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Clock-gene variants linked to diabetes

Receptor for body-clock hormone connected to disease risk.

Diabetes — genetically linked to the body's biological clock. Credit: Punchstock

Fresh evidence suggests that melatonin, a hormone that regulates the body's biological clock, is associated with type 2 diabetes.

Epidemiological studies have shown that shift workers have an increased risk of developing type 2 diabetes. And patients with type 1 diabetes have sometimes reported higher blood-sugar levels after taking synthetic melatonin, which can be used to ease jet lag or as a sleep aid.

Now, two separate studies by researchers based in Europe and the United States have found that variants of a gene called MTNR1B, which produces a receptor protein that binds and responds to melatonin, is linked to an increased chance of developing type 2 diabetes1,2.

A sweet connection

In 2007, endocrinologist Leif Groop of Lund University in Sweden and his colleagues published a genetic analysis of nearly 3,000 people, half of whom had type 2 diabetes3. Further work indicated that a sequence variation in the MTNR1B gene was associated with increased levels of glucose in the blood under fasting conditions.

Although an abnormally high fasting-glucose level is a symptom of diabetes, the study did not find a link between the variant and the disease. But Groop suspected that the study may have been too small to pick up the association.

He and his colleagues joined forces with three other groups to analyze 13 studies that included 18,236 people with type 2 diabetes and 64,453 control patients without diabetes. Now, reporting in Nature Genetics, the team shows that the MTNR1B variant Groop and his colleagues identified in the 2007 study does increase the chances of developing type 2 diabetes1: by 9% when one copy of the variant gene is present and by 18% for people with two copies.

Meanwhile, a second study published in Nature Genetics reports an association between diabetes and a different genetic variant located near the MTNR1B gene2. Study author Philippe Froguel of the Pasteur Institute in Lille, France, says his team has since found additional variations within the gene that may also be associated with the disease.

The missing mechanism

Precisely how melatonin affects disease risk is still unclear. Froguel and his colleagues hope to recreate the naturally occurring MTNR1B variations in mice and study the effects on sugar metabolism. For now, he speculates that melatonin receptors in the eyes and the brain may activate signals that are transmitted to the pancreas, the organ that makes insulin.

In a further study, Groop's team reports that those who either have type 2 diabetes or carry the MTNR1B variant they worked on also express the gene at a higher level in insulin-producing β cells in the pancreas4. When grown in culture, β cells also produce less insulin when they are exposed to melatonin. The results, says Groop, suggest that the hormone acts directly on β cells, and that therapies designed to block melatonin signalling in the pancreas could one day provide a treatment for diabetes.

Such a therapy would have to be careful not to interrupt the important functions that melatonin carries out in the brain. But many drugs cannot pass through the blood–brain barrier, and Groop believes a drug could be created that would block the receptor in the pancreas without affecting the brain.

"There is mounting evidence from genetic models that there is a strong interaction between circadian regulatory pathways and glucose metabolism," says Joseph Bass, a diabetes researcher at Northwestern University in Evanston, Illinois, who was not involved with the study. "But one of the gaps has been in understanding the implications for these findings with regard to human disease and human biology."

As for those who take synthetic melatonin, there are no data to show that the tablets increase the risk of diabetes. Short-term use to treat jet lag may be less likely to have an effect on diabetes risk than long-term use, Groop says. "Theoretically, you could predict that they may be at higher risk for diabetes," he says. "But that is just a prediction: that hasn't been shown."

References

  1. Prokopenko, I. et al. Nature Genetics advanced online publication doi:10.1038/ng.290 (2008).

  2. Froguel, P. et al. Nature Genetics advanced online publication doi:10.1038/ng.277 (2008).

  3. Diabetes Genetic Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes for BioMedical Research. Science 316, 1331–1336 (2007).

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  4. Lyssenko, V. et al. Nature Genetics advanced online publication doi101038/ng.288 (2008).

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Leif Groop

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Ledford, H. Clock-gene variants linked to diabetes. Nature (2008). https://doi.org/10.1038/news.2008.1282

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  • DOI: https://doi.org/10.1038/news.2008.1282

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