Lack of ZnT8 protects pancreatic islets from hypoxia- and cytokine-induced cell death

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 wild-type and global ZnT8-/- mice were exposed to hypoxia or cytokines and cell death was measured. To explore the role of changing intracellular Zn2+ concentrations, wild-type 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 (TNFα, IFNγ, IL1β) 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 wild-type 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 wild-type 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.

ZnT8 loss-of-function accelerates functional maturation of hESC-derived β cells and resists metabolic stress in diabetes

“…Human rare LOF mutations of ZnT8 decrease the risk of diabetes and improve insulin secretion from pancreatic β cells 1 , 13 , 21 , 22 . Moreover, it is also reported that downregulation of ZnT8 protects pancreatic β cells from cell death induced by inflammatory stress, cytokines and hypoxia 23 , 68 . Consistently, our study also demonstrates that ZnT8 LOF promotes SC-β cell function and reduces cell death triggered by metabolic stress-induced ER stress.…”

Multiple genetic variants at the SLC30A8 locus affect local super‐enhancer activity and influence pancreatic β‐cell survival and function

“…Nevertheless, we note that, in a recent study, 26 inactivation of SLC30A8 in human stem cell‐derived β‐like cells (or the introduction of the LoF R138X mutation) was protective against apoptosis under conditions of limiting Zn 2+ . Likewise, ZnT8 inactivation in mice protected islets from hypoxia and treatment with cytotoxic cytokines 51 . These earlier reports indicate that SLC30A8 may influence cell viability under stressed conditions which pertain in diabetes.…”

ZnT8 Loss of Function Mutation Increases Resistance of Human Embryonic Stem Cell-Derived Beta Cells to Apoptosis in Low Zinc Condition

“…We find that the consequences of ZnT8 loss of function lead to significantly more resistance to cell apoptosis when zinc in culture media is reduced through chelation. A recent study also found that isolated islets from SLC30A8 KO mice are protected against hypoxia-induced cell death when compared to wildtype islets [ 38 ]. Zinc supplement was reported to have protective modulation against high glucose induced apoptosis in renal tubular epithelial cells [ 16 ].…”