A specific genetic variant found in 4% of Greenland’s Inuit population dramatically increases their risk of type 2 diabetes by tenfold.
Recent research led by the University of Copenhagen and the Steno Diabetes Center Greenland, published in Nature Metabolism, has identified that this heightened risk stems solely from the muscles, making the condition unique compared to other forms of insulin resistance.
While standard diabetes medications are unlikely to help—and may even pose risks—physical activity has emerged as a promising preventive strategy.
A Rising Diabetes Epidemic in Greenland
In the 1960s, diabetes was virtually unknown in Greenland. However, the prevalence of the disease has since soared, with rates now nearly double those in Denmark.
Among the Inuit population, the group most at risk are individuals carrying a specific mutation in the TBC1D4 gene. This mutation leads to significant glucose intolerance, meaning their bodies struggle to remove sugar from the bloodstream after consuming it.
“Carriers of this variant have insulin-resistant muscles, meaning their muscle tissue does not respond effectively to insulin, which is critical because muscles handle most of the body’s sugar uptake,” explained Professor Jørgen Wojtaszewski from the University of Copenhagen’s Department of Nutrition, Exercise, and Sports.
A Unique Form of Insulin Resistance
Unlike typical cases of type 2 diabetes, where insulin resistance affects multiple organs such as the liver and fat tissue, this gene variant causes resistance solely in muscle tissue. This distinction means that carriers do not exhibit the usual signs of pre-diabetes, such as elevated fasting blood sugar or insulin levels. This makes detection particularly challenging for doctors.
“As long as the pancreas can produce enough insulin and other organs remain insulin-sensitive, these individuals don’t show obvious symptoms,” said Wojtaszewski. “But their muscle-specific insulin resistance puts them at a high risk of developing type 2 diabetes later in life.”
Exercise as a Preventive Measure
At the molecular level, the TBC1D4 mutation prevents carriers from producing a crucial protein in their muscle tissue, which affects their ability to regulate glucose uptake. Researchers tested whether physical activity could enhance insulin sensitivity in these individuals and found promising results.
Just one hour of moderate exercise increased insulin sensitivity in the muscles of gene variant carriers, albeit to a lesser extent than in non-carriers. This suggests that regular physical activity can significantly reduce the risk of diabetes for those with the mutation.
“People with this gene variant have been part of the Inuit population for hundreds of years, and they will continue to be for generations to come,” Wojtaszewski noted. “We now know that exercise is a practical, effective way to help them prevent diabetes.”
Challenges with Conventional Treatments
Current diabetes medications, which typically lower blood sugar by reducing sugar production in the liver, are not effective for gene variant carriers. Since these individuals do not have elevated fasting blood sugar, such treatments could lead to dangerously low blood sugar levels. This highlights the need for alternative approaches tailored to their unique condition.
Insights for Broader Diabetes Treatments
While the focus of this research is on the Inuit population, the findings have implications for more common forms of type 2 diabetes. The study revealed that a specific enzyme activated during physical activity positively influences TBC1D4 activity, even in individuals without the mutation.
This has sparked interest in developing drugs that mimic the effects of exercise by activating this enzyme, potentially benefiting a much larger population of people with type 2 diabetes.
Looking Ahead: Personalized Medicine and New Treatments
Efforts to map the genetic composition of Greenland’s population are still in their early stages, covering less than 10% of the population. As genetic data becomes more comprehensive, personalized advice and preventive strategies for individuals carrying this variant could become more accessible.
Meanwhile, the pharmaceutical industry is exploring molecules that can activate enzymes affecting TBC1D4 regulation. If successful, these drugs could improve insulin sensitivity in patients with more common forms of type 2 diabetes, opening the door to a new generation of treatments.
Conclusion
This groundbreaking research highlights a unique genetic challenge faced by a subset of Greenland’s Inuit population while also offering a clear, actionable solution: exercise.
By improving insulin sensitivity through physical activity, individuals with the TBC1D4 mutation can significantly reduce their diabetes risk. The study also paves the way for innovative treatments that could benefit millions of people worldwide living with type 2 diabetes.
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The research findings can be found in Nature Metabolism.
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