PDF(Pubmed)
Abstract：
Insufficient pancreatic β-cell mass and reduced insulin expression are key events in the pathogenesis of diabetes mellitus (DM). Here we demonstrate the high expression of Talin-1 in β-cells and that deficiency of Talin-1 reduces β-cell proliferation, which leads to reduced β-cell mass and insulin expression, thus causing glucose intolerance without affecting peripheral insulin sensitivity in mice. High-fat diet fed exerbates these phenotypes. Mechanistically, Talin-1 interacts with the E3 ligase smad ubiquitination regulatory factor 1 (Smurf1), which prohibits ubiquitination of the signal transducer and activator of transcription 3 (Stat3) mediated by Smurf1, and ablation of Talin-1 enhances Smurf1-mediated ubiquitination of Stat3, leading to decreased β-cell proliferation and mass. Furthermore, haploinsufficiency of Talin-1 and Stat3 genes, but not that of either gene, in β-cell in mice significantly impairs glucose tolerance and insulin expression, indicating that both factors indeed function in the same genetic pathway. Finally, inducible deletion Talin-1 in β-cell causes glucose intolerance in adult mice. Collectively, our findings reveal that Talin-1 functions as a crucial regulator of β-cell mass, and highlight its potential as a therapeutic target for DM patients.
摘要：
胰腺β细胞质量不足和胰岛素表达降低是糖尿病（DM）发病机理中的关键事件。在这里，我们证明了Talin-1在β细胞中的高表达，并且Talin-1的缺乏降低了β细胞的增殖。导致β细胞质量和胰岛素表达减少，从而引起葡萄糖耐受不良而不影响小鼠外周胰岛素敏感性。高脂肪饮食会发挥这些表型。机械上,Talin-1与E3连接酶smad泛素化调节因子1（Smurf1）相互作用，它禁止Smurf1介导的信号转导和转录激活因子3（Stat3）的泛素化，而Talin-1的消融增强Smurf1介导的Stat3的泛素化，导致β细胞增殖和质量降低。此外，Talin-1和Stat3基因的单倍体不足，但不是任何一个基因，在小鼠的β细胞中，糖耐量和胰岛素表达显着受损，表明这两种因素确实在同一遗传途径中起作用。最后,β细胞中可诱导的Talin-1缺失导致成年小鼠葡萄糖耐受不良。总的来说，我们的发现揭示了Talin-1作为β细胞质量的关键调节因子，并强调其作为DM患者治疗靶点的潜力。
