Abstract
It is difficult to accurately evaluate the efficacy of traditional Chinese medicine (TCM), which leads to the uncertainty and complexity of dose-effect analysis. In this study we established the “Focus” mode of biomarkers to characterize the dose-effect relationship of Gegen Qinlian Decoction (GQD), a TCM formula for treating type 2 diabetes mellitus (2-DM). A rat model of 2-DM was established through high fat diet feeding combined with low-dose STZ injection. Rats with 2-DM were administered high, middle or low doses (6.785, 4.071, 1.357 mg·kg−1·d−1, respectively) of GQD extract for 60 d. Metformin (300 mg·kg−1·d−1) was taken as the positive control. Blood samples were collected to assess serum biochemical indexes and metabolic profiling. After “Focus” analysis, the biochemical index triglycerides (TG) and insulin sensitivity (ISI) were identified as focused integrated biomarkers (FIBs), while arachidonic acid and docosatetraenoic acid were the metabolic FIBs. Dose-effect relationship curves of GQD were built based on these types of FIBs. Furthermore, the two dose-effect relationship curves showed similar trends with the middle dosage displaying the greatest efficacy, suggesting that insulin function and arachidonic acid metabolism played important roles in 2-DM and the responses to GQD. The metabolic FIB docosatetraenoic should be further explored for understanding its involvement in the process of 2-DM occurrence and the treatment. This “Focus” mode provides a novel strategy to evaluate the dose-effect relationship of a TCM. The system and concepts established here may also be applicable for assessing the dose-effect relationships of Western medicines.
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References
Xie WQ, Lian FM, Ji HY, Chen XY, Tong XL . Research progress on dose-effect relationship of TCM. J Tradit Chin Med 2011; 52: 1696–9.
Zhang Q, Xu G, Li J, Wang H, Li BT, Tu J, et al. Metabonomic study on the plasma of streptozotocin-induced diabetic rats treated with Ge Gen Qin Lian Decoction by ultra high performance liquid chromatography-mass spectrometry. J Pharm Biomed Anal 2016; 120: 175–80.
Zhao LH, Lian FM, Ji HY, Zhou Q, Xia L, Tong XL . Clinial examples of treatment for type 2 diabetes by professor Tong Xiao-lin using Ge-Gen-Qin-Lian decoction. Chin J Exp Tradit Med Formul 2011; 17: 249–51.
Li TJ, wang S, Meng XS, Bao YR, Guan SS, Liu B, et al. Metabolomics coupled with multivariate data and pathway analysis on potential biomarkers in gastric ulcer and intervention effects of corydalis yanhusuoalkaloid. PLoS One 2014; 9: e82499.
Zhou YT, Liao QF, Lin MN, Deng XJ, Zhang PT, Yao M, et al. Combination of H-1 NMR- and GC-MS-based metabonomics to study on the toxicity of Coptidis Rhizome in rats. PLoS One 2014; 9: e88281.
Huang M, Liang QL, Li P, Xia JF, Wang YM, Luo GA, et al. Biomarkers for early diagnosis of type 2 diabetic nephropathy: a study based on an integrated biomarker system. Mol Biosyst 2013; 9: 2134–41.
Zhang CH, Xu GL, Liu YH, Rao Y, Yu RY, Zhang ZW, et al. Anti-diabetic activities of Gegen Qinlian Decoction in high-fat diet combined with streptozotocin-induced diabetic rats and in 3T3-L1 adipocytes. Phytomedicine 2013; 20: 221–9.
Li YM, Fan XM, Wang YM, Liang QL, Luo GA . Therapeutic effects of Gegen Qinlian decoction and its mechanism of action on type 2 diabetic rats. Yao Xue Xue Bao 2013; 48: 1415–21.
Suresh Y, Das UN . Differential effect of saturated, monounsaturated, and polyunsaturated fatty acids on alloxan-induced diabetes mellitus. Prostaglandins Leukot Essent Fatty Acids 2006; 74: 199–213 .
Keane D, Newsholme P . Saturated and unsaturated (including arachidonic acid) non-esterified fatty acid modulation of insulin secretion from pancreatic β-cells. Biochem Soc Trans 2008; 36: 955–8 .
Nugent C, Prins JB, Whitehead JP, Wentworth JM, Chatterjee VK, O'Rahilly S . Arachidonic acid stimulates glucose uptake in 3T3-L1 adipocytes by increasing GLUT1 and GLUT4 levels at the plasma membrane. J Biol Chem 2001; 276: 9149–57.
Richardson AJ, Easton T, Puri BK . Red cell and plasma fatty acid changes accompanying symptom remission in a patient with schizophrenia treated with eicosapentaenoic acid. Eur Neuropsychopharmacol 2000; 10: 189–93.
