Breakdown in communication between mitochondria and the body’s biological clock may be why the cells of people with type 2 diabetes are not in synch with a normally functioning circadian rhythm.
Researchers have known for many years that circadian rhythm is clearly linked with metabolic health. The risk of developing obesity and type 2 diabetes increases if our lives are not in accordance with our circadian rhythm, such as people who work at night or have severe sleep disorders.
So far, the link between circadian rhythm and the metabolic health of people with type 2 diabetes has been less thoroughly studied.
However, a new study reveals that the dysfunctional metabolism among people with type 2 diabetes seems to be linked to a breakdown in the communication between the molecular clock that controls the circadian rhythm and the mitochondria that produce energy for the cells.
“The discovery may have implications for the treatment of type 2 diabetes including the time of day people exercise, eat or take medicine,” explains an author behind the study, Juleen R. Zierath, Professor, Karolinska Institutet, Stockholm, Sweden and Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.
The research has been published in Science Advances.
Genes control the circadian rhythm
Virtually all cells have a circadian rhythm that regulates various processes over a period of about 24 hours. This daily rhythm regulates the levels of various gene expressions, hormones and signalling molecules that affect all aspects of life, including metabolism, blood pressure, sleep and liver function.
A complex network of genes, proteins and molecules ensures that this circadian rhythm is constantly under relatively tight control. Several genes and associated proteins are switched on during the day, and others are switched off.
The three core-clock genes regulating the circadian rhythm are BMAL1, CLOCK and PER3, and removing them from laboratory animals renders them unable to differentiate between day and night.
Studied cells’ core-clock gene expression over 54 hours
The researchers wanted to discover how the molecular-clock mechanism for regulating the circadian rhythm functions among people with type 2 diabetes and therefore obtained skeletal muscle biopsies from people with type 2 diabetes and from healthy controls.
They cultured the cells from the biopsies and examined them every 4 hours for 54 hours to determine whether the molecular-clock mechanism differed between the people with type 2 diabetes and the healthy controls.
In addition to examining the molecular-clock mechanism, the researchers also examined whether the groups differed in the regulation of 200 genes related to metabolism.
The researchers also investigated the cells’ potential for oxidative capacity and oxygen metabolism to determine their functionality. The circadian rhythm regulates the cells’ uptake of oxygen like all other processes in the body.
Type 2 diabetes disrupts circadian rhythm
The cells from the people with type 2 diabetes and those from the healthy controls differed significantly.
Over the 54 hours, the time of day affected fewer genes among people with type 2 diabetes, and the expression of those that were regulated was also reduced. Thus, the time of day did not have the same effect on the cell autonomous circadian rhythms of people with type 2 diabetes versus the healthy controls.
Similarly, the individuals with type 2 diabetes had reduced circadian rhythm–regulated oxidative metabolism of cells and thereby reduced muscle function.
“The oscillations of core-clock genes were reduced, and fewer genes were involved in the circadian rhythm of people with type 2 diabetes. We are the first to show this difference in the circadian rhythm of people with type 2 diabetes and healthy controls,” says Juleen R. Zierath.
Miscommunication is the problem
The researchers then took new biopsies from people with type 2 diabetes and from healthy controls and examined whether the circadian control of gene expression and metabolism is altered at the cellular level in skeletal muscle.
Using similar methods, the researchers discovered that the gene expression in the mitochondria differed between people with and without type 2 diabetes.
Specifically, the researchers found that the degree of binding of the CLOCK and BMAL1 genes to mitochondrial genes was positively associated with insulin sensitivity and thus stronger among healthy controls than among people with type 2 diabetes.
Juleen R. Zierath explains that this finding indicates that healthy metabolism requires well-functioning communication between the mitochondrial genes and the core-clock genes.
To confirm this link, the researchers studied mice with dysfunctional core-clock genes that bind to the mitochondria, and they could see that altering the mitochondrial genes also altered the mice’s circadian rhythm.
“Our findings indicate how metabolic dysfunction can be linked to miscommunication between the mitochondria and the circadian rhythm. This results in reduced oxidative capacity of skeletal muscle cells because the mitochondria change,” explains Juleen R. Zierath.
Medicine may need to be adjusted to the circadian rhythm
Juleen R. Zierath says that the discovery of a clear link between type 2 diabetes, metabolism, mitochondria and the circadian rhythm may have clinical implications.
The research suggests that the time of day may influence how effective type 2 diabetes treatment is, including the timing of sleep, meals, physical activity and taking medicine.
“Some of the most common treatments for people with type 2 diabetes affect the mitochondria. The same applies to exercise and diet, which means that the effect can differ depending on the time of day. More and more researchers are starting to incorporate chronomedicine, ensuring that medicine is administered at the right time of day to maximise the effect in synch with the cell autonomous circadian rhythm. This will be the next interesting step to take in our research,” concludes Juleen R. Zierath.
