下丘脑SUR1-KATP通道调控胰岛β细胞去分化及再分化的作用及机制研究

β细胞功能进行性减退是糖尿病（DM）发生的中心环节。下丘脑与胰岛之间存在交互作用，且DM时下丘脑活性下降。我们前期发现下丘脑损伤可致胰岛素分泌受损，具体机制不明。β细胞去分化-再分化失调是介导DM β细胞功能进行性减退的重要原因。研究表明，下丘脑SUR1-KATP通道在感受及调节胰岛素分泌中发挥必要作用。前期运用共培养系统发现，体外干预下丘脑神经元SUR1-KATP通道未引起β细胞去分化，而体内干预下丘脑该通道可见β细胞胰岛素、PDX-1表达减少，发生去分化，且伴随着交感神经活性明显增加，综上提出假说：下丘脑SUR1-KATP通道失活参与介导β细胞去分化，交感神经过度激活介导该过程。本课题拟利用显微注射转染、膜片钳、β细胞谱系追踪、共培养等方法，体内外逐层验证下丘脑SUR1-KATP通道介导的交感神经过度激活对胰岛β细胞去分化及再分化的影响及机制，为从中枢更优化的改善β细胞功能提供新靶点。

The progressive decline of β-cell function is the main link in the occurrence of diabetes mellitus (DM). There is interaction between hypothalamus and islets, and the activity of hypothalamus decreases in DM. In the early stage, we previously found that hypothalamic injury can reduce insulin secretion, but the specific mechanism is unknown. The imbalance of dedifferentiation and redifferentiation of β cells is an important reason for the progressive decline of β cell function in DM. Studies have shown that hypothalamic SUR1-KATP channels play a necessary role in the perception and regulation of insulin signals. Using the co-culture system, we found that the intervention of hypothalamic neuronal SUR1-KATP channel in vitro did not cause β-cell dedifferentiation, while in vivo intervention of hypothalamic SUR1-KATP channel showed a decrease in insulin expression and an increase in dedifferentiation markers, accompanied by a significant increase in sympathetic nerve activity. Based on the analysis above, we hypothesize that hypothalamic SUR1-KATP channels inactivation play an important role in mediating dedifferentiation of β cells, and sympathetic overactivity might contributes to this process. In this study, microinjection, patch clamp, β-cell lineage tracing and co-culture were used to verify the effect and underlying mechanism of hypothalamic SUR1-KATP channel-mediated sympathetic overactivity on islet β-cell dedifferentiation and redifferentiation in vitro and in vivo, so as to provide a new target for improving β-cell function from the central concept.