促胰岛素分泌剂是临床常用的降糖药物，但医源性低血糖是该类药物引发的常见不良反应。研究表明，血管活性肠肽（VIP）可促进胰岛素分泌，并且我们发现这一作用只在高糖而非低糖条件下有效。这一接近于生理模式的，具有葡萄糖浓度依赖性的促胰岛素分泌作用不易引发低血糖，具有较好的临床应用前景，但作用机制仍待阐明。有证据表明胰岛β细胞Kv通道在葡萄糖依赖性促胰岛素分泌中发挥着重要作用，我们的初步研究也显示VIP具有阻断Kv通道的作用。结合相关研究进展，我们认为在VIP及其受体VPAC2调控的胰岛素分泌中，Kv通道以及腺苷酸环化酶(AC)/cAMP信号通路发挥着重要作用。本项目拟以此为切入点，采用VPAC2基因敲除小鼠，利用基因沉默、膜片钳和离子成像等技术，深入研究VIP及受体VPAC2引起的葡萄糖依赖性促胰岛素分泌作用，为进一步阐明胰岛素分泌的精细调控机制，探索新型胰岛素促泌剂的作用靶点提供实验依据。

Insulin secretagogues are the common agents used in the treatment of type 2 diabetes, but their major side effect is hypoglycemia. Studies have shown that vasoactive intestinal peptide (VIP) potentiates insulin secretion. We further found that VIP only enhanced insulin secretion under high glucose condition, but not at low glucose condition, indicating that this type of glucose-dependent insulin secretion has good prospects in the treatment of diabetes with the low risk of hypoglycemia. However, the mechanism of VIP-mediated insulin secretion remains unknown. It has been shown that Kv channels play major role in the regulation of glucose-dependent insulin secretion, and our preliminary study demonstrated that VIP inhibited Kv channel currents in pancreatic β cells. Combined with the research progress of VIP, We hypothesize that Kv channels may play important role in VIP and its VPAC2 receptor-regulated insulin secretion through adenylyl cyclase (AC) /cAMP signaling pathway. Present project intends to investigate the characterization of VIP and its VPAC2 receptor-regulated insulin secretion and the underlying mechanism by applying VPAC2 gene knockout mice and other techniques (calcium imaging, patch clamp, shRNA gene knockdown, in vivo animal experiments, as well as in vitro pancreatic islet perfusion etc.). This project would provide new insight into the regulatory mechanisms on insulin secretion, and is beneficial to seek potential therapeutic target for development of new insulin secretagogues.