One of the keys to healthy sleep and blood sugar has been found

Researchers from Osaka University have shown that the rare D-form of the amino acid alanine shows a clear circadian rhythm, and is able to affect the circadian clock and regulate gluconeogenesis, a method of glucose release, in the kidney. D-alanine upregulates genes linked to both gluconeogenesis and the circadian rhythm through the circadian transcriptional network. D-alanine is linked to many metabolic and immunological diseases, and this mechanistic insight could potentially lead to novel therapeutic approaches.

D-Alanine maintains circadian rhythm and its related physical conditions for health.

Chiral amino acids. L-and D-amino acids are same in molecular weight, bond angle, bond length, but different in characteristics. Only L-amino acids has been regarded to be present in the body until recently.

Researchers from Osaka University have shown that the rare d-form of the amino acid alanine underlies the link between the circadian clock and glucose regulation by the kidney

Osaka, Japan – Only recently was it discovered that amino acids, the building blocks of proteins, exist in two different forms: L- and D-forms. While all natural proteins consist exclusively of L-amino acids, the function of D-amino acids remained poorly understood, despite being present in the food we eat every day.

Now, a multi-institutional research team led by Osaka University has revealed a function of one D-form amino acid: D-alanine. So, what does it do, and how did they uncover its function? To understand, we need a little background information.

The circadian clock, a natural oscillation in our bodies that aligns with the 24-hour cycle of day and night, affects many biological processes. One of these is gluconeogenesis, in which new glucose can be created to maintain energy levels in lieu of carbohydrate intake. While gluconeogenesis was known to vary with circadian rhythm, the reason why was unknown.

There were some clues, however. D-alanine is found in tissues that metabolize glucose, and trace levels of D-alanine in blood and urine had been reported to vary with the circadian rhythm. Using special equipment and an advanced analytical technique, the researchers were able to detect and quantify trace levels of the rare amino acid. The team could then verify that levels of D-alanine reliably change with the circadian clock; the variations are caused by the removal of D-alanine via urine, a process controlled by the kidney. They also showed that sleep was key in regulating D-alanine levels.

“We decided to look at which genes are expressed when the kidney is exposed to D-alanine,” explains lead author of the study, Shinsuke Sakai. “We used deep-learning analysis with an iterative random-forest algorithm to identify the targeted genes. We found that D-alanine upregulates both genes linked to gluconeogenesis and genes known to be related to the circadian rhythm.”

Analysis of transcription factors, which are proteins that regulate gene expression, showed that the changes induced by D-alanine were mediated by a protein called Cry2, which is known to be a key circadian regulator. Under circadian rhythm-disturbed condition, treatment of D-alanine improved the daily rhythm.

“Through these experiments, we were able to show that D-alanine is a link between gluconeogenesis in the kidney and the circadian clock,” says senior author Tomonori Kimura, “and that D-alanine activates gluconeogenesis through the circadian transcriptional network.”

Revealing the link between D-alanine and the circadian clock represents a major step forward in our understanding of these rare D-amino acids. One exciting possibility is new treatments for diseases related to glucose, e.g., diabetes, and the circadian clock, e.g., sleep disorders.


About Osaka University

Osaka University was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world, being named Japan's most innovative university in 2015 (Reuters 2015 Top 100) and one of the most innovative institutions in the world in 2017 (Innovative Universities and the Nature Index Innovation 2017). Now, Osaka University is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.


Published: 21 Dec 2023


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Global Strategy Unit

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Japan Society for the Promotion of Science,
Japan Agency for Medical Research and Development