Generic placeholder image

Current Vascular Pharmacology

Editor-in-Chief

ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

Research Article

Preliminary Study of the Distinctive Mechanism of Shenqi Compound in Treating Rats with Type 2 Diabetes Mellitus by Comparing with Metformin

Author(s): Xiaoxu Fu, Xiujuan Zhou, Ya Liu, Yuanhong Lei, Hongyan Xie, Yulin Leng, Hong Gao* and Chunguang Xie*

Volume 21, Issue 2, 2023

Published on: 20 February, 2023

Page: [120 - 127] Pages: 8

DOI: 10.2174/1570161121666230208130349

Price: $65

Abstract

Background: In China, traditional Chinese medicine (TCM) has been used to treat type 2 diabetes mellitus (T2DM) for centuries.

Methods: To investigate how the TCM ShenQi (SQC) formulation differs from metformin, four rat groups, including control, model, T2DM rats treated using SQC (SQC group), and T2DM rats treated using metformin (Met group), were constructed. The differentially expressed genes (DEGs) between SQC and metformin groups were screened, and the co-expression modules of the DEGs were constructed based on the weighted correlation network analysis (WGCNA) method. The correlation between modules and metabolic pathways was also calculated. The potential gene targets of SQC were obtained via the TCM systems pharmacology analysis.

Results: A total of 962 DEGs between SQC and Met groups were screened, and these DEGs were significantly enriched in various functions, such as sensory perception of the chemical stimulus, NADH dehydrogenase (ubiquinone) activity, and positive regulation of the fatty acid metabolic process. In addition, seven co-expression modules were constructed after the redundancy-reduced process. Four of these modules involved specific activated or inhibited metabolic pathways. Moreover, 334 effective ingredients of SQC herbs were collected, and four genes (RNASE1 (ribonuclease A family member 1, pancreatic), ADRB1 (adrenoceptor beta 1), PPIF (peptidylprolyl isomerase F), and ALDH1B1 (aldehyde dehydrogenase 1 family member B1)) were identified as potential targets of SQC.

Conclusion: Comparing SQC with metformin to treat T2DM rats revealed several potential gene targets. These genes provide clues for elucidating the therapeutic mechanisms of SQC.

Keywords: Type 2 diabetes mellitus, traditional Chinese medicine, metformin, ShenQi compound, gene expression, drug development.

