Inhibition of D-amino Acid Metabolism May Improve Glucose Metabolism via Reduction of Insulin Resistance

Background: D-amino acids are optical isomers of L-amino acids, and D-amino acid oxidase (DAO) is an enzyme that degrades certain D-amino acids. Risperidone, one of the major drug for schizophrenia, is also known to inhibit DAO. Previously, we reported a lower incidence of eGFR decline in the risperidone group in patients with schizophrenia, suggesting a renoprotective effect of risperidone via DAO inhibition. However, the significance of DAO activity inhibition in the pathogenesis of other diseases is unknown. We recently found that treatment with risperidone in type 1 diabetic mice model reduced fasting and postprandial blood glucose levels. Therefore, we further investigated the effect of risperidone on insulin resistance. Methods: We administered risperidone to 7-week-old male C57BL/6J(B6) mice, non-diabetic mice, and DAO activity-deficient (DAO-KO) mice. We measured body weight, blood glucose levels, insulin levels, amount of food intake, urinary glucose levels, and urine volume. In vitro, we used C2C12 cells, a cell line derived from mouse rhabdomyosarcoma muscle. C2C12 cells were stimulated with risperidone at concentrations of 1 nM, 10 nM, and 50 nM. Glucose uptake experiments were performed to evaluate the glucose uptake capacity of the cells. Results: Among B6 mice, administration of risperidone showed no significant change in body weight, blood glucose levels, insulin levels, amount of food intake, urinary glucose levels, or urine volume. However, in the glucose tolerance test, the risperidone-treated group showed decreased blood glucose at 0, 30, 60, 120, and 180 minutes. In addition, insulin levels also decreased at 0 minutes(p<0.05). In DAO-KO mice, blood glucose levels decreased at 120 and 180 minutes. Insulin levels also showed a decreasing trend. These results indicated the potential role of risperidone via DAO inhibition in improving insulin sensitivity. In the insulin tolerance test, blood glucose levels were decreased in B6 mice treated with risperidone at 45 and 60 minutes (p<0.05), while no significant difference was observed in DAO-KO mice. In vitro, glucose uptake was enhanced in the risperidone groups at 1 nM and 10 nM concentrations (p<0.05). Conclusion: Risperidone, an inhibitor of DAO metabolism, may improve insulin resistance. Funding: Government Support – Non-U.S.