RNA-Seq Analysis of the Liver Transcriptome Reveals the Networks Regulating Treatment of Sitagliptin Phosphate plus Fuzhujiangtang Granule in the Zucker Diabetic Fatty Rats

Diabetes is one of the most serious chronic diseases. Numerous drugs including oral agents and traditional Chinese medicines, such as sitagliptin phosphate (SP) and Fuzhujiangtang granules (FJG), have been discovered to treat diabetes and used in combination in clinical practice. However, the exact effect and underlying mechanism of using combined medicine is not clear. In this study, we compared the antidiabetic effect of SP, FJG, and SP plus FJG (SP-FJG) using forty 8-week-old Zucker diabetic fatty (ZDF) rats and 10 age-matched Zucker lean rats as the normal control group. ZDF rats were treated with different therapies, respectively, for 6 weeks. The study showed that the fast blood glucose, random blood glucose (RBG), oral glucose tolerance test (OGTT), insulin tolerance test (ITT), homeostasis model of assessment-insulin resistance index, triglyceride (TC), superoxide dismutase, and malondialdehyde of each treatment group were improved when compared with the diabetes mellitus (DM) control group. Using SP-FJG in combination had better improvements in OGTT, fast serum insulin levels, TNF-α, and IL-6 compared with using SP individually. Besides, the increased LDL and TC caused by using SP was attenuated by using FJG in combination. Meanwhile, compared with the DM group, 1781 differentially expressed genes (DEGs) (including 1248 mRNA, 211 ncRNA, 202 cirRNA, and 120 miRNA) were enriched in 58 pathways. Through analysis of ceRNA networks, we found that rno-miR-326-3p, rno-miR-423-5p, rno-miR-15b-5p, rno-let-7c-5p, and rno-let-7b-5p were related to pharmacodynamics in different groups. By analyzing the protein-protein interaction (PPI) and coexpression networks of the transcriptomes of different groups, it is inferred that Lrrk2 and Irak3 may be pharmacodynamic genes for type 2 diabetes mellitus (T2DM). Our research compared the treatment of SP, FJG, and SP-FJG and acquainted the PPI network, coexpression network, mutations, and pharmacodynamics genes, which reveals the new mechanisms of pathogenesis of T2DM.