Graphical Abstract
[1]
Faselis C, Katsimardou A, Imprialos K, Deligkaris P, Kallistratos M, Dimitriadis K. Microvascular complications of type 2 diabetes mellitus. Curr Vasc Pharmacol 2020; 18(2): 117-24.
[http://dx.doi.org/10.2174/1570161117666190502103733] [PMID: 31057114]
[2]
Viigimaa M, Sachinidis A, Toumpourleka M, Koutsampasopoulos K, Alliksoo S, Titma T. Macrovascular complications of type 2 diabetes mellitus. Curr Vasc Pharmacol 2020; 18(2): 110-6.
[http://dx.doi.org/10.2174/1570161117666190405165151] [PMID: 30961498]
[3]
Gong G, Yuan H, Liu Y, Qi L. Investigation of the effects and mechanisms of mai tong formula on lower limb macroangiopathy in a spontaneous diabetic rat model. J Diabetes Res 2016; 2016: 8076796.
[http://dx.doi.org/10.1155/2016/8076796] [PMID: 27995148]
[4]
Yaribeygi H, Sathyapalan T, Atkin SL. Molecular mechanisms linking oxidative stress and diabetes mellitus. Oxid Med Cell Longev 2020; 2020: 8609213.
[http://dx.doi.org/10.1155/2020/8609213]
[5]
Del Prato S, Tiengo A. The importance of first-phase insulin secretion: Implications for the therapy of type 2 diabetes mellitus. Diabetes Metab Res Rev 2001; 17(3): 164-74.
[http://dx.doi.org/10.1002/dmrr.198] [PMID: 11424229]
[6]
Liu Y, Kang J, Gao H, et al. Exploration of the effect and mechanism of shenqi compound in a spontaneous diabetic rat model. Endocr Metab Immune Disord Drug Targets 2019; 19(5): 622-31.
[http://dx.doi.org/10.2174/1871530319666190225113859] [PMID: 30799801]
[7]
Niswender KD. Basal insulin: Physiology, pharmacology, and clinical implications. Postgrad Med 2011; 123(4): 17-26.
[http://dx.doi.org/10.3810/pgm.2011.07.2300] [PMID: 21680985]
[8]
Song A, Zhang C, Meng X. Mechanism and application of metformin in kidney diseases: An update. Biomed Pharmacother 2021; 138: 111454.
[http://dx.doi.org/10.1016/j.biopha.2021.111454] [PMID: 33714781]
[9]
Gnesin F, Thuesen ACB, Kähler LKA, Madsbad S, Hemmingsen B. Metformin monotherapy for adults with type 2 diabetes mellitus. Cochrane Libr 2020; 2020(6): CD012906.
[http://dx.doi.org/10.1002/14651858.CD012906.pub2] [PMID: 32501595]
[10]
Mohammed I, Hollenberg MD, Ding H, Triggle CR. A critical review of the evidence that metformin is a putative anti-aging drug that enhances healthspan and extends lifespan. Front Endocrinol 2021; 12: 718942.
[http://dx.doi.org/10.3389/fendo.2021.718942] [PMID: 34421827]
[11]
Inoue H, Tamaki Y, Kashihara Y, et al. Efficacy of DPP-4 inhibitors, GLP-1 analogues, and SGLT2 inhibitors as add-ons to metformin monotherapy in t2dm patients: A model-based meta-analysis. Br J Clin Pharmacol 2019; 85: 393-402.
[http://dx.doi.org/10.1111/bcp.13807]
[12]
Brown JB, Conner C, Nichols GA. Secondary failure of metformin monotherapy in clinical practice. Diabetes Care 2010; 33(3): 501-6.
[http://dx.doi.org/10.2337/dc09-1749] [PMID: 20040656]
[13]
Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006; 355(23): 2427-43.
[http://dx.doi.org/10.1056/NEJMoa066224] [PMID: 17145742]
[14]
Ren L, Xu Y, Ning L, et al. TCM2COVID: A resource of anti‐COVID‐19 traditional Chinese medicine with effects and mechanisms. iMeta 2022; 1(4): e42.
[http://dx.doi.org/10.1002/imt2.42] [PMID: 36245702]
[15]
Madiraju AK, Erion DM, Rahimi Y, et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 2014; 510(7506): 542-6.
[http://dx.doi.org/10.1038/nature13270] [PMID: 24847880]
[16]
Harada N. Effects of metformin on blood glucose levels and bodyweight mediated through intestinal effects. J Diabetes Investig 2020; 11(6): 1420-1.
[http://dx.doi.org/10.1111/jdi.13301] [PMID: 32428991]
[17]
Fontaine E. Metformin-induced mitochondrial complex i inhibition: facts, uncertainties, and consequences. Front Endocrinol 2018; 9: 753.
[http://dx.doi.org/10.3389/fendo.2018.00753] [PMID: 30619086]
[18]
Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med 1995; 333(9): 550-4.
[http://dx.doi.org/10.1056/NEJM199508313330903] [PMID: 7623903]
[19]
Li M, Li X, Zhang H, Lu Y. Molecular mechanisms of metformin for diabetes and cancer treatment. Front Physiol 2018; 9: 1039.
[http://dx.doi.org/10.3389/fphys.2018.01039] [PMID: 30108523]
[20]
Eurich DT, Simpson SH, Majumdar SR, Johnson JA. Secondary failure rates associated with metformin and sulfonylurea therapy for type 2 diabetes mellitus. Pharmacotherapy 2005; 25(6): 810-6.
[http://dx.doi.org/10.1592/phco.2005.25.6.810] [PMID: 15927899]
