The effect of exercise training on glucose tolerance in Greenlandic TBC1D4 loss-of-function mutation carriers

The effect of exercise training on glucose tolerance in Greenlandic TBC1D4 loss-of-function mutation carriers

Research leader: Cecilie With, Research Assistant, Steno Diabetes Center Greenland.

Research area, purpose, and research questions:
The prevalence of type 2 diabetes in Greenland is closely related to specific Greenlandic genetic variations. A Greenlandic genetic variation in the TBC1D4 gene has been associated with a 10-fold higher risk of developing type 2 diabetes, and about 4% of the Greenlanders have two copies (homozygous) of this genetic variant, which means that the gene has been inherited from both parents. The homozygous variant carriers lose the TBC1D4 protein but also 50% of the glucose transporter (GLUT4) in the skeletal muscle. GLUT4 regulates the blood glucose level resulting in decreased glucose tolerance in these individuals. Exercise training is known to improve glucose tolerance, partly by increasing the content of GLUT4 in skeletal muscle. A recent study found that the level of selfreported physical activity was inversely associated with glucose tolerance in the variant carriers. This suggests, but does not prove, that physical activity may improve glucose tolerance and thus may reduce the risk of diabetes in this population. Thus, the purpose of this study is to investigate the effects of an exercise training intervention on glucose tolerance and the underlying molecular mechanisms in Greenlandic homozygous TBC1D4 variant carriers. We foresee that this study will shed light on the beneficial effects of exercise training on glucose tolerance and promote physical activity as prescription medicine in Arctic Inuit populations. Furthermore, a better understanding of the underlying molecular mechanisms may contribute to the development of novel pharmacological treatments mimicking the molecular effects of exercise, which could be useful for those who are unable to be physically active. The main outcomes of this study are the changes in glucose tolerance and the changes in GLUT4 protein levels in the skeletal muscle, which will be examined by performing a glucose tolerance test and obtaining muscle biopsies before and after the exercise training period. We aim to recruit a group of 8 variant carriers and a control group of 8 non-carriers. The participants will perform an 8-week high-intensity interval training protocol, which combines rowing and cycling, and we attempt to design the exercise training protocol so that it can be implemented in daily living, which will also make the results from this study directly relevant for prevention and treatment guidelines to the Greenlandic population.

Methods for competence building in the form of inclusion of society and dissemination to society:
In collaboration with the Institute for Health & Nature at the University of Greenland, we want to carry out a user survey to gain input on the training intervention and the training protocol which will then be adapted accordingly to fit into Greenlanders’ everyday life, which also means that the training can be directly disseminated to the population after the end of the study. We hope that the study will contribute to new knowledge about the beneficial effects of physical activity on glucose tolerance, which can be used both for the prevention and treatment of type 2 diabetes. The study is carried out at Steno Diabetes Center Greenland allowing for implementation of knowledge through direct contact with the Greenlandic population.

Granted: 100.000 DKK.

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