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

• Published in: Diabetologia Vol. 66; no. 11; pp. 2062 - 2074
• Main Authors: de Baat, Axel, Meier, Daniel T., Rachid, Leila, Fontana, Adriano, Böni-Schnetzler, Marianne, Donath, Marc Y.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-11-2023; Springer Nature B.V
• Subjects: Beta cells; Cytotoxicity; Endoplasmic reticulum; Excitotoxicity; Glucose metabolism; Glutathione; Human Physiology; Insulin; Insulin secretion; Internal Medicine; Macrophages; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Pancreas; Secretion; Cysteine; System xc; Beta cell; CHAC1; Islet; SLC7A11; Insulin; Cystine; Glutathione
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-023-05993-6

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