Cystine/glutamate antiporter System x(c)(-) deficiency impairs insulin secretion in mice

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: [Image: see text] SUPPLEMENTARY INFORMATION: The online version of this article (10.1007/s00125-023-05993-6) contains peer-reviewed but unedited supplementary material.