PURPOSE: Interleukin-22 (IL-22) has been demonstrated to be involved in the regulation of glucose metabolism, insulin resistance and inflammation response, which indicates that IL-22 might be associated with the occurrence and progression of diabetes. This study aimed to assess serum IL-22 levels in participants with type 2 diabetes mellitus (T2DM) and analyze the association between IL-22 levels and T2DM risk. METHODS: Serum IL-22 concentrations of recruited healthy participants (n=48), newly diagnosed T2DM participants (n=46), and T2DM participants receiving placebo (n=7) or dipeptidyl peptidase-4 inhibitors (DPP-4i) sitagliptin monotherapy (n=7) were measured using a commercial enzyme-linked immunosorbent assay (ELISA) kit. Mice fed a high-fat diet (HFD) were administered sitagliptin and evaluated for IL-22 and intestinal inflammation-related indicators. RESULTS: Serum IL-22 levels were higher in the T2DM group (127.16 ± 75.35) than in healthy controls (69.18 ± 32.83, CONCLUSION: Serum IL-22 is a significant independent risk factor for T2DM, implying that circulating IL-22 may be a predictive biomarker and therapeutic target for T2DM.