Ⅱ型糖尿病药物多是针对胰岛素抵抗进行设计，但长期使用会导致胰岛β细胞功能损伤和胰岛素功能障碍。垂体腺苷酸环化酶激活肽（PACAP）及其衍生物是人体重要的神经多肽，通过VPAC2受体介导具有促胰岛素功能、改善胰岛素抵抗和保护β细胞等作用，且无低血糖症风险。课题组针对VPAC2特异激动剂RMBAY等，存在生物利用度低、稳定性差等问题，研制了高稳定性重组PACAP衍生物MHDBAY，其具有良好的葡萄糖依赖性降血糖作用。与RMBAY等比较，其半衰期提高23倍以上，达11.5小时，动物实验有效剂量为5μg/kg，无毒副作用。本研究利用VPAC2-CHO细胞、正常和胰岛素抵抗的β-细胞及3T3-L1脂肪细胞、正常和Ⅱ型糖尿病模型鼠等，系统研究VPAC2介导MHDBAY促β细胞增殖、促胰岛素基因转录和表达、促胰岛素信号转导等作用，阐明其促胰岛素功能的生物学作用及其分子机制，也为其药用研发提供实验基础。

The design of type Ⅱ diabetes drug is usually based on insulin resistance, but long-term use of these drugs may lead to damage of pancreatic β-cell function and insulin dysfunction. Pituitary adenylate cyclase-activating polypeptide(PACAP) and its derivatives are important human neural polypeptides, which can promote insulin function, improve insulin resistance, protect beta cells and so on through VPAC2 receptor-mediated effects, and has no risk of hypoglycemia. Many VPAC2-specific agonists such as RMBAY, have the defects of poor stability and low bioavailability. The recombinant PACAP derivative MHDBAY with high stability was developed by our team in early study. The recombinant MHDBAY has good glucose-dependent hypoglycemic effect. Compared to other VPAC2-specific agonists such as RMBAY, the half-life of MHDBAY was increased by more than 23 times, up to 11.5 hours, and its effective dose of the animal experiments is 5μg/kg without toxic side effects. In this study, VPAC2-CHO cells, normal pancreatic β-cells, β-cells of insulin resistance, normal 3T3-L1 cells, 3T3-L1 cells of insulin resistance, normal rats and mice and type Ⅱ diabetic rat or mice model will be used to systematically research the effects that VPAC2 mediated MHDBAY to promote β-cell proliferation, gene transcription and expression of insulin and insulin signal transduction and so on. So that the biological role of MHDBAY and its molecular mechanism of promoting insulin function are revealed, and the experimental basis of MHDBAY for its pharmaceutical research and development is provided.