Wnt和IRS2信号通路对话在胰岛细胞保护中的作用

Type 2 diabetes is characterized by reduced insulin secretion complicated with development of peripheral insulin resistance. The deterioration of beta-cell dysfunction has been believed to be pivotal in development of type 2 diabetes, and, presumably, promoting the function and survival of beta-cells might be therapeutically meaningful for the treatment of type 2 diabetes. Recent studies demonstrated that the Wnt-signaling pathway is implicated in the development of endocrine pancreas and functional regulation of mature beta-cells, including insulin secretion, and beta-cell survival and proliferation. The activation of Wnt pathway expands islet cell mass in vitro by increasing proliferation and decreasing apoptosis of beta-cells, thereby enhancing its function. But it is unclear which endogenous factors mediate Wnt signaling in the protection of beta-cells. Our previous study showed that IRS2 may mediate the protective effect of Wnt signaling on beta-cells but the mechanism need further study. In this project, we will try to study the crosstalk between Wnt signaling and IRS2 pathways during the regulation of beta-cells survival in vitro and in vivo. First, the mechanism how Wnt signaling regulate IRS2 and the effect of IRS2 and its downstream pathway on Wnt signaling will be investigated in cultured beta-cells and pancreatic islet. Second, mice expressing active β-catenin and negtive IRS2 in islet will be constructed and studied to demonstrate the role of Wnt and IRS2 in the regulation of beta-cells mass and function. This project may provide useful message for generating methods to protect pancreatic islet cells and improve the function and survival of beta-cells.

胰岛素分泌缺陷是2型糖尿病的主要致病原因之一，改善胰岛β细胞功能为2型糖尿病治疗的重要研究方向。新近研究显示Wnt信号通路可能与2型糖尿病相关，激活WNT信号通路可能通过减少高血糖所导致的胰岛β细胞损伤，增加细胞增殖从而改善胰岛分泌功能。我们前期研究首次显示IRS2/PI3K通路可能介导了Wnt/β-catenin/TCF对胰岛β细胞的保护作用，但是具体机制不清楚。本项目拟在前期研究基础上，通过胰岛细胞系和体外培养胰岛，研究IRS2介导Wnt信号对胰岛细胞增殖、凋亡和胰岛素分泌功能影响的机制以及IRS2及其下游PI3K/AKT和ERK通路与Wnt信号的复杂对话。并建立具β-catenin高表达和IRS2基因敲除共同特征的小鼠模型，在体研究IRS2与Wnt信号的对话。该项目将为Wnt信号上调在2型糖尿病中的预防及治疗作用提供理论依据，并为保护胰岛细胞和改善胰岛细胞功能的提出新思路

胰岛素分泌缺陷是 2 型糖尿病的主要致病原因之一， 改善胰岛β细胞功能为 2型糖尿病治疗的重要研究方向。新近研究显示 Wnt 信号通路可能与 2 型糖尿病相关，激活 WNT信号通路可能通过减少高血糖所导致的胰岛β细胞损伤，增加细胞增殖从而改善胰岛分泌功能。本团队前期研究首次显示 IRS2/PI3K 通路可能介导了 Wnt/β-catenin/TCF 对胰岛β细胞的保护作用，但是具体机制不明。该项目在前期工作的基础上，在INS-1 胰岛细胞系中激活WNT 通路能上调IRS-2 的表达，而激活insulin通路同样调节WNT 通路，从多个层面及多种水平上探究了 insulin 和 WNT 通路之间的复杂对话机制，完成了预期目标并取得了多方面的研究成果。并在此基础上，研究了包括WNT 通路通过下调PPAR-γ 的表达来增加胰岛细胞的增殖，以及GLP-1 受体激动剂等降糖药物通过WNT 通路来影响疾病的机制。本课题已建立了β-catactive小鼠以及IRS2-/-小鼠以供进一步的体内研究。本项目能为 Wnt 信号上调在 2 型糖尿病中的预防及治疗作用提供理论依据，并为保护胰岛细胞和改善胰岛细胞功能的提出新思路。