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NMR-based metabonomic study of Chinese medicine Gegen Qinlian Decoction as an effective treatment for type 2 diabetes in rats

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Abstract

Metabonomic profiles of the type 2 diabetic rats induced by streptozotocin and high-sugar, high fat diet on the treatment of Gegen Qinlian Decoction (GQD) for 9 weeks were investigated. Rats were randomly divided into five groups: normal control (NC), type 2 diabetes (DM), metformin hydrochloric, GQD in high and low dosages. Plasma samples for 1H NMR-based metabolomic research, serum samples for clinical biochemistry, and liver and pancreas tissues for histopathology test were collected. Compared with NC rats, metabolic pathways of DM rats were revealed to be altered by pattern analyses of plasma NMR data, which was further correlated with serum biochemistry. Cross-validated scores mean trajectory derived from PLS-DA of NMR spectra demonstrated that GQD significantly restored the abnormal metabolic state in the long run, more potent than metformin hydrochloric. Detailed analysis of the altered metabolite levels indicated that GQD significantly ameliorated the disturbance in glucose metabolism, tricarboxylic acid cycle, lipid metabolism, amino acid metabolism and gut microbial metabolism and N-acetyl group metabolism. The results confirmed the hypoglycemic efficacy of GQD and its ability to ameliorate the diabetic symptoms in a global scale. NMR-based metabonomics approach is helpful for the further understanding of diabetes-related mechanisms.

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Abbreviations

DMA:

Dimethylamine

GPC:

Glycerophosphorylcholine

GQD:

Gegen Qinlian Decoction

β-HB:

β-Hydroxybutyrate

HDL-C:

High-density lipoprotein cholesterol

HE:

Hematoxylin/eosin

HFD:

High-sugar, high fat diet

JNKs:

c-Jun amino-terminal kinases

LDL-C:

Low-density lipoprotein cholesterol

PCA:

Principal-component analysis

PLS-DA:

Partial least-squares discriminant analysis

STZ:

Streptozotocin

TC:

Total cholesterol

TCA:

Tricarboxylic acid

TG:

Triglyceride

TMAO:

Trimethylamine-N-oxide

TNF-α:

Tumor necrosis factor-α

TSP:

3-Trimethylsilyl-propionic acid

References

  • Beckwith-Hall, B., Nicholson, J., Nicholls, A., Foxall, P., Lindon, J., Connor, S., et al. (1998). Nuclear magnetic resonance spectroscopic and principal components analysis investigations into biochemical effects of three model hepatotoxins. Chemical Research in Toxicology, 11, 260–272.

    Article  CAS  PubMed  Google Scholar 

  • Bino, R. J., Hall, R. D., Fiehn, O., Kopka, J., Saito, K., Draper, J., et al. (2004). Potential of metabolomics as a functional genomics tool. Trends in Plant Science, 9, 418–425.

    Article  CAS  PubMed  Google Scholar 

  • Boden, G., Chen, X., & Stein, T. P. (2001). Gluconeogenesis in moderately and severely hyperglycemic patients with type 2 diabetes mellitus. American Journal of Physiology-Endocrinology and Metabolism, 280, E23–E30.

    CAS  PubMed  Google Scholar 

  • Bond, J. S., Failla, M. L., & Unger, D. F. (1983). Elevated manganese concentration and arginase activity inlivers of streptozotocin-induced diabetic rats. Journal of Biological Chemistry, 258, 8004–8009.

    CAS  PubMed  Google Scholar 

  • Chia, Y. Y., Liong, S. Y., Ton, S. H., & Kadir, K. B. A. (2012). Amelioration of glucose homeostasis by glycyrrhizic acid through gluconeogenesis rate-limiting enzymes. European Journal of Pharmacology, 677, 197–202.

    Article  CAS  PubMed  Google Scholar 

  • Cloarec, O., Dumas, M. E., Craig, A., Barton, R. H., Trygg, J., Hudson, J., et al. (2005). Statistical total correlation spectroscopy: an exploratory approach for latent biomarker identification from metabolic 1H NMR data sets. Analytical Chemistry, 77, 1282–1289.