[21]
Boccuzzi SJ, Wogen J, Fox J, Sung JCY, Shah AB, Kim J. Utilization of oral hypoglycemic agents in a drug-insured U.S. population. Diabetes Care 2001; 24(8): 1411-5.
[http://dx.doi.org/10.2337/diacare.24.8.1411] [PMID: 11473078]
[22]
Yi YD, Chang IM. An overview of traditional chinese herbal formulae and a proposal of a new code system for expressing the formula titles. Evid Based Complement Alternat Med 2004; 1(2): 125-32.
[http://dx.doi.org/10.1093/ecam/neh019] [PMID: 15480438]
[23]
Qiu J. A culture in the balance. Nature 2007; 448(7150): 126-8.
[http://dx.doi.org/10.1038/448126a] [PMID: 17625539]
[24]
Zhang X, Liu Y, Xiong D, Xie C. Insulin combined with C hinese medicine improves glycemic outcome through multiple pathways in patients with type 2 diabetes mellitus. J Diabetes Investig 2015; 6(6): 708-15.
[http://dx.doi.org/10.1111/jdi.12352] [PMID: 26543546]
[25]
Duan Y, Gao H, Su H, et al. Exploring the protective effect of shenqi compound on skeletal muscle in diabetic macrovasculopathy mice. Endocr Metab Immune Disord Drug Targets 2020; 20(6): 943-51.
[http://dx.doi.org/10.2174/1871530320666200225094756] [PMID: 32096754]
[26]
Fu X, Zhou X, Liu Y, et al. Exploration of sqc formula effect on type 2 diabetes mellitus by whole transcriptome profile in rats. Endocr Metab Immune Disord Drug Targets 2021; 21(7): 1261-9.
[http://dx.doi.org/10.2174/1871530321666210225125141] [PMID: 33632114]
[27]
Gao H, Duan Y. Comparison of efficacy of shenqi compound and rosiglitazone in the treatment of diabetic vasculopathy analyzing multi-factor mediated disease-causing modules. PLoS One 2018; 13: e0207683.
[http://dx.doi.org/10.1371/journal.pone.0207683]
[28]
Stuart T, Butler A, Hoffman P, et al. Comprehensive integration of single-cell data. Cell 2019; 177(7): 1888-1902.e21.
[http://dx.doi.org/10.1016/j.cell.2019.05.031] [PMID: 31178118]
[29]
Zhou Y, Zhou B, Pache L, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 2019; 10(1): 1523.
[http://dx.doi.org/10.1038/s41467-019-09234-6] [PMID: 30944313]
[30]
Langfelder P, Horvath S. WGCNA: An R package for weighted correlation network analysis. BMC Bioinformatics 2008; 9(1): 559.
[http://dx.doi.org/10.1186/1471-2105-9-559] [PMID: 19114008]
[31]
Kanehisa M, Furumichi M, Sato Y, Ishiguro-Watanabe M, Tanabe M. KEGG: Integrating viruses and cellular organisms. Nucleic Acids Res 2021; 49(D1): D545-51.
[http://dx.doi.org/10.1093/nar/gkaa970] [PMID: 33125081]
[32]
Hänzelmann S, Castelo R, Guinney J. GSVA: Gene set variation analysis for microarray and RNA-Seq data. BMC Bioinformatics 2013; 14(1): 7.
[http://dx.doi.org/10.1186/1471-2105-14-7] [PMID: 23323831]
[33]
Ru J, Li P, Wang J, et al. TCMSP: A database of systems pharmacology for drug discovery from herbal medicines. J Cheminform 2014; 6(1): 13.
[http://dx.doi.org/10.1186/1758-2946-6-13] [PMID: 24735618]
[34]
Conway JR, Lex A, Gehlenborg N. UpSetR: An R package for the visualization of intersecting sets and their properties. Bioinformatics 2017; 33(18): 2938-40.
[http://dx.doi.org/10.1093/bioinformatics/btx364] [PMID: 28645171]
[35]
Zhang Y, Liu T, Hu X, et al. CellCall: Integrating paired ligand–receptor and transcription factor activities for cell–cell communication. Nucleic Acids Res 2021; 49(15): 8520-34.
[http://dx.doi.org/10.1093/nar/gkab638] [PMID: 34331449]
[36]
Unnikrishnan R, Mohan V. Why screening for type 2 diabetes is necessary even in poor resource settings. J Diabetes Complications 2015; 29(7): 961-4.
[http://dx.doi.org/10.1016/j.jdiacomp.2015.05.011] [PMID: 26099834]
[37]
Frisbee JC, Lewis MT, Kasper JD, Chantler PD, Wiseman RW. Type 2 diabetes mellitus in the Goto-Kakizaki rat impairs microvascular function and contributes to premature skeletal muscle fatigue. J Appl Physiol 2019; 126(3): 626-37.
[http://dx.doi.org/10.1152/japplphysiol.00751.2018] [PMID: 30571284]
[38]
Cheng TY, Chou YJ, Huang N, Pu C, Chou YJ, Chou P. Exploring the role of multiple chronic conditions in traditional Chinese medicine use and three types of traditional Chinese medicine therapy among adults in Taiwan. J Altern Complement Med 2015; 21(6): 350-7.
[http://dx.doi.org/10.1089/acm.2014.0227] [PMID: 25966281]
[39]
Zhang F, Hu C, Cheng S, et al. The investigation of the effect and mechanism of sophora moorcroftiana alkaloids in combination with albendazole on echinococcosis in an experimental rats model. Evid Based Complement Alternat Med 2018; 2018: 3523126.
