Pancreatic β-cell dysfunction plays a decisive role in the progression of type 2 
diabetes. Retinol-binding protein 4 (RBP4) is a prominent adipokine in type 2 
diabetes, although its effect on β-cell function remains elusive, and the 
underlying mechanisms are unknown. Here, we found that elevated circulating RBP4 
levels were inversely correlated with pancreatic β-cell function in db/db mice 
across different glycemic stages. RBP4 directly suppressed glucose-stimulated 
insulin secretion (GSIS) in primary isolated islets and INS-1E cells in a dose- 
and time-dependent manner. RBP4 transgenic (RBP4-Tg) overexpressing mice showed 
a dynamic decrease of GSIS, which appeared as early as 8 weeks old, preceding 
the impairment of insulin sensitivity and glucose tolerance. Islets isolated 
from RBP4-Tg mice showed a significant decrease of GSIS. Mechanistically, we 
demonstrated that the stimulated by retinoic acid 6 (STRA6), RBP4's only known 
specific membrane receptor, is expressed in β-cells and mediates the inhibitory 
effect of RBP4 on insulin synthesis through the Janus kinase 2/STAT1/ISL-1 
pathway. Moreover, decreasing circulating RBP4 level could effectively restore 
β-cell dysfunction and ameliorate hyperglycemia in db/db mice. These 
observations revealed a role of RBP4 in pancreatic β-cell dysfunction, which 
provides new insight into the diabetogenic effect of RBP4.