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

Researchers 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

January 23, 2024
Osaka University
Researchers 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.

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.

Story Source:

Materials provided by Osaka University. Note: Content may be edited for style and length.

Journal Reference:

  1. Shinsuke Sakai, Youichi Tanaka, Yusuke Tsukamoto, Shihoko Kimura-Ohba, Atsushi Hesaka, Kenji Hamase, Chin-Ling Hsieh, Eiryo Kawakami, Hiraku Ono, Kotaro Yokote, Mitsuaki Yoshino, Daisuke Okuzaki, Hiroyo Matsumura, Atsuko Fukushima, Masashi Mita, Maiko Nakane, Masao Doi, Yoshitaka Isaka, Tomonori Kimura. d-Alanine Affects the Circadian Clock to Regulate Glucose Metabolism in Kidney. Kidney360, 2023; DOI: 10.34067/KID.0000000000000345

Cite This Page:

Osaka University. "One of the keys to healthy sleep and blood sugar has been found." ScienceDaily. ScienceDaily, 23 January 2024. <>.
Osaka University. (2024, January 23). One of the keys to healthy sleep and blood sugar has been found. ScienceDaily. Retrieved February 22, 2024 from
Osaka University. "One of the keys to healthy sleep and blood sugar has been found." ScienceDaily. (accessed February 22, 2024).

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