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Scientists have, for the past 30 years, been investigating the regenerative potential of insulin-producing β-cells in the pancreas. Newly reported studies in diabetic mice by researchers at the University of Geneva (UNIGE) and the University Hospitals of Geneva (HUG), now suggest that the ability of β-cells to regenerate is under the influence of the mechanism that controls the body’s circadian rhythms—the natural 24-hour clock that regulates some metabolic functions. The investigators’ work uncovered an essential role for the core clock component, BMAL1, in this process. The team suggests the results offer up new perspectives that might ultimately help in the development of strategies to promote β-cell regeneration in both type 1 diabetes (T1D) and type 2 diabetes (T2D).

Reporting their findings in Genes & Development, lead investigator Charna Dibner, PhD, and colleagues, concluded, “In summary, our data strongly suggest that regeneration of β cells is tightly coupled to diurnal rhythm.” Dibner is head of the Circadian Endocrinology Laboratory at UNIGE Faculty of Medicine’s departments of medicine and cell physiology and metabolism, as well as at the Diabetes Centre, and at the HUG. In their paper, titled, “The core clock transcription factor BMAL1 drives circadian β-cell proliferation during compensatory regeneration of the endocrine pancreas,” the scientists further stated that, “these findings have important translational potential and should be considered in patients with T1D and T2D, as reboosting circadian rhythms by lifestyle adaptations may help to prevent the aggravation of the disease.”

Diabetes is characterized by partial destruction of the pancreatic islet β-cells that produce insulin, and regenerating these cells represents an outstanding clinical challenge,” the authors noted. In fact, certain body tissues, such as the skin or liver, can and do repair themselves after damage. This process of compensatory proliferation, through which remaining cells begin to actively divide to replace those that have been damaged, is a biological mechanism that is both well known, but poorly understood.

“And this is particularly true for pancreatic beta cells, whose regenerative mechanism stays largely unexplored despite decades of research,” explained Dibner. “However, deciphering this phenomenon and above all finding out how to promote it could be a game changer for controlling diabetes.” Unlike fast regenerating tissues, such as the liver, “the regeneration of β cells is a long-lasting process that takes a few weeks and even months in mice,” the team noted. “Unraveling mechanisms of regulation of β-cell regeneration is of a fundamental clinical importance in the search of new therapeutic approaches for management of diabetes mellitus.”

The circadian system allows organisms to synchronize physiology and behavior over a 24-hour cycle, the researchers continued. “The importance of temporal coordination of cell proliferation has emerged in the context of reparative regeneration in tissues that bear intrinsic regenerative capacity, such as liver, intestine, and skeletal muscle.” Such circadian clocks in pancreatic islets also participate in the regulation of glucose homeostasis. “Molecular clocks operative in pancreatic islets play a critical role in islet cell physiology and in regulating glucose homeostasis,” they further wrote. “Thus, understanding the functional link between changes of the molecular clockwork, islet dysfunction and β-cell regeneration potential is an important challenge.”

To explore the connection between internal biological clocks and β-cell regeneration, Dibner’s team observed two groups of mice with only 20% of their β-cells remaining, following massive, targeted ablation of these cells. Mice in one group had functional circadian clocks, whereas in the other group expression of a key circadian clock gene was blocked, and so they had dysfunctional clocks, and were effectively arrhythmic.

The arrhythmic mice lacked the BMAL1 gene, which codes for a transcription factor known for its key action in the functioning of the circadian clock. The results of the team’s studies showed that there was virtually no compensatory β-cell regeneration in these arrhythmic mice. “… the regeneration of pancreatic β cells did not proceed in the absence of the essential core clock component BMAL1, leading to fatal diabetes in a high proportion of animals,” they wrote.

Image of pancreatic islets showing proliferation markers (red staining) in the nuclei (blue) of insulin-producing-cells (green). [UNIGE/Dibner]

The team said their results represent evidence that the proliferation of residual β-cells, in this case as a result of massive β-cell ablation, follows a circadian pattern. “The result was very clear,” said research co-lead Volodymyr Petrenko, PhD, a researcher in the Dibner laboratory.

“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 noted that cell regeneration was significantly greater at night, when mice are active. “We now show that the highest proliferation rate occurs during the activity phase in the middle of night, and that it coincides with the peaks of rhythmic expression of the genes encoding key regulators of the cell cycle,” they wrote.

“Our analyses show that the BMAL1 gene is essential for the regeneration of beta cells,” explained Petrenko. In addition, large-scale transcriptomic analyses over a 24-hour period, conducted in collaboration with Bart Vandereycken, PhD, 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.

“BMAL1 seems to be indeed central for our investigation,” stressed Dibner. “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.”

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

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