    Article  CAS  PubMed  Google Scholar 

  • Dandona, P., Aljada, A., & Bandyopadhyay, A. (2004). Inflammation: the link between insulin resistance, obesity and diabetes. Trends in Immunology, 25, 4–7.

    Article  CAS  PubMed  Google Scholar 

  • Dandona, P., Aljada, A., & Mohanty, P. (2002). The anti-inflammatory and potential anti-atherogenic effect of insulin: A new paradigm. Diabetologia, 45, 924–930.

    Article  CAS  PubMed  Google Scholar 

  • Dennis, J. W., Granovsky, M., & Warren, C. E. (1999). Glycoprotein glycosylation and cancer progression. Biochimica et Biophysica Acta, 1473, 21–34.

    Article  CAS  PubMed  Google Scholar 

  • Dumas, M. E. (2006). Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proceedings of the National Academy of Sciences USA, 103, 12511–12516.

    Article  CAS  Google Scholar 

  • Eckersall, P., Saini, P., & McComb, C. (1996). The acute phase response of acid soluble glycoprotein, α1-acid glycoprotein, ceruloplasmin, haptoglobin and C-reactive protein, in the pig. Veterinary Immunology and Immunopathology, 51, 377–385.

    Article  CAS  PubMed  Google Scholar 

  • El-Deredy, W. (1997). Pattern recognition approaches in biomedical and clinical magnetic resonance spectroscopy: A review. NMR in Biomedicine, 10, 99–124.

    Article  CAS  PubMed  Google Scholar 

  • Fan, T. W. M. (1996). Metabolite profiling by one- and two-dimensional NMR analysis of complex mixtures. Progress in Nuclear Magnetic Resonance Spectroscopy, 28, 161–219.

    Article  CAS  Google Scholar 

  • Groop, L. C., Bonadonna, R. C., DelPrato, S., Ratheiser, K., Zyck, K., Ferrannini, E., et al. (1989). Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. Journal of Clinical Investigation, 84, 205–213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gu, Y., Zhang, Y. F., Shi, X. Z., Li, X. Y., Hong, J., Chen, J., et al. (2010). Effect of traditional Chinese medicine berberine on type 2 diabetes based on comprehensive metabonomics. Talanta, 81, 766–772.

    Article  CAS  PubMed  Google Scholar 

  • Han, S., Mathias, E., & Ba, Y. (2007). Proton NMR determination of Mg2 + and Ca2 + concentrations using tetrasodium EDTA complexes. Journal of Chemistry, 1, 1–5.

    Google Scholar 

  • Higai, K., Azuma, Y., Aoki, Y., & Matsumoto, K. (2003). Altered glycosylation of α1-acid glycoprotein in patients with inflammation and diabetes mellitus. Clinica Chimica Acta, 329, 117–125.

    Article  CAS  Google Scholar 

  • Hirosumi, J., Tuncman, G., Chang, L. F., Gorgun, C. Z., Uysal, K. T., Maeda, K., et al. (2002). A central role for JNK in obesity and insulin resistance. Nature, 420, 333–336.

    Article  CAS  PubMed  Google Scholar 

  • Itoh, N., Sakaue, S., Nakagawa, H., Kurogochi, M., Ohira, H., Deguchi, K., et al. (2007). Analysis of N-glycan in serum glycoproteins from db/db mice and humans with type 2 diabetes. American Journal of Physiology-Endocrinology and Metabolism, 293, 1069–1077.

    Article  Google Scholar 

  • Jankevics, A., Liepinsh, E., Liepinsh, E., Vilskersts, R., Grinberga, S., Pugovics, O., et al. (2009). Metabolomic studies of experimental diabetic urine samples by 1H NMR spectroscopy and LC/MS method. Chemometrics and Intelligent Laboratory Systems, 97, 11–17.

