Effects and dynamics of D-alanine in diabetes

Background D-alanine, a rare enantiomer of alanine, mediates renal gluconeogenesis and protects against viral infections by regulating the circadian clock’s transcriptional network. These features of D-alanine are associated with the diabetes, which disrupts circadian rhythm and worsens Covid-19 outcomes. This study examined the effects and dynamics of D-alanine in diabetic conditions. Methods Blood and urine levels of D-alanine were measured in diabetic model mice and patients with diabetic kidney disease using a two-dimensional high-performance liquid chromatography system. Gluconeogenic activity of D-alanine was assessed by glucose production assay in ex vivo -cultured kidney cells. Glucose tolerance test was performed in mice treated with D-alanine. Results The circadian rhythm of D-alanine, present in healthy mice, was disrupted in diabetic model mice. Patients with diabetic kidney disease showed abnormal urinary excretion of D-alanine. In diabetic mice, D-alanine stimulated gluconeogenesis in kidneys. Although D-alanine treatment temporarily raised blood glucose levels, repetitive treatment of D-alanine did not worsen glucose tolerance in the tested conditions. Conclusions An abnormal circadian rhythm of D-alanine is a hallmark of diabetes. In diabetic mice, D-alanine affects kidney function without worsening the diabetic conditions. D-Alanine may provide a therapeutic option for diabetes by correcting circadian rhythms and treating viral infections.