Abstract
Pancreatic β-cells depend on the well-balanced regulation of cytosolic zinc concentrations, providing sufficient zinc ions for the processing and storage of insulin, but avoiding toxic effects. The zinc transporter ZnT8, encoded by SLC30A8,is a key player regarding islet cell zinc homeostasis, and polymorphisms in this gene are associated with altered type 2 diabetes susceptibility in man. The objective of this study was to investigate the role of ZnT8 and zinc in situations of cellular stress as hypoxia or inflammation. Isolated islets of WT and global ZnT8−/− mice were exposed to hypoxia or cytokines and cell death was measured. To explore the role of changing intracellular Zn2+ concentrations, WT islets were exposed to different zinc concentrations using zinc chloride or the zinc chelator N,N,N′,N′-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN). Hypoxia or cytokine (TNF-α, IFN-γ, IL1-β) treatment induced islet cell death, but to a lesser extent in islets from ZnT8−/− mice, which were shown to have a reduced zinc content. Similarly, chelation of zinc with TPEN reduced cell death in WT islets treated with hypoxia or cytokines, whereas increased zinc concentrations aggravated the effects of these stressors. This study demonstrates a reduced rate of cell death in islets from ZnT8−/− mice as compared to WT islets when exposed to two distinct cellular stressors, hypoxia or cytotoxic cytokines. This protection from cell death is, in part, mediated by a reduced zinc content in islet cells of ZnT8−/− mice. These findings may be relevant for altered diabetes burden in carriers of risk SLC30A8 alleles in man.
Highlights
Pancreatic β-cells are highly dependent on the micronutrient zinc for the processing and storage of insulin (Chabosseau and Rutter 2016), which is released in response to rising glucose concentrations
It was hypothesized that a possible change of long-term glucose levels could lead to the change in the susceptibility of pancreatic islet cells to cell death described above
This study provides further evidence that the regulation of intracellular zinc content is a fundamental process for islet cell function and survival
Summary
Pancreatic β-cells are highly dependent on the micronutrient zinc for the processing and storage of insulin (Chabosseau and Rutter 2016), which is released in response to rising glucose concentrations. High concentrations of intracellular zinc, resulting from exogenous administration or release from intracellular stores, are toxic and potentially lethal for cells (Plum, et al 2010). This has been shown in different tissues, such as cortical neurons (Kim, et al 1999), and in pancreatic islet cells, where zinc is cytotoxic in a dose-dependent manner (Kim, et al 2000). Three main protein families are responsible for the maintenance of zinc homeostasis: the metallothioneins (MTs), the zinc importers (ZIP, SLC39A) and the zinc transporters (ZnT, SLC30A)
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