Physical activity protects Greenlanders against a special subtype of diabetes

Diet and lifestyle 19. jun 2021 3 min Professor Torben Hansen Written by Kristian Sjøgren

Many indigenous Arctic people with diabetes have two copies of a gene variant, resulting in a specific subtype of type 2 diabetes that does not improve by administering insulin. New research shows that physical activity works really well.

Indigenous Arctic people, including those in Greenland, may be predisposed to a specific subtype of type 2 diabetes that is not found elsewhere.

If they carry two copies of a TBC1D4 loss-of-function gene variant, their muscles take up less glucose after a meal, leading to the development of this subtype of type 2 diabetes that cannot be treated by administering insulin.

Researchers from Denmark previously discovered this common gene variant and the associated form of diabetes. The same research group now shows that Greenlanders may not need medicine to lower their blood glucose.

Instead, they should carry out at least one hour of solid exercise daily.

“Indigenous Arctic people differ genetically from other population groups, and this includes this specific subtype of non-autoimmune diabetes. We have previously demonstrated that people who have two copies of the muscle-expressed TBC1D4 loss-of-function variant cannot get insulin to stimulate glucose uptake in their muscles after intake of carbohydrate. Our latest research shows that individuals with this subtype of diabetes being physically active for just one hour a day, such as through traditional hunting or fishing, may reduce the effect of having two copies of the TBC1D4 loss-of-function variant gene” explains Torben Hansen, Professor at the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.

The research has been published in Diabetologia.

Prehistory has left its mark in Inuit genes

The prehistory of the Inuit in Alaska, Canada, and Greenland is fascinating. Their ancestors migrated across the straits between Siberia and North America 20,000 years ago.

Over the ensuing millennia, they survived in one of the harshest regions on Earth while moving further and further east.

The first Inuit arrived in Greenland 1,000 years ago.

The many thousands of years in an environment that challenges survival have left genetic marks in the genomes of these indigenous people. This has enabled them to survive on a diet with very little carbohydrate and large amounts of fat and protein.

But the harsh environment has also left its mark on the genetics of disease, with some gene variants being overrepresented.

“In 2014, we published a study in Nature showing that many indigenous Greenlanders with diabetes have two copies of a muscle-specific TBC1D4 loss-of-function gene variant. Other researchers have also identified this variant among Inuit in Canada and Alaska, but otherwise the variant does not exist outside the Arctic,” says Torben Hansen.

TBC1D4 is interesting because it encodes a protein that is important for insulin-stimulated uptake of glucose into the muscles. The protein does not function if the mutation occurs in both copies of TBC1D4 and then insulin cannot stimulate the uptake of glucose into the muscles after a meal. Further, when the muscles cannot absorb glucose, insulin treatment is not effective for this subtype of type 2 diabetes.

“We therefore need to find other types of treatment,” explains Torben Hansen.

Greenland has 56,000 inhabitants. About 10% have diabetes, and about 15% of these have two copies of the TBC1D4 variant. The prevalence is probably the same among the Inuit living in Canada (65,000), Denmark (16,500) and the United States (16,500).

2,655 participants

Researchers from the University of Copenhagen, the Greenland Center for Health Research, Denmark’s National Institute of Public Health and Steno Diabetes Center Copenhagen reviewed how lifestyle and physical activity affect the levels of blood glucose of people with two copies of the TBC1D4 variant. One source of data was the Inuit Health in Transition study.

2,655 Greenlanders participated, and the researchers mapped their genome to determine who carries the TBC1D4 variant.

The researchers also asked the participants to fill out a questionnaire on physical activity. The researchers performed standardized glucose tolerance tests to determine how much the participants reduced their blood glucose after consuming water containing 75 grams of dissolved sugar.

“Healthy people can reduce their blood glucose to normal within 2 hours after intake of glucose. But not if they have diabetes. We wanted to determine how lifestyle influences the rate at which individuals with two copies of the TBC1D4 variant can reduce their blood glucose,” says Torben Hansen.

Exercise is the medicine for combatting this subtype of diabetes

The results showed very clearly that the people with high physical activity were much better at lowering their blood glucose than people with low physical activity – even though they lacked a functional muscle-specific TBC1D4 protein.

Exercise was so effective in reducing blood glucose that individuals with two copies of the TBC1D4 variant and high physical activity were able to reduce their blood glucose equally well as healthy people without type 2 diabetes.

Conversely, the people who were physically inactive had difficulty in lowering blood glucose.

The discovery very clearly indicates that the genetics of disease among the Inuit have only become a major problem now that many individuals also have a lifestyle associated with a diet with high sugar content and other types of carbohydrates and much less physical activity.

Torben Hansen says that the discovery is directly relevant clinically for the many Inuit who have this very special Arctic subtype of type 2 diabetes.

“This is a very positive result that can easily be communicated to people with diabetes in Arctic communities. One hour of strenuous exercise a day will significantly reduce blood glucose without other medication. The clear message is therefore that being active is healthy for everyone, but if you have the TBC1D4 variant, the negative effect of a modern lifestyle can be counteracted even better by being more physically active,” he concludes.

We perform genetic, microbiome and metabolome studies in monogenic diabetes, childhood obesity, Inuit in Greenland and large-scale genetic epidemiolog...

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