Our previous research suggests that 3-deoxyglucosone (3DG), formed in the caramelization course and Maillard reactions in food, is an independent factor for the development of prediabetes. Since the relationship between type 2 diabetes (T2D) and intestinal microbiota is moving from correlation to causality, we investigated the alterations in the composition and function of the intestinal microbiota in 3DG-induced prediabetic rats. Rats were given 50 mg/kg 3DG by intragastric administration for two weeks. Microbial profiling in faeces samples was determined through the 16S rRNA gene sequence. The glucagon-like peptide 2 (GLP-2) and lipopolysaccharide (LPS) levels in plasma and intestinal tissues were measured by ELISA and Limulus test, respectively. 3DG treatment did not significantly change the richness and evenness but affected the composition of intestinal microbiota. At the phylum level, 3DG treatment increased the abundance of nondominant bacteria Proteobacteria but did not cause the change of the dominant bacteria. Meanwhile, the abundance of the Prevotellaceae family and Parasutterela genus and the Alcaligencaeae family and Burkholderiales order and its attachment to the Betaproteobacteria class were overrepresented in the 3DG group. The bacteria of Candidatus Soleaferrea genus, Gelria genus, and Thermoanaerobacteraceae family and its attachment to Thermoanaerobacterales order were apparently more abundant in the control group. In addition, 45 KEGG pathways were altered after two-week intragastric administration of 3DG. Among these KEGG pathways, 13 KEGG pathways were involved in host metabolic function related to amino acid metabolism, carbohydrate metabolism, metabolism of cofactors and vitamins, and metabolism of terpenoids and polyketides. Moreover, the increased LPS levels and the decreased GLP-2 concentration in plasma and intestinal tissues were observed in 3DG-treated rats, together with the impaired fasting glucose and oral glucose tolerance. The alterations in composition and function of the intestinal microbiota were observed in 3DG-treated rats, which provides a possible mechanism linking exogenous 3DG intake to the development of prediabetes.
Type 2 diabetes (T2D) is a major global public health burden, with β-cell dysfunction a key component in its pathogenesis. However, the exact pathogenesis of β-cell dysfunction in T2D is yet to be fully elucidated. Ferroptosis, a recently discovered regulated form of non-apoptotic cell death, plays a vital role in the development of diabetes and its complications. The current study aimed to identify the key molecules involved in β-cell ferroptosis3 in patients with T2D using the mRNA expression profile data of GSE25724 by bioinformatic approaches. The differentially expressed mRNAs (DE-mRNAs) in human islets of patients with T2D were screened using the islet mRNA expression profiling data from the Gene Expression Omnibus and their intersection with ferroptosis genes was then obtained. Ferroptosis-related DE-mRNA functional and pathway enrichment analysis in T2D islet were performed. Using a protein-protein interaction (PPI) network constructed from the STRING database, Cytoscape software identified ferroptosis-related hub genes in the T2D islet with a Degree algorithm. We constructed a miRNA-hub gene network using the miRWalk database. We generated a rat model of T2D to assess the expression of hub genes. A total of 1,316 DE-mRNAs were identified in the islet of patients between T2D and non-T2D (NT2D), including 221 and 1,095 up- and down-regulated genes. Gene set enrichment analysis revealed that the ferroptosis-related gene set was significantly different in islets between T2D and NT2D at an overall level. A total of 33 ferroptosis-related DE-mRNAs were identified, most of which were significantly enriched in pathways including ferroptosis. The established PPI network with ferroptosis-related DE-mRNAs identified five hub genes (JUN, NFE2L2, ATG5, KRAS, and HSPA5), and the area under the ROC curve of these five hub genes was 0.929 in the Logistic regression model. We constructed a regulatory network of hub genes and miRNAs, and the results showed that suggesting that hsa-miR-6855-5p, hsa-miR-9985, and hsa-miR-584-5p could regulate most hub genes. In rat model of T2D, the protein expression levels of JUN and NFE2L2 in pancreatic tissues were upregulated and downregulated, respectively. These results contribute to further elucidation of ferroptosis-related molecular mechanisms in the pathogenesis of β-cell dysfunction of T2D.
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