Antagonistic interaction between Nodal and insulin modulates pancreatic β-cell proliferation and survival

Cell Communication and Signaling

Linling Fan¹  Rui Liu¹  Qinghua Wang¹  Junfeng Li¹  Liwei Ren¹  Yaojing Jiang¹  Wenjuan Liu¹  Zhihong Wang¹  Harry K. Lau² 

[1] Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University;Division of Endocrinology and Metabolism, Keenan Research Centre for Biomedical Science of St. Michael’s Hospital;

关键词: Nodal;    Insulin;    Diabetes;    β-Cell;    Autocrine;   

DOI  :  10.1186/s12964-018-0288-0

来源: DOAJ

【 摘 要 】

Abstract Background 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. Methods 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. Results 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. Conclusions Our data suggest that the antagonistic interaction between Nodal and insulin has a role in the regulation of β-cell mass and secretion.

【 授权许可】

Unknown