CMap analysis identifies Atractyloside as a potential drug candidate for type 2 diabetes based on integration of metabolomics and transcriptomics

Abstract

Background: This research aimed at exploring the mechanisms of alterations of metabolites and pathways in T2D from the perspective of metabolomics and transcriptomics, as well as uncovering novel drug candidate for T2D treatment. Methods: Metabolites in human plasma from 42 T2D patients and 45 non-diabetic volunteers were detected by liquid chromatography-mass spectrometer (LC-MS). Microarray dataset of the transcriptome was obtained from Gene Expression Omnibus (GEO) database. Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used to conduct pathway enrichment analysis. Connectivity Map (CMap) was employed to select potential drugs for T2D therapy. In vivo assay was performed to verify above findings. The protein expression levels of ME1, ME2 and MDH1 were detected by Western blot to determine the status of NAD/NADH cofactor system. Results: In our study, differentially expressed metabolites were selected out between healthy samples and T2D samples with selection criteria P value 2, including N-acetylglutamate and Malate. Genes set enrichment analysis (GSEA) revealed that 34 pathways were significantly enriched in T2D. Based on CMap analysis and animal experiments, Atractyloside was identified as a potential novel drug for T2D treatment via targeting ME1, ME2 and MDH1 and regulating the NAD/NADH cofactor system. Conclusion: The present research revealed differentially expressed metabolites and genes, as well as significantly altered pathways in T2D via an integration of metabolomics, transcriptomics and CMap analysis. It was also demonstrated that comprehensive analysis based on metabolomics and transcriptomics was an effective approach for identification and verification of metabolic biomarkers and alternated pathways.