Novel Zn²⁺ Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents

Type 2 diabetes (T2D) occurs when there is insufficient insulin release to control blood glucose, due to insulin resistance and impaired β-cell function. The GPR39 receptor is expressed in metabolic tissues including pancreatic β-cells and has been proposed as a T2D target. Specifically, GPR39 agonists might improve β-cell function leading to more adequate and sustained insulin release and glucose control. The present study aimed to test the hypothesis that GPR39 agonism would improve glucose stimulated insulin secretion in vivo. A high throughput screen, followed by a medicinal chemistry program, identified three novel potent Zn2+ modulated GPR39 agonists. These agonists were evaluated in acute rodent glucose tolerance tests. The results showed a lack of glucose lowering and insulinotropic effects not only in lean mice, but also in diet-induced obese (DIO) mice and Zucker fatty rats. It is concluded that Zn2+ modulated GPR39 agonists do not acutely stimulate insulin release in rodents.2型糖尿病（Type 2 Diabetes, T2D）的发病机制为胰岛素抵抗与β细胞功能受损，致使胰岛素分泌不足，无法有效调控血糖。GPR39受体在包括胰腺β细胞在内的代谢组织中均有表达，且已被提议作为T2D的潜在治疗靶点。具体而言，GPR39激动剂或可改善β细胞功能，从而实现更充足且持久的胰岛素分泌与血糖调控。本研究旨在验证以下假说：GPR39激动作用可在活体水平改善葡萄糖刺激的胰岛素分泌。研究通过高通量筛选结合药物化学研发流程，成功发现了三种新型强效的Zn²+调控型GPR39激动剂。随后在啮齿类动物急性葡萄糖耐量试验中对上述激动剂开展了活性评价。结果显示，这些激动剂不仅在瘦型小鼠中未产生降糖与促胰岛素分泌作用，在饮食诱导肥胖（DIO）小鼠及Zucker肥胖大鼠中同样无此类效应。综上可得出结论：Zn²+调控型GPR39激动剂无法在啮齿类动物体内急性刺激胰岛素分泌。