[http://dx.doi.org/10.1155/2018/3523126] [PMID: 29785189]
[40]
Zhang X, Wang H, Xie C, et al. Shenqi compound ameliorates type-2 diabetes mellitus by modulating the gut microbiota and metabolites. J Chromatogr B Analyt Technol Biomed Life Sci 2022; 1194: 123189.
[http://dx.doi.org/10.1016/j.jchromb.2022.123189] [PMID: 35219959]
[41]
Barnard EA. Biological function of pancreatic ribonuclease. Nature 1969; 221(5178): 340-4.
[http://dx.doi.org/10.1038/221340a0] [PMID: 4974403]
[42]
Garnett ER, Raines RT. Emerging biological functions of ribonuclease 1 and angiogenin. Crit Rev Biochem Mol Biol 2022; 57(3): 244-60.
[http://dx.doi.org/10.1080/10409238.2021.2004577] [PMID: 34886717]
[43]
Lv H, Dao FY, Lin H. DeepKla: An attention mechanism‐based deep neural network for protein lysine lactylation site prediction. iMeta 2022; 1(1): e11.
[http://dx.doi.org/10.1002/imt2.11]
[44]
Lomax JE, Eller CH, Raines RT. Comparative functional analysis of ribonuclease 1 homologs: Molecular insights into evolving vertebrate physiology. Biochem J 2017; 474(13): 2219-33.
[http://dx.doi.org/10.1042/BCJ20170173] [PMID: 28495858]
[45]
Zernecke A, Preissner KT. Extracellular ribonucleic acids (RNA) enter the stage in cardiovascular disease. Circ Res 2016; 118(3): 469-79.
[http://dx.doi.org/10.1161/CIRCRESAHA.115.307961] [PMID: 26846641]
[46]
Zhang Y, Liu T, Wang J, et al. Cellinker: A platform of ligand–receptor interactions for intercellular communication analysis. Bioinformatics 2021; 37(14): 2025-32.
[http://dx.doi.org/10.1093/bioinformatics/btab036] [PMID: 33471060]
[47]
Burguete-Garcia AI, Martinez-Nava GA, Valladares-Salgado A, et al. Association of β1 and β3 adrenergic receptors gene polymorphisms with insulin resistance and high lipid profiles related to type 2 diabetes and metabolic syndrome. Nutr Hosp 2014; 29(6): 1327-34.
[http://dx.doi.org/10.3305/nh.2014.29.6.7367] [PMID: 24972470]
[48]
Carlsson M, Orho-Melander M, Hedenbro J, Groop LC. Common variants in the β2-(Gln27Glu) and β3-(Trp64Arg) -adrenoceptor genes are associated with elevated serum NEFA concentrations and Type II diabetes. Diabetologia 2001; 44(5): 629-36.
[http://dx.doi.org/10.1007/s001250051670] [PMID: 11380082]
[49]
Salopuro T, Lindström J, Eriksson JG, et al. Common variants in β2- and β3-adrenergic receptor genes and uncoupling protein 1 as predictors of the risk for type 2 diabetes and body weight changes. The Finnish Diabetes Prevention Study. Clin Genet 2004; 66(4): 365-7.
[http://dx.doi.org/10.1111/j.1399-0004.2004.00313.x] [PMID: 15355441]
[50]
Chang TJ, Tsai MH, Jiang YD, et al. The Arg16Gly polymorphism of human β2-adrenoreceptor is associated with type 2 diabetes in Taiwanese people. Clin Endocrinol 2002; 57(5): 685-90.
[http://dx.doi.org/10.1046/j.1365-2265.2002.01661.x] [PMID: 12390345]
[51]
Dionne IJ, Garant MJ, Nolan AA, et al. Association between obesity and a polymorphism in the β1-adrenoceptor gene (Gly389Arg ADRB1) in Caucasian women. Int J Obes 2002; 26(5): 633-9.
[http://dx.doi.org/10.1038/sj.ijo.0801971] [PMID: 12032746]
[52]
Huang Y, Wang J, Zhao Y, et al. cncRNAdb: A manually curated resource of experimentally supported RNAs with both protein-coding and noncoding function. Nucleic Acids Res 2021; 49(D1): D65-70.
[http://dx.doi.org/10.1093/nar/gkaa791] [PMID: 33010163]
[53]
Tavecchio M, Lisanti S, Bennett MJ, Languino LR, Altieri DC. Deletion of cyclophilin d impairs β-oxidation and promotes glucose metabolism. Sci Rep 2015; 5(1): 15981.
[http://dx.doi.org/10.1038/srep15981] [PMID: 26515038]
[54]
Fujimoto K, Chen Y, Polonsky KS, Dorn GW II. Targeting cyclophilin D and the mitochondrial permeability transition enhances β-cell survival and prevents diabetes in Pdx1 deficiency. Proc Natl Acad Sci 2010; 107(22): 10214-9.
[http://dx.doi.org/10.1073/pnas.0914209107] [PMID: 20479245]
[55]
Singh S, Chen Y, Matsumoto A, et al. ALDH1B1 links alcohol consumption and diabetes. Biochem Biophys Res Commun 2015; 463(4): 768-73.
[http://dx.doi.org/10.1016/j.bbrc.2015.06.011] [PMID: 26086111]
[56]
Anastasiou V, Ninou E, Alexopoulou D, et al. Aldehyde dehydrogenase activity is necessary for beta cell development and functionality in mice. Diabetologia 2016; 59(1): 139-50.
[http://dx.doi.org/10.1007/s00125-015-3784-4] [PMID: 26518685]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy