People intake metals from their environment. This study investigated type 2 diabetes mellitus (T2DM) related to internal exposure to metals and attempted to identify possible biomarkers. A total of 734 Chinese adults were enrolled, and urinary levels of ten metals were measured. Multinomial logistic regression model was used to assess the association between metals and impaired fasting glucose (IFG) and T2DM. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein–protein interaction were used to explore the pathogenesis of T2DM related to metals. After adjustment, lead (Pb) was positively associated with IFG (odds ratio [OR] 1.31, 95% confidence interval [CI] 1.06–1.61) and T2DM (OR 1.41, 95% CI 1.01–1.98), but cobalt was negatively associated with IFG (OR 0.57, 95% CI 0.34–0.95). Transcriptome analysis showed 69 target genes involved in the Pb-target network of T2DM. GO enrichment indicated that the target genes are enriched mainly in the biological process category. KEGG enrichment indicated that Pb exposure leads to non-alcoholic fatty liver disease, lipid and atherosclerosis, and insulin resistance. Moreover, there is alteration of four key pathways, and six algorithms were used to identify 12 possible genes in T2DM related to Pb. SOD2 and ICAM1 show strong similarity in expression, suggesting a functional correlation between these key genes. This study reveals that SOD2 and ICAM1 may be potential targets of Pb exposure-induced T2DM and provides novel insight into the biological effects and underlying mechanism of T2DM related to internal exposure to metals in the Chinese population.