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 rhythms 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 from diabetic model mice. Although D-alanine treatment temporarily raised blood glucose levels, repetitive treatment of D-alanine did not worsen glucose tolerance. 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 condition and also acts on the kidney from, whereas treatment of D-alanine does not worsen the diabetic conditions. D-Alanine may provide a therapeutic option for diabetes by correcting circadian rhythms and treating viral infections.

The authors have declared no competing interest.

This study was supported by Japan Society for the Promotion of Science (22K194140) and Manpei Suzuki Diabetes Foundation.

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The study protocol was approved by the Ethical Committees of Osaka University (#22571).

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