VPAC2介导PACAP衍生多肽MDY通过脂肪细胞外泌体miR-141-3p/PTEN信号轴改善胰岛素抵抗的分子机制

PACAP及其受体VPAC2是胰岛素抵抗的重要调节因子，但其分子作用机制尚不明晰。课题组前期成功研制了特异激活VPAC2的新型高稳定性长效重组PACAP衍生多肽MDY，具有显著改善胰岛素抵抗模型小鼠的葡萄糖耐量和血脂水平、葡萄糖依赖性促胰岛素分泌、有效改善胰岛素抵抗的生物学作用；首次发现MDY可有效升高胰岛素抵抗模型小鼠脂肪细胞外泌体中miR-141-3p（Exo-miR-141-3p）水平，miR-141-3p可经外泌体被有效递送至肝细胞和胰岛β细胞，并通过下调靶基因Pten的表达参与调节胰岛素抵抗。本研究将在前期基础上，利用MDY这一新工具，深入研究和阐明VPAC2介导MDY通过Exo-miR-141-3p/PTEN信号轴调控肝糖原及脂质合成、抑制糖异生、抑制炎症因子表达及氧化应激损伤、促进胰岛β细胞增殖及胰岛素基因表达进而改善胰岛素抵抗的分子机理，也为MDY的药用研发提供实验数据。

PACAP and its receptor VPAC2 are important regulators of insulin resistance，but its molecular mechanism of action is still unclear. MDY, a new long-acting recombinant PACAP-derived peptide that can specifically activate VPAC2 and possess high stability, has been successfully developed by our team in the preliminary studies. MDY can significantly improve the glucose tolerance and blood lipid level of insulin-resistant mice, and has the biological effects of promoting glucose-dependent insulin secretion and effectively improving insulin resistance. For the first time it was found in our study that MDY could effectively increase the level of adipocyte-derived exosomal miR-141-3p (Exo-miR-141-3p) in insulin-resistant mice. miR-141-3p can be effectively delivered to hepatocytes and pancreatic β cells via exosomes, and is involved in the regulation of insulin resistance by down-regulating the expression of its target gene Pten. Based on our preliminary work, MDY, as a new tool, will be used to deeply study the molecular mechanism that MDY regulates hepatic glycogen and lipid synthesis, inhibits gluconeogenesis, inhibits the expression of inflammatory factors and oxidative stress injury, promotes the proliferation of pancreatic β cells and the expression of insulin gene. So that it will be clarified that MDY can effectively improve insulin resistance through Exo-miR-141-3p/PTEN signaling axis by VPAC2-specific activation. This will also provide experimental data for MDY in clinical pharmaceutical research and development against insulin resistance.