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Circadian rhythms drive beta cell regeneration

The cell regeneration phenomenon describes the process in which functional cells start proliferating to compensate for the loss. The perfect examples are skin, liver, the organs that repair themselves after damage.

For three decades, scientists have been examining the regenerative potential of beta cells, pancreatic cells accountable for insulin production.

The beta-cell populace is partially destroyed when diabetes occurs, and recovering these cells represents a unique clinical challenge.

In a new study by the University of Geneva and the University Hospitals of Geneva (HUG), scientists studied diabetic mice to observe the regeneration mechanism. They observed that this regeneration mechanism was under the influence of circadian rhythms – the molecular clocks regulating metabolic functions according to a 24-hour cycle of alternating day-night.

Scientists also identified the significant role of the core clock component BMAL1 in this process.

To explore the connection between internal biological clocks and beta-cell regeneration, scientists first observed two groups of mice with only 20% beta cells remaining after massive targeted ablation. Mice in the first group were arrhythmic, whereas the control group had perfectly functional clocks.

Volodymyr Petrenko, a researcher in Dr. Dibner’s laboratory and the leading scientist in this study, said, “The result was very clear: the mice bearing dysfunctional clocks were unable to regenerate their beta cells, and suffered from severe diabetes, while the control group animals had their beta cells regenerated; in just a few weeks, their diabetes was under control. By measuring the number of dividing beta cells across 24 hours, the scientists also noted that regeneration is significantly greater at night when the mice are active.”

“The arrhythmic mice lacked the BMAL1 gene, which codes for the protein of the same name, a transcription factor known for its key activities in the functioning of the circadian clock. Our analyses show that the BMAL1 gene is essential for the regeneration of beta cells.”

“Also, large-scale transcriptomic analyses over 24 hours, conducted in collaboration with Prof. Bart Vandereycken at the Mathematics Department of the UNIGE, revealed that the genes responsible for regulating cell cycle and proliferation were not only upregulated but also acquired circadian rhythmicity.”

Dr. Charna Dibner, head of the Circadian Endocrinology Laboratory at UNIGE Faculty of Medicine’s the Departments of Medicine, and Cell Physiology and Metabolism, said, “BMAL1 seems to be indeed central for our investigation. However, whether the regeneration requires functional circadian clocks themselves, or only BMAL1, whose range of functions goes beyond clocks, remains unclear. That is what we would like to find out at present.”

“The scientists also want to explore the function of alpha cells, which produce glucagon, the hormone that antagonizes insulin, in this model. The arrhythmic mice indeed showed very high levels of glucagon in the blood. A detailed understanding of these mechanisms must now be pursued, in an attempt to explore the possibility of triggering beta cell regeneration in humans in the future.”

To be read in the journal Gene and Development, these results allow new perspectives to be envisaged to promote beta cell regeneration.

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