Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China.
Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, China.
Cell Commun Signal. 2018 Nov 8;16(1):79. doi: 10.1186/s12964-018-0288-0.
Insulin signaling pathway in β-cell is essential to promote β-cells proliferation and survival, while Nodal-ALK7-Smad3 signaling involves β-cells apoptosis. We attempted to address inter-relationship between Nodal and insulin in modulating β-cell proliferation and apoptosis.
Using INS-1 β-cells and isolated rat islets, we examined the effects of Nodal, insulin, or the two combined on β-cell proliferation and/or apoptosis.
The β-cells under high-glucose or palmitate conditions showed significant up-regulation of Nodal expression and activation of its downstream signaling pathway resulted in increased cleaved caspase-3. Insulin treatment led to significantly attenuated Nodal-induced cell apoptotic pathway. Similar results were found in directly Nodal-treated β-cell that insulin could partially block Nodal-induced up-regulation of ALK7-Smad3-caspase-3 signaling pathways with significantly attenuated β-cell apoptosis. Interestingly, we found that insulin-induced Akt activation and downstream molecules including GSK-3β, β-catenin and ERK1/2 was significantly attenuated by the co-treatment with Nodal, resulted in decreased cell proliferation. Furthermore, Nodal decreased glucose-evoked calcium influx and played a negative role during glucose-stimulated insulin secretion in the β-cells. Immunocytochemistry studies showed that Nodal treatment translocated Smad3 from cytosol mostly to the nucleus; however, co-treatment with insulin significantly decreased Smad3 nuclear localization. Co-immunoprecipitation experiments showed a directly interaction between Smad3 and Akt, and this interaction was enhanced by co-treatment with insulin.
Our data suggest that the antagonistic interaction between Nodal and insulin has a role in the regulation of β-cell mass and secretion.
β 细胞中的胰岛素信号通路对于促进β细胞增殖和存活至关重要，而 Nodal-ALK7-Smad3 信号通路则涉及β细胞凋亡。我们试图探讨 Nodal 和胰岛素在调节β细胞增殖和凋亡方面的相互关系。
使用 INS-1 β细胞和分离的大鼠胰岛，我们研究了 Nodal、胰岛素或两者联合对β细胞增殖和/或凋亡的影响。
在高葡萄糖或棕榈酸条件下，β细胞中 Nodal 的表达显著上调，其下游信号通路的激活导致 cleaved caspase-3 的增加。胰岛素处理导致 Nodal 诱导的细胞凋亡途径显著减弱。在直接用 Nodal 处理的β细胞中也发现了类似的结果，即胰岛素可以部分阻断 Nodal 诱导的 ALK7-Smad3-caspase-3 信号通路的上调，从而显著减少β细胞凋亡。有趣的是，我们发现胰岛素诱导的 Akt 激活及其下游分子，包括 GSK-3β、β-catenin 和 ERK1/2，被 Nodal 的共同处理显著减弱，导致细胞增殖减少。此外，Nodal 降低了葡萄糖诱导的钙内流，并在β细胞的葡萄糖刺激胰岛素分泌中发挥负作用。免疫细胞化学研究表明，Nodal 处理将 Smad3 从细胞质主要转位到细胞核；然而，胰岛素的共同处理显著降低了 Smad3 的核定位。共免疫沉淀实验表明 Smad3 和 Akt 之间存在直接相互作用，而这种相互作用在胰岛素共同处理时增强。
我们的数据表明，Nodal 和胰岛素之间的拮抗相互作用在调节β细胞质量和分泌方面发挥作用。
