A team from Geneva, Switzerland, has shown that a disruption of the temporal adipose features in type 2 diabetes leads to stiffening of the membrane of endocrine cells in the pancreas, which may alter their function.
Like all living things, human physiological processes are influenced by circadian rhythms. Disruption of our internal clocks due to an increasingly unbalanced lifestyle is linked to the explosion in cases of type 2 diabetes. By what mechanism? A team from the University of Geneva (UNIGE) and the University Hospitals of Geneva (HUG) in Switzerland have lifted part of the veil: this disorder disrupts the metabolism of fats in cells that secrete the glucose-regulating hormones. Sphingolipids and phospholipids, which are lipids on the cell membrane, appear to be particularly affected. This change in lipid profiles then causes the membranes of these cells to stiffen. These results, to be read in the journal Biology PlusProvide further evidence for the importance of circadian rhythms in metabolic disorders.
Fats have a variety of cellular functions. As a major component of cell membranes, it is involved in the signaling pathways through which cells communicate with each other and with their environment. “We’ve known for some time that circadian disruption is closely associated with metabolic diseases, such as type 2 diabetes, in which the body is no longer able to effectively regulate blood sugar levels,” explains Charna Dipner, professor in the departments. surgery, cellular physiology and metabolism, as well as at the Diabetes Center at the UNIGE and HUG School of Medicine, who led this research. “It has also been shown that lipids play an important role in metabolic disorders. But the effect of circadian rhythms on lipid function has remained unknown.”
Complex in the laboratory Human molecular clocks model
The islets of Langerhans are clusters of different types of endocrine cells found in the pancreas, and they are particularly responsible for the secretion of insulin and glucagon, the hormones that regulate blood glucose. To understand how lipids are affected by circadian rhythms, scientists analyzed oscillation profiles for more than 1,000 lipids in human islets of People with type 2 diabetes It is healthy individuals. “The experimental design we used is particularly complex,” explains Volodymyr Petrenko, a researcher in the Sharna Dipner lab and first author of this study. “When we study a muscle, for example, we can take a biopsy every hour. But when it comes to internal organs such as the heart, liver or pancreas, as in this case, that is of course impossible. So we had to develop a model of disrupted molecular clocks in the laboratory with human pancreatic islets.”
In an organism, the central clock of the brain coordinates the peripheral clocks in the cells of all organs according to external stimuli. In the lab, scientists have artificially replaced this central clock to resynchronize cells. “In fact,in the laboratory, each cell maintains its own rhythm but without extensive coordination. However, our work is specifically aimed at understanding how rhythms, which are formed in a multicellular population essential for the functioning of the endocrine pancreas as an entity, to control intracellular lipid metabolism,” adds Volodymyr Petrenko.
Comparing carrots from people with type 2 diabetes and from healthy subjects showed that lipid profiles fluctuate much more during the day than previously thought. “Not only are the fat island profiles in diabetics and non-diabetics different, but the way they oscillate throughout the day is different as well.”
In addition, the scientists observed a particularly large change in the temporal profile of phospholipids and sphingolipids, two classes of lipids that make up the main components of the cell membrane.
Recent studies have shown a link between these phosphates and sphingolipids and the loss of insulin production capacity typical of type 2 diabetes. Our study goes in the same direction: we observed that islets with disrupted clocks had an accumulation of phosphorous and sphingolipids resulting in membrane stiffness. This may affect the cell’s ability to detect environmental signals and thus release insulin when needed.”
Sharna Dipner, Professor, Departments of Surgery, Cellular Physiology and Metabolism
Moreover, the scientists were able to reproduce the phenomena in healthy pancreatic cells by artificially disrupting their circadian clocks. Studies will continue to understand the exact cause and mechanism of this phenomenon.
Encourage lifestyle changes?
This work establishes for the first time a direct link between the disruption of circadian clocks and the lipid changes typical of diabetics. This basic research data lays the foundation for research with patients. The Charna Dibner research team is currently conducting two application studies: The first, in collaboration with nutritionists at the University of Geneva Hospitals, explores the potential benefits of intermittent fasting from a personalized medicine perspective, considering the exact profile of each. An individual. The second, in collaboration with Maastricht University in the Netherlands, aims to resynchronize patients with the help of sunlamps.
Petrenko, V., et al. (2022) Type 2 diabetes disrupts the circadian coordination of lipid metabolism and membrane fluidity in human pancreatic islets. Biology Plus. doi.org/10.1371/journal.pbio.3001725.