    Article  CAS  Google Scholar 

  • Kong, W. J., Zhang, H., Song, D. Q., Xue, R., Zhao, W., Wei, J., et al. (2009). Berberine reduces insulin resistance through protein kinase C–dependent up-regulation of insulin receptor expression. Metabolism, Clinical and Experimental, 58, 109–119.

    Article  CAS  Google Scholar 

  • Lee, Y. S. (2006). Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes, 55, 2256–2264.

    Article  CAS  PubMed  Google Scholar 

  • Lee, Y. S., Choi, J. W., Hwang, I., Lee, J. W., Lee, J. H., Kim, A. Y., et al. (2010). Adipocytokine orosomucoid integrates inflammatory and metabolic signals to preserve energy homeostasis by resolving immoderate inflammation. Journal of Biological Chemistry, 285, 22174–22185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li, H., Wang, L., Yan, X. Z., Liu, Q. J., Yu, C. H., Wei, H. D., et al. (2011). A proton nuclear magnetic resonance metabonomics approach for biomarker discovery in nonalcoholic fatty liver disease. Journal of Proteome Research, 10, 2797–2806.

    Article  CAS  PubMed  Google Scholar 

  • Li, W. L., Zheng, H. C., Bukuru, J., & De Kimpe, N. (2004). Natural medicines used in the traditional Chinese medical system for therapy of diabetes mellitus. Journal of Ethnopharmacology, 92, 1–21.

    Article  CAS  PubMed  Google Scholar 

  • Lindon, J. C., Holmes, E., Bollard, M. E., Stanley, E. G., & Nicholson, J. K. (2004). Metabonomics technologies and their applications in physiological monitoring, drug safety assessment and disease diagnosis. Biomarkers, 9, 1–31.

    Article  CAS  PubMed  Google Scholar 

  • Lindon, J. C., Holmes, E., & Nicholson, J. K. (2001). Pattern recognition methods and applications in biomedical magnetic resonance. Progress in Nuclear Magnetic Resonance Spectroscopy, 39, 1–40.

    Article  CAS  Google Scholar 

  • Lindon, J. C., Nicholson, J. K., & Everett, J. R. (1999). NMR Spectroscopy of Biofluids. Annual Reports on NMR Spectroscopy, 38, 1–88.

    Article  CAS  Google Scholar 

  • Liu, M. L., Nicholson, J. K., & Lindon, J. C. (1996). High-resolution diffusion and relaxation edited one-and two-dimensional 1H NMR spectroscopy of biological fluids. Analytical Chemistry, 68, 3370–3376.

    Article  CAS  PubMed  Google Scholar 

  • Maher, A. D., Cloarec, O., Patki, P., Craggs, M., Holmes, E., Lindon, J. C., et al. (2009). Dynamic biochemical information recovery in spontaneous human seminal fluid reactions via 1H NMR kinetic statistical total correlation spectroscopy. Analytical Chemistry, 81, 288–295.

    Article  CAS  PubMed  Google Scholar 

  • Markus, W., & Kaddurah-Daouk, R. (2000). Creatine and creatinine metabolism. Physiological Reviews, 80, 1107–1213.

    Google Scholar 

  • Martin, J. C., Canlet, C., Delplanque, B., Agnani, G., Lairon, D., Gottardi, G., et al. (2006). 1H NMR metabonomics can differentiate the early atherogenic effect of dairy products in hyperlipidemic hamsters. Atherosclerosis, 1, 127–133.

    Google Scholar 

  • Meezan, E., Meezan, E. M., Jones, K., Moore, R., Barnes, S., & Prasain, J. K. (2005). Contrasting effects of puerarin and daidzin on glucose homeostasis in mice. Journal of Agricultural and Food Chemistry, 53, 8760–8767.

    Article  CAS  PubMed  Google Scholar 

  • Mooradian, A. D. (2009). Dyslipidemia in type 2 diabetes mellitus. Nature Clinical Practice Endocrinology & Metabolism, 5, 150–159.

