Regeneration of Insulin-Producing Beta-Cell by Circadian Clock

For the past 30 years, scientists have been studying the regenerative capacity of β-cells in the pancreas that contain insulin. Newly published studies by researchers at the University of Geneva (UNIGE) and the University Hospitals of Geneva (HUG) in diabetic mice now indicate that the capacity of β-cells to regenerate is affected by the mechanism that controls the circadian rhythms of the body, the normal 24-hour clock that regulates certain metabolic functions. In this phase, the work of the investigators uncovered an important function for the core clock variable, BMAL1. The team suggests that the findings provide new insights that could potentially help to improve strategies for promoting β-cell regeneration in both type 1 (T1D) and type 2 (T2D) diabetes.

"In summary, our results strongly indicate that regeneration of β cells is closely linked to diurnal rhythm," concluded lead researcher Charna Dibner, PhD, and colleagues, documenting their findings in Genes & Growth. Dibner is head of the Circadian Endocrinology Laboratory at the Departments of Medicine and Cell Physiology and Metabolism of the UNIGE Faculty of Medicine, as well as at the Diabetes Center. The scientists further claimed in their paper, "The core clock transcription factor BMAL1 drives circadian β-cell proliferation during compensatory regeneration of the endocrine pancreas" that these results have important translational potential and should be taken into account in T1D and T2D patients, as reboosting circadian rhythms through lifestyle adaptations can help prevent aggrava."

Diabetes is characterised by partial loss of the insulin-producing pancreatic islet β-cells, and it is an excellent clinical task to rebuild these cells, the authors stated. In fact, some body tissues can and do repair themselves after injury, such as the skin or liver. This process of compensatory proliferation is a biological mechanism that is both well known, but poorly understood, by which remaining cells begin to actively divide to replace those that have been destroyed.

And this is particularly true for pancreatic beta cells, whose regenerative function, despite decades of study, remains largely unexplored,” explained Dibner. "However, it may be a game changer for diabetes management to decode this phenomenon and above all, figure out how to facilitate it Unlike quick regenerating tissues, such as the liver, "beta cell regeneration is a long-lasting process in mice that takes a few weeks and even months," the team noted. The disruption of β-cell regeneration control mechanisms is of fundamental clinical significance in the quest for new therapeutic methods for the treatment of diabetes mellitus.

The circadian system helps organisms to synchronise physiology and behaviour, the researchers continued, over a 24-hour period. "In the sense of reparative regeneration in tissues that carry intrinsic regenerative ability, such as liver, intestine, and skeletal muscle, the importance of temporal synchronisation of cell proliferation has emerged." Such circadian clocks in pancreatic islets also participate in the control of homeostasis of glucose. "In islet cell physiology and in controlling glucose homeostasis, molecular clocks working in pancreatic islets play a critical role," they wrote. It is therefore a significant challenge to understand the functional connection between changes in molecular clockwork, islet dysfunction and the potential for β-cell regeneration.

Dibner's team studied two groups of mice with only 20 percent of their β-cells left, following large targeted ablation of these cells, to explore the link between internal biological clocks and β-cell regeneration. Mice had working circadian clocks in one group, while a main circadian clock gene expression was blocked in the other group, and so they had defective clocks and were essentially arrhythmic.

The BMAL1 gene, which codes for a transcription factor known for its key action in the functioning of the circadian clock, was absent in the arrhythmic mice. The findings of the team's experiments showed that in these arrhythmic mice there was virtually no compensatory β-cell regeneration. "... in the absence of the critical core clock component BMAL1, regeneration of pancreatic β-cells did not proceed, leading to fatal diabetes in a high proportion of animals," they wrote.

The team said their findings are proof that the proliferation of residual β-cells, in this case due to major ablation of β-cells, follows a circadian pattern. "The result was quite obvious," said research co-leader Volodymyr Petrenko, PhD, a Dibner laboratory researcher.

"The mice carrying defective clocks were unable to regenerate their beta cells and suffered from extreme diabetes, while the animals in the control group had their beta cells regenerated; their diabetes was under control in only a few weeks." By calculating the number of dividing beta cells over 24 hours, the scientists observed that at night, while mice are ac ac, cell regeneration was substantially greater. "We are now showing that the highest rate of proliferation occurs in the middle of the night during the operation process, and that it corresponds with the peaks of rhythmic expression of the genes that encode main cell cycle regulators," they wrote.

Their study shows that the BMAL1 gene is necessary for beta cell regeneration,” Petrenko clarified. In addition, 24-hour large-scale transcriptomic analyses performed in collaboration with Bart Vandereycken, PhD, at the UNIGE mathematics department, revealed that not only upregulated, but also acquired circadian rhythmicity were the genes responsible for regulating cell cycle and proliferation.

"It seems that BMAL1 is also central to our investigation," Dibner stressed. However it remains uncertain whether regeneration involves the functioning circadian clocks themselves, or just BMAL1, whose functional range goes beyond the clocks. That is what we want to explore at the moment.

Interestingly, there were also very high levels of glucagon in the blood in the arrhythmic mice, and scientists also want to explore the role of alpha-cells in this model that generate glucagon, the hormone that antagonises insulin. "In an effort to explore the possibility of causing β-cell regeneration in humans in the future, a thorough understanding of these mechanisms must now be sought," concluded the authors.