Meier, D. T. | Search bioRxiv

bioRxiv2023

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

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.

molecular biology↗

bioRxiv2019

Air pollution mediates diabetes by disrupting gut innate mucosal immunity

Air pollution has emerged as an unexpected risk factor for diabetes1-6. The mechanisms linking air pollution and diabetes remain, however, unknown. It has been postulated that lung exposure mediates diabetes via systemic inflammation and insulin resistance7-9. By contrast, gut exposure to pollutants has received little attention, even though a large proportion of air pollution particles are swallowed after mucociliary clearance from the upper airways10. Here, we identified intestinal macrophages as key mediators linking air pollutants with impaired beta-cell function. Upon oral exposure to air pollution, intestinal macrophages up-regulated inflammatory- and interferon-response pathways, which disrupted their normal differentiation towards an anti-inflammatory/resident phenotype. The resulting pro-inflammatory milieu in the gut impaired beta-cell identity and function via local cytokine secretion from macrophages as genetic and pharmacological macrophage or IL-1{beta} ablation protected mice from developing air pollution-induced diabetes. These data establish intestinal macrophage-derived cytokines as key mediators of air pollution associated beta-cell dysfunction, thus pointing towards novel therapeutic strategies.

immunology↗