To identify potential mechanisms influencing the occurrence of diabetic peripheral neuropathy (DPN) in type 2 diabetes mellitus (T2DM) through bioinformatics techniques. Methods: The relevant dataset (GSE24290) was downloaded from the Gene Expression Omnibus (GEO) database. Differential expression analysis was conducted on the dataset using the R package 'limma'. GO and KEGG enrichment analyses of the target genes were performed using the 'org.Hs.eg.db' and 'clusterProfiler' packages. The protein-protein interaction network of the relevant genes was obtained from the STRING website (https://cn. string-db.org/). The molecular network was visualized using the 'Networkx' and 'Netwulf' libraries in Python. Clinical samples were referenced to determine whether the identified factors influencing disease occurrence were consistent with Chinese samples. Finally, Mendelian randomization (MR) analysis was employed to determine the gene-level causal effect relationship between the identified influencing factors and the risk of T2DM and T2DM DPN. Results: After differential analysis of the GEO database data, the GO and KEGG results showed that the biological pathways of differential genes were mainly concentrated in fat metabolism processes. The STRING results indicated that the commonality of genes related to lipid metabolism pathways was to promote the occurrence and development of hyperlipidemia. In Chinese clinical samples, the expression levels of total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, and apolipoprotein B were higher in the T2DM group and T2DM DPN group compared to the healthy control group (P<0.05). Compared to the T2DM group, the expression levels of blood lipid-related indicators were higher, but the difference was not statistically significant (P>0.05). The MR analysis results showed no causal effect relationship between blood lipids-T2DM and hyperlipidemia-T2DM DPN. MR-Egger, WME, Weighted mode, and Simple mode were used to determine the stability of the MR results, and scatter plots, leave-one-out analysis, and funnel plots confirmed the reliability of the results. Conclusion: Hyperlipidemia is a potential influencing factor for the occurrence of T2DM DPN, but no causal effect relationship was found at the gene level.