Abstract
Backgroundβ-cells are extremely rich in zinc and zinc homeostasis is regulated by zinc transporter proteins. β-cells are sensitive to cytokines, interleukin-1β (IL-1β) has been associated with β-cell dysfunction and -death in both type 1 and type 2 diabetes. This study explores the regulation of zinc transporters following cytokine exposure.MethodsThe effects of cytokines IL-1β, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) on zinc transporter gene expression were measured in INS-1-cells and rat pancreatic islets. Being the more sensitive transporter, we further explored ZnT8 (Slc30A8): the effect of ZnT8 over expression on cytokine induced apoptosis was investigated as well as expression of the insulin gene and two apoptosis associated genes, BAX and BCL2.ResultsOur results showed a dynamic response of genes responsible for β-cell zinc homeostasis to cytokines: IL-1β down regulated a number of zinc-transporters, most strikingly ZnT8 in both islets and INS-1 cells. The effect was even more pronounced when mixing the cytokines. TNF-α had little effect on zinc transporter expression. IFN-γ down regulated a number of zinc transporters. Insulin expression was down regulated by all cytokines. ZnT8 over expressing cells were more sensitive to IL-1β induced apoptosis whereas no differences were observed with IFN-γ, TNF-α, or a mixture of cytokines.ConclusionThe zinc transporting system in β-cells is influenced by the exposure to cytokines. Particularly ZnT8, which has been associated with the development of diabetes, seems to be cytokine sensitive.
Highlights
E-cells are extremely rich in zinc and zinc homeostasis is regulated by zinc transporter proteins
We have previously shown that the zinc content of E-cells is glucose dependent [11]
In this study we found that INS-1E cells over expressing ZnT8 were more sensitive to IL-1E induced apoptosis
Summary
E-cells are extremely rich in zinc and zinc homeostasis is regulated by zinc transporter proteins. The zinc content of pancreatic E-cells is among the highest in the body [1] and zinc plays an important structural role in many proteins by binding protein molecules in dimers and, in the case of insulin, in oligomers. Zinc is an important determinant of E-cell survival and a co-factor in metalloenzymes and zinc-dependent transcription factors [3,4]. Evidence that E-cell derived zinc is a major regulator of glucagon secretion is emerging [5,6]. The activity of E-cell L-type calcium channels, involved in insulin secretion, is partly regulated by zinc [7]. We have previously shown that the zinc content of E-cells is glucose dependent [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
