Study title: The core clock transcription factor BMAL1 drives circadian β-cell proliferation during compensatory regeneration of the endocrine pancreas Journal Genes & Development, Nov. 2020
Press Release from the University of Geneva on this study:
Some parts of our body, such as the skin or the liver, can regenerate after an illness. Cells still functional proliferate to compensate for losses. Thus, for the past thirty years, scientists have been studying the potential for regeneration of beta cells in the pancreas, responsible for producing insulin. As their impairment is largely responsible for the onset of diabetes, the possibility of regenerating them is a hope for treatment. By studying diabetic mice, scientists from the University of Geneva (UNIGE) and the University Hospitals of Geneva (HUG) observed that their regeneration mechanism was influenced by circadian rhythms – the molecular clocks regulating cellular metabolic functions. on a 24 hour cycle. Furthermore, scientists have identified the essential role of a key component of circadian rhythms, the BMAL1 molecule. These results, to read in the journal Genes and Development , allow to consider new perspectives to promote the regeneration of beta cells.
Compensatory proliferation, during which cells actively divide to replace their sisters lost after a disease, is a known biological mechanism, but still poorly resolved. “This is particularly true of pancreatic beta cells, whose regeneration mechanism remains poorly understood, despite decades of research,” explains Charna Dibner, head of the circadian endocrinology laboratory in the Departments of Medicine and Cell Physiology and metabolism as well as at the Faculty of Diabetes Center of the Faculty of Medicine of UNIGE and at the HUG. “However, deciphering this phenomenon and especially finding how to encourage it could be a game-changer in the therapeutic control of diabetes.”
An essential day-night alternation
In order to better understand the connection between the biological clock and the regeneration of beta cells, Charna Dibner’s team first observed two groups of mice that only had 20% beta cells after ablation. The first group was a line of mice genetically modified to be arrhythmic, while the second group, used as a control, had perfectly functioning clocks. “Mice without clocks are unable to regenerate their beta cells and suffer from severe diabetes. The beta cells of the second group regenerate and their diabetes is under control in just a few weeks, ”explains Volodymyr Petrenko, researcher at UNIGE and principal investigator of this work. By measuring the number of beta cell divisions over a 24 hour period,
The BMAL1 gene, a metronome of cellular activity
The arrhythmic mice used in the study lack the BMAL1 gene, encoding the protein of the same name, which is a transcription factor known for its essential action in the functioning of circadian clocks. “Our analyzes show that this gene is essential for the regeneration of beta cells,” adds Volodymyr Petrenko.
In addition, thanks to transcriptional analyzes carried out over a period of 24 hours, carried out in collaboration with Bart Vandereycken from the Department of Mathematics at UNIGE, the researchers highlighted the fact that the genes responsible for cycle regulation and of cell proliferation, were not only overexpressed, but also acquired the circadian rhythm. “Thus, BMAL1 seems to be at the heart of our investigation,” says Charna Dibner. “However, it is not yet clear whether, for regeneration to take place, proper functioning circadian clocks are required, or whether only BMAL1, whose scope of functions goes beyond clocks, is necessary. This is what we want to find out in the future ”.
The scientists also want to explore, in this model, the behavior of alpha cells producing glucagon, the hormone antagonist of insulin. Arrhythmic mice had very high levels of glucagon in the blood. Understanding these mechanisms may help trigger the regeneration of beta cells in humans, a hope for treatment for people with diabetes. whose scope of functions goes beyond clocks, is necessary. This is what we want to find out in the future ”.
Why is this interesting to me?
Circadian rhythm seems to be at the heart of many chronic diseases, and circadian rhythm disruption is one thing that everyone can impact via lifestyle changes. This is one area where education — just getting the word out about the importance of light, sleep, and meal timing — could make a huge impact for people with prediabetes or diabetes.
I find it interesting how genetic variants come into play here also. Researchers have known for more than a decade that BMAL1 genetic variants increase susceptibility to diabetes. Now we know that BMAL1 is at the heart of regenerating damaged beta cells.