Mitochondria of diabetic patients can’t keep track of time

Illustration

Circadian rhythm in skeletal muscle cells of type 2 diabetic patients vs healthy individuals. Illustration by Brendan Gabriel, produced with Biorender.

Muscle cells in patients with type 2 diabetes have a disrupted biological clock discover researchers at the University of Copenhagen and Karolinska Institutet. The findings, published in the journal Science Advances, suggest that treatments for type 2 diabetes may be more or less effective depending on the time of day they are given.

Almost all cells regulate their biological processes over a 24-hour period, otherwise called a cell’s circadian rhythm. To do so, cells use a biological clock that cycles different genes on and off throughout the day and night.

Scientists already know that our metabolic health can suffer when our biological clock breaks down, due to shift work or sleep disorders, for example. However, it’s unclear how exactly the biological clock of people with type 2 diabetes differs from healthy people.

Now a team of international scientists has shown that the skeletal muscle in people with type 2 diabetes has a different circadian rhythm. They argue that this might arise because of a communication breakdown between a cell’s time keeping molecules and mitochondria, which produce chemical energy for cells.

May help fine-tune timing of treatment

Juleen Zierath, photo: Ulf Sirborn.

“The promise of this research is that it may help us to fine tune the timing of interventions and other medications to treat type 2 diabetes, in order to optimize their effectiveness,” says Professor Juleen R. Zierath from Karolinska Institutet and the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) at the University of Copenhagen.

In the study, the scientists first obtained skeletal muscle cells from people with type 2 diabetes and measured which genes showed cycling behavior over two days and compared them with cells from similar healthy people. They discovered that cells from people with type 2 diabetes had fewer, and some different, cycling genes.

They carried out further experiments using data generated from clinical tests in people with type 2 diabetes and mice, as well as cell-based experiments. These experiments demonstrated that mitochondria communicate with the molecules that keep time in our cells, and that this communication is disrupted in people with type 2 diabetes.

Some of the most widely used pharmacological treatments for type 2 diabetes affect mitochondria, meaning that they may work differently depending on the time of day they are taken. As a result, these findings highlight the importance of considering cellular rhythms when prescribing treatments for type 2 diabetes.

Exercise and diet can affect time-keeping genes

Brendan Gabriel and Ali Altintas

From left: Brendan Gabriel and Ali Altintas.
Photos: Novo Nordisk Foundation Center for Basic Metabolic Research.

“Exercise and diet are regularly used treatment interventions for people with type 2 diabetes, and both of these treatments can affect the time-keeping molecules and mitochondria,” says Brendan Gabriel, researcher at the Department of Physiology and Pharmacology, Karolinska Institutet.

Brendan Gabriel is first author on the paper together with Assistant Professor Ali Altintas from CBMR.

“Given that disrupted sleeping patterns are known to be associated with an increased risk of developing type 2 diabetes, our findings provide evidence of how these disruptions may link to the molecular biology within cells,” says Ali Altintas.

The study has been financed by AstraZeneca SciLifeLab Research Programme, Novo Nordisk Foundation, Swedish Diabetes Foundation, Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Strategic Research Programme in Diabetes at Karolinska Institutet, the Stockholm County Council, the Swedish Research Council for Sport Science, the Wenner-Gren Foundation, the European Foundation for the Study of Diabetes, the Biochemical Society, the Marie Skłodowska-Curie Actions, NIH, Sigurd och Elsa Goljes Minne, Lars Hierta Memorial Foundations.

This news article is based on a press release from the University of Copenhagen.

Publication

Disrupted circadian oscillations in type 2 diabetes are linked to altered rhythmic mitochondrial metabolism in skeletal muscle.” Brendan M. Gabriel, Ali Altıntas, Jonathon A. B. Smith, Laura Sardon-Puig, Xiping Zhang, Astrid L. Basse, Rhianna C. Laker, Hui Gao, Zhengye Liu, Lucile Dollet, Jonas T. Treebak, Antonio Zorzano, Zhiguang Huo, Mikael Rydén, Johanna T. Lanner, Karyn A. Esser, Romain Barrès, Nicolas J. Pillon, Anna Krook, Juleen R. Zierath, Science Advances, online Oct. 20, 2021, doi: 10.1126/sciadv.abi9654

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