Lim SN, Gladman SJ, Dyall SC, Patel U, Virani N, Kang JX, et al. Transgenic mice with high endogenous omega-3 fatty acids are protected from spinal cord injury. Neurobiol Dis 2013; 51: 104–12.
van der Kemp WJ, Klomp DW, Kahn RS, Luijten PR, Hulshoff Pol HE . A meta-analysis of the polyunsaturated fatty acid composition of erythrocyte membranes in schizophrenia. Schizophr Res 2012; 141: 153–61.
Hamazaki K, Hamazaki T, Inadera H . Fatty acid composition in the postmortem amygdala of patients with schizophrenia, bipolar disorder, and major depressive disorder. J Psychiatr Res 2012; 46: 1024–8.
Vega-López S, Calle MC, Fernandez ML, Kollannoor-Samuel G, Chhabra J, Todd M, et al. Triglyceride screening may improve cardiometabolic disease risk assessment in Latinos with poorly controlled type 2 diabetes. J Health Care Poor Underserved 2013; 24: 1739–55.
Vega GL, Barlow CE, Grundy SM, Leonard D, DeFina LF . Triglyceride–to–high density-lipoprotein-cholesterol ratio is an index of heart disease mortality and of incidence of type 2 diabetes mellitus in men. J Invest Med 2014; 62: 345–9.
Sacks FM, Hermans MP, Fioretto P, Valensi P, Davis T, Horton E, et al. Association between plasma triglycerides and high-density lipoprotein cholesterol and microvascular kidney disease and retinopathy in type 2 diabetes mellitus A global case–control study in 13 countries. Circulation 2014; 129: 999–1008.
Idei M, Hirayama S, Miyake N, Kon M, Horiuchi Y, Ueno T, et al. Mean postprandial triglyceride concentration is an independent risk factor for carotid atherosclerosis in patients with type 2 diabetes. Clin Chim Acta 2014; 430: 134–9.
Okuno A, Kaji N, Takahashi A, Nagakubo D, Ohno-Ichiki K, Shirai M, et al. Role of insulin resistance in the pathogenesis and development of type 2 diabetes in WBN/Kob-Leprfa rats. J Vet Med Sci 2013; 75: 1557–61.
Hata A, Ninomiya T, Mukai N, Hirakawa Y, Hata J, Ozawa M, et al. Magnesium intake decreases type 2 diabetes risk through the improvement of insulin resistance and inflammation: the Hisayama Study. Diabetic Med 2013; 30: 1487–94.
Ndisang JF, Rastogi S, Vannacci A . Insulin resistance, type 1 and type 2 diabetes, and related complications: current status and future perspective. J Diabetes Res 2014; 2014: 276475.
Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao P . Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res 2005; 52: 313–20.
Zhao C, Mao J, Ai J, Shenwu M, Shi T, Zhang D, et al. Integrated lipidomics and transcriptomic analysis of peripheral blood reveals significantly enriched pathways in type 2 diabetes mellitus. BMC Med Genomics 2013; 6: S12.
Zhang QB, Fillmore TL, Schepmoes AA, Clauss TR, Gritsenko MA, Mueller PW, et al. Serum proteomics reveals systemic dysregulation of innate immunity in type 1 diabetes. J Exp Med 2013; 210: 191–203.
Wahl S, Krug S, Then C, Kirchhofer A, Kastenmüller G, Brand T, et al. Comparative analysis of plasma metabolomics response to metabolic challenge tests in healthy subjects and influence of the FTO obesity risk allele. Metabolomics 2014; 10: 386–401.
Wheelock CE, Goss VM, Balgoma D, Nicholas B, Brandsma J, Skipp PJ, et al. Application of 'omics technologies to biomarker discovery in inflammatory lung diseases. Eur Respir J 2013; 42: 802–25.
Lonn E, Bosch J, Teo KK, Pais P, Xavier D, Yusuf S . The polypill in the prevention of cardiovascular diseases key concepts, current status, challenges, and future directions. Circulation 2010; 122: 2078–88.
PILL Collaborative Group, Rodgers A, Patel A, Berwanger O, Bots M, Grimm R, et al. An international randomised placebo-controlled trial of a four-component combination pill (“polypill”) in people with raised cardiovascular risk. PLoS One 2011; 6: e19857.
Acknowledgements
This work was supported by the Chinese National “973” Project (Grant No 2010CB530600) and the National Natural Science Foundation of China (Grant No 81130066 and 81302731). We are thankful to Dr Qun SHAO of the University of Bradford for providing us with the FormRules and INForm software used in these studies.
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Huang, Zq., Fan, Xm., Wang, Ym. et al. A new method to evaluate the dose-effect relationship of a TCM formula Gegen Qinlian Decoction: “Focus” mode of integrated biomarkers. Acta Pharmacol Sin 38, 1141–1149 (2017). https://doi.org/10.1038/aps.2016.165
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DOI: https://doi.org/10.1038/aps.2016.165
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