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.

中文翻译：

---

Kindlin-2调节MafA和β-catenin的表达，从而调节小鼠的β细胞功能和质量。

β细胞功能障碍和β细胞质量减少是糖尿病的标志性事件。在这里，我们显示β细胞表达丰富的Kindlin-2，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末端区域与MafA结合并使其稳定，从而激活胰岛素表达。Kindlin-2的损失至少或部分地减少了β细胞中Ca2 +的释放，从而损害了体外和小鼠原代人和小鼠胰岛中胰岛素的分泌。Kindlin-2丢失会激活GSK-3β，并下调β-catenin，从而导致β细胞增殖和质量降低。Kindlin-2的损失会降低早期胰腺发育过程中β细胞的百分比，并同时增加α细胞的百分比。β细胞中β-catenin的遗传激活恢复了Kindlin-2缺失诱导的糖尿病样表型。最后，β细胞Kindlin-2的诱导型缺失导致成年小鼠的糖尿病表型。总的来说，我们的结果建立了Kindlin-2的重要功能，并为糖尿病提供了潜在的治疗靶标。