Kindlin-2 modulates MafA and beta-catenin expression to regulate beta-cell function and mass in mice
Kindlin-2 modulates MafA and beta-catenin expression to regulate beta-cell function and mass in mice
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Kindlin-2 调节 MafA 和 β-catenin 表达以调节小鼠 β 细胞功能和质量
DOI：
10.1038/s41467-019-14186-y
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发表时间：
2020
影响因子：
16.6
通讯作者：
Xiao Guozhi
中科院分区：
文献类型：
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作者：
Zhu Ke;Lai Yumei;Cao Huiling;Bai Xiaochun;Liu Chuanju;Yan Qinnan;Ma Liting;Chen Di;Kanaporis Giedrius;Wang Junqi;Li Luyuan;Cheng Tao;Wang Yong;Wu Chuanyue;Xiao Guozhi
β细胞功能障碍和β细胞量减少是糖尿病的标志性事件。在这里，我们发现β细胞表达丰富的Kindlin-2，并且删除其表达会导致严重的糖尿病样表型，而不会明显引起外周胰岛素抵抗。Kindlin-2通过其C-末端区域结合并稳定MafA，MafA激活胰岛素表达。Kindlin-2损失通过减少（至少部分地）β-细胞中的Ca 2+释放而损害体外和小鼠中原代人和小鼠胰岛中的胰岛素分泌。Kindlin-2缺失激活GSK-3β并下调β-连环蛋白，导致β细胞增殖和质量降低。Kindlin-2的丢失降低了胰腺发育早期β细胞的百分比，同时增加了α细胞的百分比。β-细胞中β-连环蛋白的遗传激活恢复由Kindlin-2丢失诱导的糖尿病样表型。最后，β细胞Kindlin-2的可诱导缺失导致成年小鼠的糖尿病表型。总的来说，我们的研究结果确立了Kindlin-2的重要功能，并为糖尿病提供了潜在的治疗靶点。
β-Cell dysfunction and reduction in β-cell mass are hallmark events of diabetes mellitus. Here we show that β-cells express abundant Kindlin-2 and deleting its expression causes severe diabetes-like phenotypes without markedly causing peripheral insulin resistance. Kindlin-2, through its C-terminal region, binds to and stabilizes MafA, which activates insulin expression. Kindlin-2 loss impairs insulin secretion in primary human and mouse islets in vitro and in mice by reducing, at least in part, Ca2+release in β-cells. Kindlin-2 loss activates GSK-3β and downregulates β-catenin, leading to reduced β-cell proliferation and mass. Kindlin-2 loss reduces the percentage of β-cells and concomitantly increases that of α-cells during early pancreatic development. Genetic activation of β-catenin in β-cells restores the diabetes-like phenotypes induced by Kindlin-2 loss. Finally, the inducible deletion of β-cell Kindlin-2 causes diabetic phenotypes in adult mice. Collectively, our results establish an important function of Kindlin-2 and provide a potential therapeutic target for diabetes.