In the current study, we characterize several models in which systemic elevations in D-serine were associated with improved glucose tolerance and hyperinsulinemia in mice, including a genetic loss of the D-serine catabolic enzyme D-amino acid oxidase (DAAO) and following an intraperitoneal (i.p.)injection of 1–3 g/kg of D-serine in multiple wildtype (WT) mouse strains. Here, DAO is linked to hyperinsulinism.