Abstract
BackgroundInsulin 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.MethodsUsing 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.ResultsThe 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.ConclusionsOur data suggest that the antagonistic interaction between Nodal and insulin has a role in the regulation of β-cell mass and secretion.
Highlights
Insulin signaling pathway in β-cell is essential to promote β-cells proliferation and survival, while Nodal–ALK7–Smad3 signaling involves β-cells apoptosis
Insulin decreases high-glucose- or palmitate-induced apoptosis through reducing nodal–ALK7–phosphorylated Smad3 (p-Smad3) expression To examine whether insulin protected stress-stimulated β-cell apoptosis and if this is through the modulation of
Cell treated with high-glucose and palmitate showed significant elevated Nodal–ALK7– p-Smad3 expression led to increased cleaved caspase-3 protein level when compared to control group (Fig. 1)
Summary
Insulin signaling pathway in β-cell is essential to promote β-cells proliferation and survival, while Nodal–ALK7–Smad signaling involves β-cells apoptosis. Activation of the Akt signaling pathway is critical for mediating autocrine insulin action on the β-cell to maintain appropriate mass and insulin production [7]. Defects in this signaling pathway cause impaired insulin secretion and reduced β-cell mass, supporting the perception that β-cells use a mechanism involving insulin signaling pathways for their expansion [8]. Nodal is a member of the TGF-β superfamily and induces β-cell apoptosis through the activation of the ALK7–Smad3–caspase-3 signaling pathway, while suppressing Akt signaling pathway responsible for cell growth and survival, as demonstrated in our previous reports [9, 10]. Nodal, which is expressed only in the β-cell and not in the α-cell [9] is found to be upregulated upon challenging β-cells with high glucose, palmitate, or cytotoxic cytokines, suggesting its important role in inducing and/or mediating stressor-induced apoptosis in the β-cells
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