Melatonin Links Gene Variant to Type 2 Diabetes Risk

Marcia Frellick

May 19, 2016

The natural sleep hormone melatonin inhibits insulin secretion among people with a very common variation in the gene coding for the melatonin receptor and may help explain a higher risk of type 2 diabetes among that large population, new research shows.

Almost a third of people (30%) are thought to have the variant, which causes pancreatic beta cells to become more sensitive to melatonin and in turn impairs their ability to secrete insulin.

The new data may hold clues as to why people who work overnight or who have sleep disorders may have a higher risk of type 2 diabetes, although that connection is less clear, the authors say.

Link May Help Design New Drugs

Understanding the link between the melatonin receptor 1b gene variant (MTNR1B), melatonin, and type 2 diabetes may also help in designing new drugs for the disease, senior author of the new study, Hindrik Mulder, MD, PhD, associate professor at Lund University in Sweden, told Medscape Medical News.

Findings from the study by Tiinamaija Tuomi, MD, PhD, of the Endocrinology and Abdominal Center in Helsinki University Hospital in Finland, and colleagues, were published online May 12 in Cell Metabolism.

Dr Mulder said the findings build on their previous work from 2009, which concluded that people who had the gene variant had a higher risk of type 2 diabetes.

Two Phases of Study

The current study consisted of an experimental phase and then a clinical investigation.

In the experimental portion, the researchers studied pancreatic islet cells from human donors and found that people with the MTNR1B gene variant had more melatonin receptors.

Those who had two copies of the variant had greater numbers of receptors on the islet cells than those who had one.

From there, researchers set out to find the consequences of having a greater number of melatonin receptors.

They added melatonin to the cells and saw that this had a negative effect on insulin secretion. Then they examined mice that lacked the receptor to see if the reverse were true and found it was — the mice without the receptors secreted more insulin.

But how would humans react with more melatonin? The clinical examination began by recruiting 23 nondiabetic people who were carriers of two copies of the gene variant and 22 noncarriers. All participants were about the same age and had similar body mass index (BMI). There was also no difference in their family history of diabetes.

Participants were given 4 mg of melatonin (about the amount in the typical over-the-counter pill) before bedtime over 3 months.

By the end of the study, people without the risk gene variant had significantly more insulin secretion than those with the variant and were better able to efficiently clear blood glucose.

Should People With the Variant Avoid Melatonin Pills?

Dr Mulder said the results have implications for personalized medicine in that they show that treatments for type 2 diabetes may need to be different depending on the presence or absence of this gene variant.

The findings should also help direct whether people should take melatonin and how much. He notes that melatonin is not available over the counter in Sweden, but it is in places such as the United States.

As to whether people should avoid over-the-counter melatonin pills, Dr Mulder said current science doesn't support that.

But theoretically, this practice could be detrimental, he said, "because if you carry the risk variant of the melatonin receptor, the effects of the hormone are likely to be exaggerated. This may be harmful if you have additional risk for developing type 2 diabetes. More studies are required to establish this."

A person's level of melatonin varies throughout the day and is affected by light. When it's dark, the level of melatonin increases, which is why people use melatonin pills to help regulate sleep or prevent jet leg.

He said night workers and those who travel in different time zones frequently have inconsistent melatonin secretion, so if these people carry the gene variant too, the effects of melatonin may be increased at certain times, at least in the cells that secrete insulin.

"If I had multiple risks for diabetes, I think I would avoid having an (overnight) shift job," he said. "I think the ambient light would have some effect on melatonin levels."

But he said working overnight is also associated with factors such as less healthy eating and being less active, which are also linked to type 2 diabetes, so it's hard to dissect out cause and effect.

Dr Mulder also doesn't recommend — based on these results — that people get their genes mapped to see if they have the variant.

Because large studies have identified more than 100 genes that may play a role in type 2 diabetes, scientists don't yet know how important this particular variant of this particular gene is.

In future studies, Dr Mulder said his team will work to find out why the gene variant changes the level of the melatonin receptor. "We've only proven that it does, but now we need to know exactly how," he said.

The authors received support from the European Foundation for the Study of Diabetes, Swedish Research Council, Pahlsson Foundation, Medical Faculty at Lund University, Diabetes Wellness Sweden and the Swedish Diabetes Foundation, Novo Nordisk Foundation, Family Ernfors Fund, European Research Council, Sigrid Jusélius Foundation, Folkhalsan Research Foundation (Finland), Academy of Finland, Nordic Center of Excellence in Disease Genetics, Signe and Ane Gyllenberg Foundation, Swedish Cultural Foundation in Finland, Finnish Diabetes Research Foundation, Foundation for Life and Health in Finland, Finnish Medical Society, Paavo Nurmi Foundation, Helsinki University Central Hospital Research Foundation, Perklén Foundation, Ollqvist Foundation, Narpes Health Care Foundation, and Ahokas Foundation. The study has also been supported by the Ministry of Education in Finland; Municipal Heath Care Center and Hospital in Jakobstad; and Health Care Centers in Vasa, Narpes, and Korsholm.

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Cell Metab. Published online May 12, 2016. Article


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