Cystine/glutamate antiporter system Xc- deficiency impairs insulin secretion.

Abstract

System Xc-, encoded by Slc7a11, is an antiporter that exports glutamate and imports cystine. Cystine is used for protein synthesis and incorporation in thiol peptides such as glutathione, which function as cofactors for reactive oxygen species scavenging enzymes. Glutamate export by astrocytes through system Xc- has been implicated in excitotoxicity, a form of neurotoxicity that has been postulated to also occur in insulin-producing beta-cells in the pancreatic islets. This study describes the implications of Slc7a11 deficiency on glucose metabolism in both constitutive and myeloid cells-specific knockout mice. Constitutive Slc7a11 deficiency leads to drastically lowered glutathione levels in the pancreatic islets and immune cells in addition to diminished insulin secretion both in vitro and in vivo. Macrophage-specific deletion did not have a significant impact on metabolism or islet function. These findings suggest that system Xc- is required for glutathione maintenance and insulin production in beta-cells, but is dispensable for islet macrophage function.