Cystine/glutamate antiporter System xc- deficiency impairs insulin secretion in mice

Abstract

Abstract Aims/hypothesis Glutamate-induced cytotoxicity (excitotoxicity) has been detected in pancreatic beta cells. The cystine/glutamate antiporter System x c - exports glutamate to the extracellular space and is therefore implicated as driving excitotoxicity. As of yet, it has not been investigated whether System x c - contributes to pancreatic islet function. Methods This study describes the implications of deficiency of System x c - on glucose metabolism in both constitutive and myeloid cell-specific knockout mice using metabolic tests and diet-induced obesity. Pancreatic islets were isolated and analysed for beta cell function, glutathione levels and ER stress. Results Constitutive System x c - deficiency led to an approximately threefold decrease in glutathione levels in the pancreatic islets as well as cystine shortage characterised by upregulation of Chac1 . This shortage further manifested as downregulation of beta cell identity genes and a tonic increase in endoplasmic reticulum stress markers, which resulted in diminished insulin secretion both in vitro and in vivo. Myeloid-specific deletion did not have a significant impact on metabolism or islet function. Conclusions/interpretation These findings suggest that System x c - is required for glutathione maintenance and insulin production in beta cells and that the system is dispensable for islet macrophage function. Graphical Abstract

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