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. 2024 Aug 6;14(1):60.
doi: 10.1038/s41387-024-00323-0.

Pathogenic gene connections in type 2 diabetes and non-alcoholic fatty liver disease: a bioinformatics analysis and mouse model investigations experiments

Chao Chen  1 , Kunhuan Yang  2 , Yuhan Zhang  2 , Meiqi Lu  2 , Xiaoyan Zhao  2 , Zheng Wan  3
Affiliations

Pathogenic gene connections in type 2 diabetes and non-alcoholic fatty liver disease: a bioinformatics analysis and mouse model investigations experiments

Chao Chen et al. Nutr Diabetes. .

Abstract

Background: Type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) are prevalent metabolic disorders with overlapping pathophysiological mechanisms. A comprehensive understanding of the shared molecular pathways involved in these conditions can advance the development of effective therapeutic interventions.

Methods: We used two datasets sourced from the Gene Expression Omnibus (GEO) database to identify common differentially expressed genes (DEGs) between T2D and NAFLD. Subsequently, we conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses to identify the enriched biological processes and signaling pathways. In addition, we performed a protein-protein interaction (PPI) network analysis to identify hub genes with pivotal roles. To validate our findings, we established a type 2 diabetic mouse model with NAFLD.

Results: Our analysis identified 53 DEGs shared between T2D and NAFLD. Enrichment analysis revealed their involvement in signal transduction, transcriptional regulation, and cell proliferation as well as in the ferroptosis signaling pathways. PPI network analysis identified ten hub genes, namely CD44, CASP3, FYN, KLF4, HNRNPM, HNRNPU, FUBP1, RUNX1, NOTCH3, and ANXA2. We validated the differential expression of FYN, HNRNPU, and FUBP1 in liver tissues of a type 2 diabetic mouse model with NAFLD.

Conclusions: Our study offers valuable insights into the shared molecular mechanisms underlying T2D and NAFLD. The identified hub genes and pathways present promising prospects as therapeutic targets to address these prevalent metabolic disorders.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Schematic diagram of the overall workflow of this study.
The study retrieved datasets GSE185011 and GSE89632 from the GEO database to explore the relationship between type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). Common differentially expressed genes (DEGs) were identified using GEO2R. Gene Ontology (GO) and KEGG enrichment analyses were performed on these DEGs. A protein–protein interaction (PPI) network identified hub genes. Validation was done using a type 2 diabetic mouse model with NAFLD (db/db mice), identifying three key genes.
Fig. 2
Fig. 2. Identification of differentially expressed genes (DEGs) in Type 2 diabetes (T2D) (GSE185011) and non-alcoholic fatty liver disease (NAFLD) (GSE89632) using GEO2R.
A Volcano plots of the DEGs in GSE89632. The negative log10-transformed adjusted P values (Y axis) are plotted against the average log2 fold changes (X axis) in gene expressions. Identified DEGs are shown in red (log2FC > 1) and blue (log2FC < -1) with adjusted P < 0.05. B Heatmap of the DEGs in GSE89632. C Upregulated genes shared between GSE89632 and GSE185011. D Volcano plots of the DEGs in GSE185011. The negative log10-transformed adjusted P values (Y axis) are plotted against the average log2 fold changes (X axis) in gene expressions. Identified DEGs are shown in red (log2FC > 1) and blue (log2FC < -1) with adjusted P < 0.05. E Heatmap of the DEGs in GSE185011. F Downregulated genes shared between GSE89632 and GSE185011.
Fig. 3
Fig. 3. Functional analyses of common differentially expressed genes (DEGs).
Red, blue, green, and dark blue indicated biological process (BP), molecular function (MF), and cellular component (CC), and KEGG pathway analyses, respectively.
Fig. 4
Fig. 4. Protein-protein interaction (PPI) network establishment and hub gene identification.
A PPI network of common genes. Genes in red and blue boxes represent upregulated genes and downregulated genes, respectively. B Ten most significant genes involved in the PPI network.
Fig. 5
Fig. 5. Non-alcoholic fatty liver disease (NAFLD) in diabetic db/db mice.
A Schematic illustration of the experimental procedure. db/m and db/db mice were fed normal diet until the age of 8 months (M). B Images comparing db/m and db/db mice. Blue arrows indicate db/m mice, red arrows indicate db/db mice. C Body weight of db/m and db/db mice. D Blood glucose analysis of db/m and db/db mice. E Images comparing the livers of db/m and db/db mice. F Liver weight of db/m and db/db mice. Statistical analyses in C, D, and F were performed using Student’s t-test. *P < 0.05; ***P < 0.001. G H&E staining of liver sections from db/m and db/db mice. Scale bars, 100 μm (upper panels) and 50 μm (lower panels). Each dot represents one mouse; n ≥ 3 in each group.
Fig. 6
Fig. 6. The mRNA levels of FYN, HNRNPU, and FUBP1 in db/db and db/m mouse livers.
A–C qRT-PCR analysis of FYN, HNRNPU, and FUBP1 in the liver of db/db (n = 3) and db/m (n = 3) mice. Statistical analyses in A–C were performed using Student’s t-test. **P < 0.01; ***P < 0.001.
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