    Article  CAS  Google Scholar 

  • Morris, S. M., Jr. (1992). Regulation of enzymes of urea and arginine synthesis. Annual of Review Nutrition, 12, 81–101.

    Article  CAS  Google Scholar 

  • Nicholson, J. K., Connelly, J., Lindon, J. C., & Holmes, E. (2002). Metabonomics: A platform for studying drug toxicity and gene function. Nature Reviews Drug Discovery, 1, 153–162.

    Article  CAS  PubMed  Google Scholar 

  • Nicholson, J. K., & Foxall, P. J. D. (1995). 750 MHz 1H and 1H–l3C NMR spectroscopy of human blood plasma. Analytical Chemistry, 67, 793–811.

    Article  CAS  PubMed  Google Scholar 

  • Nicholson, J. K., & Wilson, I. D. (2003). Understanding ‘global’ systems biology: Metabonomics and the continuum of metabolism. Nature Reviews Drug Discovery, 2, 668–676.

    Article  CAS  PubMed  Google Scholar 

  • Odunsi, K., Wollman, R. M., Ambrosone, C. B., Hutson, A., McCann, S. E., Tammela, J., et al. (2005). Detection of epithelial ovarian cancer using 1H-NMR-based metabonom ics. International Journal of Cancer, 113, 782–788.

    Article  CAS  PubMed  Google Scholar 

  • Raubenheimer, P. J. (2006). A choline-deficient diet exacerbates fatty liver but attenuates insulin resistance and glucose intolerance in mice fed a high-fat diet. Diabetes, 55, 2015–2020.

    Article  CAS  PubMed  Google Scholar 

  • Rossini, A. A., Like, A. A., Chick, W. L., Appel, M. C., & Cahill, G. F. (1977). Studies of streptozotocin-induced insulitis and diabetes. Proceedings of the National Academy of Sciences USA, 74, 2485–2489.

    Article  CAS  Google Scholar 

  • Salek, R. M., Maguire, M. L., Bentley, E., Rubtsov, D. V., Hough, T., Cheeseman, M., et al. (2007). A metabolomic comparison of urinary changes in type 2 diabetes in mouse, rat, and human. Physiological Genomics, 29, 99–108.

    Article  CAS  PubMed  Google Scholar 

  • Sano, T., Umeda, F., Hashimoto, T., Nawata, H., & Utsumi, H. (1998). Oxidative stress measurement by in vivo electron spin resonance spectroscopy in rats with streptozotocin-induced diabetes. Diabetologia, 41, 1355–1360.

    Article  CAS  PubMed  Google Scholar 

  • Shockcor, J. P., & Holmes, E. (2005). Metabonomic applications in toxicity screening and disease diagnosis. Integrated Strategies for Drug Discovery Using Mass Spectrometry (pp. 121–147).

  • Sicree, R., Shaw, J., Zimmet, P., & Tapp, R. (2003). The global burden of diabetes. Diabetes Atlas Second Edition (pp. 15–78).

  • Srinivasan, K., & Ramarao, P. (2007). Animal model in type 2 diabetes research: An overview. (2007). Indian Journal of Medical Research, 125, 451–472.

    CAS  PubMed  Google Scholar 

  • Srinivasan, K., Viswanad, B., Asrat, L., Kaul, C. L., & Ramarao, P. (2005). Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: A model for type 2 diabetes and pharmacological screening. Pharmacological Research, 52, 313–320.

    Article  CAS  PubMed  Google Scholar 

  • Timbrell, J. A. (1998). Biomarkers in toxicology. Toxicology, 129, 1–12.

    Article  CAS  PubMed  Google Scholar 

  • Tyler Burt, C., & Ribolow, H. (1994). Glycerol phosphorylcholine (GPC) and serine ethanolamine phosphodiester (SEP): Evolutionary mirrored metabolites and their potential metabolic roles. Comparative Biochemistry and Physiology Part B: Comparative Biochemistry, 108, 11–20.

