBM). Journal of Clinical Oncology. Scholar
  5. Giovannucci, E., et al. (2010). Diabetes and cancer: A consensus report. CA: A Cancer Journal for Clinicians, 60, 207–221.Google Scholar
  6. Jaacks, L. M., Siegel, K. R., Gujral, U. P., & Narayan, K. V. (2016). Type 2 diabetes: A 21st century epidemic. Best Practice & Research Clinical Endocrinology & Metabolism, 30, 331–343.CrossRefGoogle Scholar
  7. Jerby-Arnon, L., et al. (2014). Predicting cancer-specific vulnerability via data-driven detection of synthetic lethality. Cell, 158, 1199–1209.CrossRefGoogle Scholar
  8. Liu, C. Y., & Feng, G.-S. (2014). NCOA5, a molecular link between type 2 diabetes and liver cancer. Hepatobiliary Surgery and Nutrition, 3, 106–108.PubMedPubMedCentralGoogle Scholar
  9. Lorenzo Scappaticcio, M. I. M., Bellastella, G., Giugliano, D., & Esposito, K. (2017). Insights into the relationships between diabetes, prediabetes, and cancer. Endocrine, 56(2), 231–239.CrossRefGoogle Scholar
  10. Lou, Y., Fan, F., Mu, Y., & Dong, X. (2018). The implication of diabetes metabolomics in the early diagnosis and pathogenesis of pancreatic cancer. Journal of Biological Regulators and Homeostatic Agents, 32, 75–82.PubMedGoogle Scholar
  11. Lu, J., Xie, G., Jia, W., & Jia, W. (2013). Metabolomics in human type 2 diabetes research. Frontiers of Medicine, 7, 4–13.CrossRefGoogle Scholar
  12. Mantovani, A., & Targher, G. (2017). Type 2 diabetes mellitus and risk of hepatocellular carcinoma: Spotlight on nonalcoholic fatty liver disease. Annals of Translational Medicine. Scholar
  13. Mook-Kanamori, D. O., et al. (2014). 1, 5-Anhydroglucitol in saliva is a noninvasive marker of short-term glycemic control. The Journal of Clinical Endocrinology & Metabolism, 99, E479–E483.CrossRefGoogle Scholar
  14. Osuka, S., & Van Meir, E. G. (2017). Overcoming therapeutic resistance in glioblastoma: The way forward. The Journal of Clinical Investigation, 127, 415–426.CrossRefGoogle Scholar
  15. Park, E. J., et al. (2010). Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell, 140, 197–208.CrossRefGoogle Scholar
  16. Peng, Z., Liu, C., & Wu, M. (2018). New insights into long noncoding RNAs and their roles in glioma. Molecular cancer, 17, 61.CrossRefGoogle Scholar
  17. Setiawan, V. W., et al. (2014). Diabetes and racial/ethnic differences in hepatocellular carcinoma risk: The multiethnic cohort. Journal of the National Cancer Institute. Scholar
  18. Singh, S. K., et al. (2004). Identification of human brain tumour initiating cells. Nature, 432, 396.CrossRefGoogle Scholar
  19. Villanueva, A., & Luedde, T. (2016). The transition from inflammation to cancer in the liver. Clinical Liver Disease, 8, 89–93.CrossRefGoogle Scholar
  20. Welter, M., et al. (2018). Data for serum 1, 5 anhydroglucitol concentration in different populations. Data in Brief, 20, 753–760.CrossRefGoogle Scholar
  21. Yang, J. D., Mohamed, H. A., Cvinar, J. L., Gores, G. J., Roberts, L. R., & Kim, W. R. (2016). Diabetes mellitus heightens the risk of hepatocellular carcinoma except in patients with hepatitis C cirrhosis. The American Journal of Gastroenterology, 111, 1573–1580.CrossRefGoogle Scholar
  22. Yousri, N. A., et al. (2015). A systems view of type 2 diabetes-associated metabolic perturbations in saliva, blood and urine at different timescales of glycaemic control. Diabetologia, 58, 1855–1867.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pathology, School of Basic Medical Sciences & Sir Run Run Hospital & State Key Laboratory of Reproductive Medicine & Key Laboratory of Antibody Technique of National Health CommissionNanjing Medical UniversityNanjingChina
  2. 2.Laboratory of Cancer Genomics, Division of Cellular and Molecular ResearchNational Cancer CentreSingaporeSingapore
  3. 3.Holistic Integrative Pharmacy Institutes (HIPI)Hangzhou Normal UniversityHangzhouChina
  4. 4.Department of Hepatobiliary Oncology, Cancer CenterSun Yat-sen UniversityGuangzhouChina
  5. 5.Institute of Molecular and Cell Biology, A*STARSingaporeSingapore
  6. 6.Department of Biochemistry, Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
  7. 7.Cancer and Stem Cell Biology ProgramDuke-NUS Medical SchoolSingaporeSingapore

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