Could resetting our internal clocks help control diabetes?

Researchers recently proved the link between disturbances to our circadian clocks and type 2 diabetes, and also how to correct them.

Our circadian clocks (from Latin "circa diem," about a day) allow us to anticipate the periodic changes of time and adjust to these changes. Nearly every cell in the body includes molecular clocks that regulate and synchronize metabolic functions to a 24-hour cycle of day-night changes.

Increasing evidence shows that disturbances in our internal clocks -- whether from frequent time zone changes, irregular working hours, or aging -- significantly affect the development of metabolic diseases, including type-2 diabetes. These disturbances prevent the proper functioning of the cells in the pancreas that secrete insulin and glucagon, the hormones that regulate blood sugar levels.

Researchers at the University of Geneva and at the University Hospitals of Geneva, Switzerland, were able to demonstrate, for the first time, that pancreatic cells derived from people with Type 2 diabetic human donors have compromised circadian clocks, which happens when hormone secretion is disturbed.

The rhythms of pancreatic cells in people with type-2 diabetes exhibit both reduced circadian oscillations and poor synchronization, the researchers found. As a result, insulin and glucagon secretion is no longer coordinated. These effects were the same when pancreatic cells from health donors were subjected to artificially disrupted circadian clocks.

These results were published in the Proceedings of the National Academy of Sciences of the United States. The research team was led by Charna Dibner, principle investigator in the Departments of Medicine and of Cell Physiology and Metabolism and Diabetes Centre at the University Hospitals of Geneva Faculty of Medicine, and at the University Hospitals of Geneva.

The verdict is indisputable," said Dibner.

Setting the right time again

This study offers insight into an innovative approach for diabetes care. In step two of their research, the scientists used a clock modulator molecule dubbed Nobiletin, which is derived from lemon peel, to successfully "repair" the disrupted cellular clocks and partially restore cell function.

"By acting on one of the core-clock components, it resets efficiently the amplitude of the oscillations in the human islets," said researcher Volodymyr Petrenko. "And as soon as we got the clocks back in sync, we also observed an improvement in insulin secretion."

It's all in the timing

Circadian clocks represent the daily cycles governing cellular functions. Several elements need to be synchronized, the main one being light, which regulates the central clock located in the cerebral hypothalamus. Like a conductor in the orchestra, it regulates the peripheral clocks present in organs and cells.

"Pancreatic cells are also subject to the rhythm of fasting and food intake, and to a tight hormonal regulation," said Dibner. "Coordinating all levels of regulation therefore allows the optimization of metabolic functions. Clock deregulation in the pancreas leads to a compromised function: they are not anymore anticipating food-derived signals. Indeed, if you eat the same food but at night rather than during the day, you may gain weight much faster, due to a suboptimal response of your metabolism."

Dibner said the study is the first proof that repairing compromised circadian clocks may improve pancreatic islet hormone secretion.

Our society is experiencing an epidemic in metabolic diseases, with shifted working and eating schedules, and lack of sleep, she said.

"By re-synchronizing the perturbed molecular clocks, either by personalized eating and exercise schedules or with the help of clock modulator molecules, we hope to ultimately be able to provide an innovative solution to an epidemical metabolic problem affecting an ever-increasing proportion of the world's population," she said.

Source: University of Geneva and at the University Hospitals of Geneva: unige.ch/communication