1718-P: Retinol-Binding Protein 4, an Adipokine Provoking Pancreatic Beta-Cell Apoptosis in Type 2 Diabetes

Pancreatic b-cell apoptosis plays a decisive role in the progression of type 2 diabetes. Retinol-binding protein 4 (RBP4) is a prominent adipokine in type 2 diabetes(T2D), has been confirmed to that it may be involved in the pathogenesis of insulin resistance and T2D, but the underlying mechanisms of RBP4 inducing islet b-cell apoptosis are unknown. The stimulated by retinoic acid6 (STRA6), RBP4’s only known specific membrane receptor, is expressed in b-cells and mediates the inhibitory effect of RBP4 on insulin synthesis. Here, we found that at the cellular level apo-RBP4 can induce apoptosis in pancreatic b-cells by binding to STRA6. Compared to holo-RBP4, apo-RBP4 has a stronger induction effect, and this induction effect is dose-dependent. We also found that elevated circulating RBP4 levels were inversely correlated with pancreatic b-cell apoptosis in T2D mice across different glycemic stages. Islets isolated from RBP4 overexpressing mice showed a significant decrease of GSIS while injecting shRBP4 AAV mice showed a recovery of GSIS. Moreover, decreasing circulating RBP4 level could effectively restore b-cell dysfunction and ameliorate hyperglycemia in T2D mice. These observations revealed a role of RBP4 in promoting apoptosis of pancreatic b cells, which provides new insight into the diabetogenic effect of RBP4.