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

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

doi:10.1007/s00125-021-05461-z

Abstract

Aims/hypothesisThe 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.MethodsIn 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.ResultsPhysical 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/interpretationPhysical 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 repositoryThe 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

Highlights

Type 2 diabetes is a growing global health problem and its prevalence is rapidly increasing in Greenland and in other Arctic populations [1,2,3]
We found that homozygous TBC1 domain family member 4 (TBC1D4) p.Arg684Ter variant carriers had highly elevated levels of 2 h plasma glucose compared with non-carriers (β[main effect of being homozygous TBC1D4 risk variant carrier] = 4.2 mmol/l, p = 1.2 × 10−40, n = 2655), which is consistent with our previous observation [4]
The effect of physical activity on 2 h plasma glucose levels was significantly greater among homozygous carriers of the TBC1D4 variant compared with heterozygous carriers and non-carriers (β[interaction] = −0.015 [mmol/l] / [kJ kg−1 day−1], p = 0.0085, n = 2655; Fig. 1b, Table 1 and electronic supplementary material (ESM) Fig. 2a)

Summary

Introduction

Type 2 diabetes is a growing global health problem and its prevalence is rapidly increasing in Greenland and in other Arctic populations [1,2,3]. Homozygous carriers are characterised by postprandial hyperglycaemia (on average these individuals had 3.8 mmol/l higher 2 h plasma glucose during an OGTT), impaired glucose tolerance and 10.3-fold increased odds of developing type 2 diabetes [4]. Based on the variant’s high frequency and the clinical characterisation of homozygous TBC1D4 risk variant carriers, it has been suggested that diagnostic strategies for type 2 diabetes should include 2 h OGTT and/or TBC1D4 genotype risk stratification in Arctic populations [5,6,7]

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