Retinol-Binding Protein 4 Activates STRA6, Provoking Pancreatic β-Cell Dysfunction in Type 2 Diabetes

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.