Study shows direct link between circadian clock disruption and lipid changes in diabetics

Study shows direct link between circadian clock disruption and lipid changes in diabetics

The team from Geneva, Switzerland shows that disruption of lipid temporal profiles in type 2 diabetes stiffens the membrane of pancreatic endocrine cells, which could alter their function.

Like all living things, human physiological processes are affected by circadian rhythms. Disruption of our internal clocks due to increasingly unbalanced lifestyles is directly related 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 is lifting part of the veil: this disorder disrupts lipid metabolism in cells that secrete glucose-regulating hormones. Sphingolipids and phospholipids, lipids located on the cell membrane, appear to be particularly affected. This change in lipid profiles then leads to the rigidity of the membrane of these cells. These results to read in the journal PLOS Biologyprovide further evidence for the importance of circadian rhythms in metabolic disorders.

Lipids have various cellular functions. As one of the main components of cell membranes, they participate in signaling pathways through which cells communicate with each other and with their surroundings. “We’ve known for some time that disruption of the circadian clock is closely related to metabolic diseases such as type 2 diabetes, where the body is no longer able to effectively regulate blood sugar,” explains Charna Dibner, professor in the Department of Surgery and Cell Physiology and Metabolism, further in the Diabetology Center of the Faculty of Medicine of UNIGE and HUG, who led this research. “Lipids are also shown to play a significant role in metabolic disorders. But the impact of circadian rhythms on lipid functions has remained unknown.”

Complex in vitro a model of the human molecular clock

The islets of Langerhans are clusters of different types of endocrine cells located in the pancreas, which are mainly responsible for the secretion of insulin and glucagon, hormones that regulate blood glucose levels. To understand how lipids are affected by circadian rhythms, the researchers analyzed the oscillatory profiles of more than 1,000 lipids in human islets from people with type 2 diabetes and from healthy individuals. “The experimental design we used is particularly complex,” explains Volodymyr Petrenko, a researcher in Charna Dibner’s lab and first author of the study. “When we study a muscle, for example, we can perform a biopsy every hour. But when it comes to internal organs such as the heart, liver or pancreas, as in this case, this is of course impossible. We therefore had to develop a model of disrupted molecular clocks in vitro with human pancreatic islets.”

In a living organism, the central clock in the brain controls the peripheral clocks in the cells of all organs according to external stimuli. In the laboratory, scientists therefore artificially replaced this central clock to resynchronize the cells. “Actually,in vitro, each cell maintains its own rhythm, but without overall coordination. However, our work is focused precisely on understanding how rhythms created in a multicellular population, which are necessary for the functioning of the endocrine pancreas as an entity, control intracellular lipid metabolism,” adds Volodymyr Petrenko.

Membrane reinforcement

A comparison of islets from people with type 2 diabetes and from healthy people showed that lipid profiles oscillate much more during the day than previously thought. “And not only are the islet lipid profiles different in diabetics and non-diabetics, but also the way they oscillate during the day.”

In addition, the researchers observed a particularly large change in the temporal profile of phospholipids and sphingolipids, two classes of lipids that are major components of the cell membrane.

Recent studies have shown a link between these phospho- and sphingolipids and the loss of insulin production capacity typical of type 2 diabetes. Our study goes in the same direction: we observed that clock-disrupted islets had an accumulation of phospho- and sphingolipids that stiffened the membrane. This can affect the cell’s ability to detect signals from the environment and therefore secrete insulin when needed.”

Charna Dibner, Professor, Department of Surgery and Cell Physiology and Metabolism

In addition, the researchers were able to reproduce the phenomena with healthy pancreatic cells by artificially disrupting their circadian clock. Studies will continue to understand the exact cause and mechanism of this phenomenon.

Promoting lifestyle changes?

This work demonstrates for the first time a direct link between the disruption of the circadian clock and the lipid changes typical of diabetics. These basic research data lay the foundation for research with patients. Charna Dibner’s research team is currently conducting two applied studies: the first, in collaboration with nutritionists from the University Hospitals of Geneva, is investigating the potential benefits of intermittent fasting from the perspective of personalized medicine, taking into account the precise circadian profile of each. individual. The second, in collaboration with Maastricht University in the Netherlands, aims to resynchronize patients using solar lamps.


Link to journal:

Petrenko, V., et al. (2022) Type 2 diabetes disrupts circadian orchestration of lipid metabolism and membrane fluidity in human pancreatic islets. PLOS Biology.

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