Obesity and adipokines are associated with development of type 2 diabetes. However, limited longitudinal studies have examined their roles on declining β-cell function over time. This report assessed three adiposity measures (BMI, percent body fat, trunk fat), insulin resistance, and fifteen adipokines in relationship to longitudinal change in β-cell function measured by disposition index (DI) from frequently-sampled-intravenous-glucose-tolerance testing. The results showed that three factors were significantly and independently associated with rate of change in DI over time: rate of change in BMI (negative), rate of change in IL-6 (negative), and baseline adiponectin (positive). The association was the strongest for changing BMI and was largely explained by changing insulin resistance; the association with changing IL-6 was also largely explained by changing insulin resistance. Baseline adiponectin remained positively associated after adjustment for changing insulin resistance, suggesting an independent effect of adiponectin to preserve or improve β-cell function. These findings provide evidence and potential mechanisms for the role of obesity in promoting β-cell dysfunction, highlighting the potential importance of mitigating obesity and its metabolic effects in preventing and treating type 2 diabetes.