Serum from type 2 diabetes patients consuming a three-meal diet resets circadian rhythms in cultured hepatocytes

Shani Tsameret, Daniela Jakubowicz*, Zohar Landau, Julio Wainstein, Tali Ganz, Itamar Raz, Nava Chapnik, Oren Froy

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Aims: Feeding regimens alter circadian rhythms in peripheral tissues, but the mechanism is not understood. We aimed to study whether soluble factors, rather than neuronal-based communication, directly influence circadian rhythms in the liver, in response to a nutritional treatment in type 2 diabetes (T2D) patients. Methods: Cultured hepatocytes were treated with serum of insulin-treated T2D patients following either a three-meal diet (3Mdiet) or six-meal diet (6Mdiet) and the circadian expression of clock and metabolic genes was measured. Results: Serum of the 3Mdiet group led to increased amplitudes and daily mRNA levels of the positive limb of the circadian clock (Clock, Bmal1, Rorα). In parallel, serum of the 3Mdiet group led to the downregulation of the negative limb of the circadian clock (Cry1 and Per1), compared to both baseline and 6Mdiet. In contrast, serum of the 6Mdiet group led to a more distorted expression pattern. The catabolic genes Sirt1 and Ampk were significantly upregulated only by serum of the 3Mdiet group. Conclusions: Our results show that serum of type 2 diabetes patients consuming the 3Mdiet contains soluble factors that reset circadian rhythms leading to an expression pattern similar to that of healthy people. This clock pattern contributes to improved glucose metabolism.

Original languageAmerican English
Article number108941
JournalDiabetes Research and Clinical Practice
StatePublished - Aug 2021

Bibliographical note

Funding Information:
Funding was received from the Israeli Ministry of Health (grant no. 3-00000-12856). Shani Tsameret is a fellow of the AdR Women Doctoral Program.

Publisher Copyright:
© 2021 Elsevier B.V.


  • Circadian rhythms
  • Clock
  • Meals
  • Metabolism
  • Oscillation


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