Combining Bioinformatics and Molecular Docking Technology to Explore the Target Protein Markers for the Treatment of T2DM Based on Hepatic Gluconeogenesis Inhibitory Strategies

OBJECTIVE To screen the marker target protein of type 2 diabetes mellitus (T2DM) based on hepatic gluconeogenesis inhibition strategy.METHODS The microarray data set of human liver tissue was downloaded from NCBI database,and T2DM susceptibility genes were screened by GEO2R online analysis tool.Gluconeogenesis related targets were retrieved from GeneCards and OMIM databases.The interaction targets between T2DM and hepatic gluconeogenesis were obtained by integrating data,and the marker target proteins were screened by constructing a protein-protein interaction network.Gene ontology and pathway enrichment analysis were performed in Metascape database.The interaction ability between T2DM therapeutic drugs and marker target proteins was predicted by means of molecular docking.Finally,the effect of the marker target proteins in the liver tissue of spontaneous T2DM KKAy mice was validated by combining metformin.RESULTS A total of 1 143 T2DM susceptibility genes and 958 gluconeogenesis related targets were identified,56 targets of T2DM interacting with hepatic gluconeogenesis were obtained,and two marker target proteins PTPRC and VCAM1 were screened by network analysis.The interaction targets were mainly enriched in glucose catabolic process,canonical glycolysis,glycolytic process through glucose-6-phosphate,and other biological processes.And they functioned through the regulation of pathways such as Glycolysis/Gluconeogenesis,AGE-RAGE signaling pathway in diabetic complications,and endocrine resistance.The 26 hypoglycemic drugs all had good spatial matching,energy matching and different degrees of binding ability with marker targets.The blood glucose of T2DM model group was significantly higher than that of normal group,and decreased significantly after treatment.The protein expression levels of PTPRC and VCAM1 in the liver tissue of the mice in the T2DM model group were significantly higher than those in the normal group,and they were significantly lower after metformin treatment.CONCLUSION This study systematically screened and verified two marker target proteins in human liver tissue that may affect hepatic gluconeogenesis in T2DM,reveal the regulatory pathway of hepatic gluconeogenesis in T2DM,and provide a basis for in-depth study of the prevention and treatment mechanism of hepatic gluconeogenesis and looking for new targets of hypoglycemic drugs.