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

• Main Authors: Schnurr, Theresia M, Jørsboe, Emil, Chadt, Alexandra, Dahl-Petersen, Inger K, Kristensen, Jonas M, Wojtaszewski, Jørgen FP, Springer, Christian, Bjerregaard, Peter, Brage, Søren, Pedersen, Oluf, Moltke, Ida, Grarup, Niels, Al-Hasani, Hadi, Albrechtsen, Anders, Jørgensen, Marit E, Hansen, Torben
• Format: Article in Journal/Newspaper
• Language: English
• Published: Springer Science and Business Media LLC 2021
• Subjects: Arctic; Gene-environment interaction; Lifestyle therapy; Physical activity; Postprandial hyperglycaemia; TBC1D4 loss-of-function; Adult; Blood Glucose; Diabetes Mellitus; Type 2; Exercise; Female; GTPase-Activating Proteins; Genetic Predisposition to Disease; Genotyping Techniques; Glucose Tolerance Test; Greenland; Humans; Hyperglycemia; Insulin; Inuit; Life Style; Loss of Function Mutation; Male; Middle Aged; Postprandial Period; greenlandic; inuit
• Online Access: https://www.repository.cam.ac.uk/handle/1810/321851; https://doi.org/10.17863/CAM.69310

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.