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Vaspin is a novel adipocytokine that has potential insulin-sensitizing effects. The aim of this study is to explore the role of vaspin in the progression of type 2 diabetes mellitus (T2DM) in humans through a longitudinal process. This was a 2-year follow-up study that included 132 patients with T2DM and 170 non-diabetic subjects. The serum vaspin and adiponectin levels were determined with ELISA. Anthropometric measurements, circulating glucose, hemoglobin A1c, insulin level, liver function, kidney function, and lipid profile were measured for each participant. The new onset of T2DM was counted in non-diabetic subjects and the glycemic control was analyzed in T2DM patients at follow-up. At enrollment, the serum vaspin and adiponectin levels were lower in T2DM patients compared with non-diabetic subjects. Significant positive correlation between serum vaspin and HDL-C levels (r = 0.23, P = 0.006) was observed in non-diabetic controls. The serum vaspin concentration was also significantly correlated with body mass index (BMI) (r = 0.19, P = 0.028), waist-hip ratio (WHR) (r = 0.17, P = 0.035) and homeostasis model assessment of insulin resistance (HOMA-IR) (r = 0.14, P = 0.029) in T2DM patients. In cohort analyses, it was found that lower serum vaspin [odds ratio (OR) = 0.52, 95% confidence interval (CI): 0.10–0.87, P = 0.015] and adiponectin (OR = 0.35, 95% CI: 0.20–0.72, P = 0.015) levels at baseline were risk factors for new onset of T2DM at follow-up. The percentage of insulin treatment in T2DM patients was higher in the sub-group with lower serum vaspin level than that in the sub-group with higher vaspin level at follow-up (55.3% vs. 44.7%, P = 0.020). Our study indicates that low serum concentration of vaspin is a risk factor for the progression of T2DM. [ABSTRACT FROM AUTHOR]