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Body and mind

People with diabetes have disrupted circadian insulin production

New research shows that the islet cells in the pancreas of people with type 2 diabetes are completely out of sync with the body’s circadian clock. The research suggests that the circadian clock may be reset to its normal synchronization and thus mitigate type 2 diabetes and other metabolic diseases.

The circadian clock in the insulin-producing islet cells in the pancreas is out of sync with the normal circadian rhythm among people with type 2 diabetes.

This is the conclusion of a new study published in the Proceedings of the National Academy of Sciences of the United States of America.

In the study, the researchers found a malfunction in the circadian clock of people with type 2 diabetes that causes their metabolism to be dysregulated in relation to the circadian rhythm.

The discovery emphasizes a link between the circadian clockwork and the risk of developing metabolic diseases but also suggests a possible way to reset the body’s internal clock and thus mitigate the severity of type 2 diabetes.

“Our study is the first to show that people with diabetes can be treated by resetting the body’s internal clock. In the future, this may help to alleviate the current epidemic of metabolic diseases seen globally, which may in part result from the fact that many people’s modern lifestyles have disrupted their circadian clocks,” explains Charna Dibner, Research Group Leader, Faculty Diabetes Center, University of Geneva.

The circadian clock controls almost everything

The circadian clock is a fundamental biological function in organisms that governs most aspects of physiology and behaviour.

The circadian clock regulates people’s sleep patterns, the secretion of hormones at different times of the day and body temperature.

For example, this biological clock lowers body temperature at night and secretes hormones that affect digestion at the times of day when we tend to eat. This primes our digestive system to process food, even before we put it in our mouths.

This circadian clock also regulates the activity of various organs, so that they are alert at the times of the day when they are needed and so that they do not use energy and resources to maintain a high level of activity when this is unnecessary.

For example, the liver does not need to be especially active at night when, under normal circumstances, we do not have a very high level of metabolic activity.

The circadian clock is controlled by light and darkness, which affects several clock genes, including one appropriately named CLOCK.

The discovery of the clock genes also led to a Nobel Prize for researchers behind the discovery in 2017.

“The clock genes act like a conductor of a symphony orchestra, and the coordination between the clock genes and the circadian rhythm optimizes metabolic function. For example, if you hypothetically eat the same food during the day and at night, you will gain more weight if you eat it at night, because you eat at a time when the circadian clock has not primed our metabolism to handle the food,” says Charna Dibner.

Circadian clock and type 2 diabetes linked in mice and people

The researchers behind the new study previously showed that disrupting the functioning of rodents’ clock genes and their circadian clock dysregulates how the pancreas secretes insulin and glucagon.

Insulin and glucagon control blood glucose and thus also the risk of developing type 2 diabetes.

The researchers also previously showed that destroying the circadian oscillators in human pancreatic islet cells disrupts the strict regulation of how and when these cells secrete insulin and glucagon.

The question the researchers investigated in the new study is whether the pancreatic islet cells of people with type 2 diabetes exhibit signs of disruption to the circadian clock and whether the disruption affects how the pancreatic islet cells function.

Pancreatic islet cells from people with diabetes out of sync with the circadian rhythm

The researchers used bioluminescence-fluorescence time-lapse microscopy to track the activity of the clock genes over time in living human pancreatic islet cells.

The researchers compared the activity of the clock genes in pancreatic islet cells from people with type 2 diabetes to those in healthy people and found very clearly that the circadian clock was disrupted among the people with diabetes.

This disruption included the amplitude and oscillations of the circadian clock and its ability to synchronize with the circadian rhythm.

“The result is that the secretion of hormones is no longer coordinated. Further, the disruptions we found among people with type 2 diabetes were comparable to those we found in cells in which we had artificially destroyed the circadian clock,” explains Charna Dibner.

Flavonoid from citrus peel may stabilize the circadian clock

After the researchers established the link in human cells from people with type 2 diabetes, they tried to enhance the functioning of the clock genes by using nobiletin.

Nobiletin is a flavonoid present in the peel of citrus fruits, and research has shown that it can reset the clocks of the pancreatic islets.

Nobiletin affects a core clock protein and resets the clock’s amplitude and synchronization effectively.

The researchers treated pancreatic islet cells from people with type 2 diabetes with nobiletin and improved insulin secretion.

“This is the first evidence that resetting the circadian clock can restore the normal hormonal functioning of the pancreas. This is what we will be investigating in animal models and hopefully later in humans,” says Charna Dibner.

Regular meal times and exercise can reset the circadian clock

Charna Dibner says that the circadian clock can be influenced in several ways so that it can become synchronized with the normal circadian rhythm, which may improve how the metabolism functions.

In addition to nobiletin, eating habits can also help to reset the circadian clock to its normal state.

Irregular meal times help to disrupt the circadian clock, and regular meal times can therefore help to put it back on an even keel.

Regular exercise can do this too.

“Ultimately, we hope to find innovative solutions to an epidemic metabolic problem that affects people all over the world,” says Charna Dibner.

In pancreatic islets from type 2 diabetes patients, the dampened circadian oscillators lead to reduced insulin and glucagon exocytosis” has been published in the Proceedings of the National Academy of Sciences of the United States of America. The Novo Nordisk Foundation awarded a grant to co-author Nikhil R. Gandasi for the project Mechanisms Affecting Islet Hormone Secretion During Type 2 Diabetes and a grant to another co-author, Anders Tengholm, for the project Cyclic AMP Signalling in Islet Hormone Secretion.

Charna Dibner
Biologist
Circadian oscillation of biological processes has been described in most of the light-sensitive organisms on earth. It reflects the existence of underlying intrinsic biological clocks with near 24 hour oscillation periods. It is well established that circadian clocks play a crucial role in the regulation of key metabolic processes. Moreover, there is an emerging evidence for connection between metabolic pathologies and the circadian clockwork. The long-term goal of our laboratory is to identify the molecular basis of circadian rhythmicity in rodent and human peripheral tissues in physiological, and in obesity/type 2 diabetes conditions. We have setup the experimental system for long-term recording of circadian reporter oscillations in human primary cultured cells from different tissue types at population and single cell levels. Using this powerful approach, we scrutinize the role of the oscillators present in a- and ß- cells in pancreatic islet function, and the impact of glucose metabolism on a- and ß- cell oscillators, in mouse and human models. Also, human skeletal muscle clock molecular makeup and its roles in regulating myokine secretion and insulin resistance development have been tackled. The prevalence of obesity and diabetes in modern society is taking on enormous proportions. It is therefore of major importance to identify the molecular basis of circadian rhythmicity in rodent and human peripheral tissues in physiological conditions, and upon obesity/T2D. In addition, we are interested in the connection between circadian clock and cancer, and in particular the thyroid cancer. We explore the molecular makeup of human thyroid clocks in physiology and upon thyroid malignancies, in an attempt to bring new insights into the role of circadian clocks in thyroid cancer, and to apply these changes for thyroid malignancies diagnostics in clinics.