Physical activity attenuates postprandial hyperglycaemia in homozygous TBC1D4 loss-of-function mutation carriers
Creators: name: Schnurr, Theresia M.
name: Jørsboe, Emil
name: Chadt, Alexandra
name: Dahl-Petersen, Inger K.
name: Kristensen, Jonas M.
name: Wojtaszewski, Jørgen F. P.
name: Springer, Christian
name: Bjerregaard, Peter
name: Brage, Søren
name: Pedersen, Oluf
name: Moltke, Ida
name: Grarup, Niels
name: Al-Hasani, Hadi
name: Albrechtsen, Anders
name: Jørgensen, Marit E.
name: Hansen, Torben
Publisher: name: Apollo - University of Cambridge Repository
Year: 2021
Subjects: Article
Arctic
Gene-environment interaction
Lifestyle therapy
Physical activity
Postprandial hyperglycaemia
TBC1D4 loss-of-function

description: Funder: Karen Elise Jensens Fond; doi: http://dx.doi.org/10.13039/501100004046
description: Funder: European Foundation for the Study of Diabetes; doi: http://dx.doi.org/10.13039/501100001648
description: Funder: NunaFonden
description: Funder: Danish Diabetes Academy; doi: http://dx.doi.org/10.13039/100015223
description: Funder: Lundbeckfonden; doi: http://dx.doi.org/10.13039/501100003554
description: Funder: Villum Fonden; doi: http://dx.doi.org/10.13039/100008398
description: Funder: Det Frie Forskningsråd; doi: http://dx.doi.org/10.13039/501100004836
description: Funder: Steno Diabetes Center
description: Funder: Commission for Scientific Research Greenland
description: Funder: Novo Nordisk Foundation Center for Basic Metabolic Research; doi: http://dx.doi.org/10.13039/501100011747
description: Funder: Medical Research Council Greenland
description: Funder: Medical Research Council Denmark
description: Abstract: 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 (https://www.ebi.ac.uk/ega/dacs/EGAC00001000736) under accession EGAD00010001428. Graphical abstract: