Gestational diabetes mellitus (GDM) is one of the most common diseases associated with pregnancy, however, the underlying mechanisms remain unclear. Based on the well documented role of inflammation in type 2 diabetes, the aim was to investigate the role of inflammation in GDM. We established a mouse model for GDM on the basis of its two major risk factors, obesity and aging. In these GDM mice, we observed increased Interleukin-1β (IL-1β) expression in the uterus and the placenta along with elevated circulating IL-1β concentrations compared to normoglycemic pregnant mice. Treatment with an anti-IL-1β antibody improved glucose-tolerance of GDM mice without apparent deleterious effects for the fetus. Finally, IL-1β antagonism showed a tendency for reduced plasma corticosterone concentrations, possibly explaining the metabolic improvement. We conclude that IL-1β is a causal driver of impaired glucose tolerance in GDM.

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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 co-factors 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.