Physical activity attenuates postprandial hyperglycaemia in homozygous TBC1D4 loss-of-function mutation carriers

Theresia M. Schnurr, Emil Jørsboe, Alexandra Chadt, Inger K. Dahl-Petersen, Jonas M. Kristensen, Jørgen F.P. Wojtaszewski, Christian Springer, Peter Bjerregaard, Søren Brage, Oluf Pedersen, Ida Moltke, Niels Grarup, Hadi Al-Hasani, Anders Albrechtsen, Marit E. Jørgensen, Torben Hansen*

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Aims/hypothesis: The common muscle-specific TBC1D4 p.Arg684Ter loss-of-function variant defines a subtype of non-autoimmune diabetes in Arctic populations. Homozygous carriers are characterised by elevated postprandial glucose and insulin levels. Because 3.8% of the Greenlandic population are homozygous carriers, it is important to explore possibilities for precision medicine. We aimed to investigate whether physical activity attenuates the effect of this variant on 2 h plasma glucose levels after an oral glucose load. Methods: In a Greenlandic population cohort (n = 2655), 2 h plasma glucose levels were obtained after an OGTT, physical activity was estimated as physical activity energy expenditure and TBC1D4 genotype was determined. We performed TBC1D4–physical activity interaction analysis, applying a linear mixed model to correct for genetic admixture and relatedness. Results: Physical activity was inversely associated with 2 h plasma glucose levels (β[main effect of physical activity] −0.0033 [mmol/l] / [kJ kg−1 day−1], p = 6.5 × 10−5), and significantly more so among homozygous carriers of the TBC1D4 risk variant compared with heterozygous carriers and non-carriers (β[interaction] −0.015 [mmol/l] / [kJ kg−1 day−1], p = 0.0085). The estimated effect size suggests that 1 h of vigorous physical activity per day (compared with resting) reduces 2 h plasma glucose levels by an additional ~0.7 mmol/l in homozygous carriers of the risk variant. Conclusions/interpretation: Physical activity improves glucose homeostasis particularly in homozygous TBC1D4 risk variant carriers via a skeletal muscle TBC1 domain family member 4-independent pathway. This provides a rationale to implement physical activity as lifestyle precision medicine in Arctic populations. Data repository: The Greenlandic Cardio-Metabochip data for the Inuit Health in Transition study has been deposited at the European Genome-phenome Archive ( under accession EGAD00010001428. Graphical abstract: [Figure not available: see fulltext.]

Udgave nummer8
Sider (fra-til)1795-1804
StatusUdgivet - aug. 2021

Bibliografisk note

Funding Information:
HAH has served as consultant at Bayer AG, MEJ has received research grants from Amgen, Sanofi-Aventis, AstraZeneca and Boehringer Ingelheim. MEJ holds shares in Novo Nordisk. The remaining authors declare no relationships or activities that might bias, or be perceived to bias, their work.

Funding Information:
The collection of data for the Greenland Inuit Cohort was supported by Karen Elise Jensen’s Foundation, NunaFonden, the Medical Research Council of Denmark, the Medical Research Council of Greenland and the Commission for Scientific Research in Greenland. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research centre at the University of Copenhagen and is partly funded by an unrestricted donation from the Novo Nordisk Foundation. This project was also supported by funds from the Danish Council for Independent Research (Medical Sciences), the Steno Diabetes Center, the Villum Foundation, the Danish Diabetes Academy, the Novo Nordisk Foundation (NNF14OC0013057, NNF15OC0017918 and NNF16OC0019986) and the Lundbeck Foundation. This work was supported by the Medical Research Council UK (MC UU 12015/3 to SB). HAH received grants from the European Foundation for the Study of Diabetes and Novo Nordisk. None of the funding agencies had any role in the study design or in the collection or interpretation of the data.

Publisher Copyright:
© 2021, The Author(s).


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