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

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.

Keywords: Arctic; Gene-environment interaction; Lifestyle therapy; Physical activity; Postprandial hyperglycaemia; TBC1D4 loss-of-function.

Fig. 1

Physical activity attenuates the effect of the common muscle-specific TBC1D4 p.Arg684Ter loss-of-function variant on 2 h plasma glucose levels in 2655 Greenlanders. (a) Raw data points (physical activity measured as physical activity energy expenditure on the x-axis and 2 h plasma glucose levels on the y-axis) stratified by TBC1D4 p.Arg684Ter genotype. (b) Illustration of the TBC1D4–physical activity interaction effect on 2 h plasma glucose levels relative to a standard individual in Greenlanders. For each individual, the respective mean physical activity energy expenditure per day is plotted on the x-axis. The y-axis displays the difference in 2 h plasma glucose levels for each individual compared with a standard individual (defined as non-carrier having an assumed physical activity energy expenditure of 50 kJ kg⁻¹ day⁻¹ [~ median of the cohort, illustrated by the black circle]). The predictions were performed using the estimated effect sizes from the primary analytical model and 95% CIs are shown. HE, heterozygous TBC1D4 p.Arg684Ter variant carriers; HO, homozygous TBC1D4 p.Arg684Ter variant carriers; PAEE, physical activity energy expenditure; WT, non-carriers