    Article  Google Scholar 

  • Viant, M. R., Rosenblum, E. S., & Tjeerdema, R. S. (2003). NMR-based metabolomics: A powerful approach for characterizing the effects of environmental stressors on organism health. Environmental Science Technology, 37, 4982–4989.

    Article  CAS  PubMed  Google Scholar 

  • Waisundara, V. Y., Hsu, A., Tan, B. K. H., & Huang, D. (2009). Baicalin improves antioxidant status of streptozotocin-induced diabetic wistar rats. Journal of Agricultural and Food Chemistry, 57, 4096–4102.

    Article  CAS  PubMed  Google Scholar 

  • Waisundara, V. Y., Siu, S. Y., Hsu, A., Huang, D., & Tan, B. K. H. (2011). Baicalin upregulates the genetic expression of antioxidant enzymes in Type-2 diabetic Goto-Kakizaki rats. Life Sciences, 88, 1016–1025.

    Article  CAS  PubMed  Google Scholar 

  • Xiong, F. L., Sun, X. H., Gan, L., Yang, X. L., & Xu, H. B. (2006). Puerarin protects rat pancreatic islets from damage by hydrogen peroxide. European Journal of Pharmacology, 529, 1–7.

    Article  CAS  PubMed  Google Scholar 

  • Yin, J., Xing, H. L., & Ye, J. P. (2008). Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism, Clinical and Experimental, 57, 712–717.

    Article  CAS  Google Scholar 

  • Zeng, L. X., Dong, J. C., Yu, W. Q., Huang, J. H., Liu, B. J., & Feng, X. T. (2010). Baicalin attenuates inflammation by inhibiting NF-kB activation in cigarette smoke induced inflammatory models. Pulmonary Pharmacology Therapeutics, 23, 411–419.

    Article  CAS  Google Scholar 

  • Zhang, Y. F., Li, X. Y., Zou, D. J., Liu, W., Yang, J. L., Zhu, N., et al. (2008a). Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. Journal of Clinical Endocrinology and Metabolism, 93, 2559–2565.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, W., Liu, C. Q., Wang, P. W., Sun, S. Y., Su, W. J., Zhang, H. J., et al. (2010a). Puerarin improves insulin resistance and modulates adipokine expression in rats fed a high-fat diet. European Journal of Pharmacology, 649, 398–402.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, S., Nagana Gowda, G. A., Asiago, V., Shanaiah, N., Barbas, C., & Raftery, D. (2008b). Correlative and quantitative 1H NMR-based metabolomics reveals specific metabolic pathway disturbances in diabetic rats. Analytical Biochemistry, 383, 76–84.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, H., Wei, J., Xue, R., Wu, J. D., Zhao, W., Wang, Z. Z., et al. (2010b). Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression. Metabolism, Clinical and Experimental, 59, 285–292.

    Article  Google Scholar 

  • Zhao, L. C., Gao, H. C., Lian, F. L., Liu, X., Zhao, Y. X., & Lin, D. H. (2011). 1H-NMR-based metabonomic analysis of metabolic profiling in diabetic nephropathy rats induced by streptozotocin. American Journal of Physiology-Renal Physiology, 300, F947–F956.

    Article  CAS  PubMed  Google Scholar 

  • Zhou, J. Y., Zhou, S. W., Tang, J. L., Zhang, K. B., Guang, L. X., Huang, Y. P., et al. (2009). Protective effect of berberine on beta cells in streptozotocin- and high-carbohydrate/high-fat diet-induced diabetic rats. European Journal of Pharmacology, 606, 262–268.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was funded by NSFC (81173526), NCET (#NCET-11-0738), the Scaling Project for Innovation Scholars, NSF of Jiangsu Province (BK2008039), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) and the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT-IRT1193).

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Correspondence to Junsong Wang or Lingyi Kong.

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Tian, N., Wang , J., Wang, P. et al. NMR-based metabonomic study of Chinese medicine Gegen Qinlian Decoction as an effective treatment for type 2 diabetes in rats. Metabolomics 9, 1228–1242 (2013). https://doi.org/10.1007/s11306-013-0535-8

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