Physical activity attenuates postprandial hyperglycaemia in homozygous TBC1D4 loss-of-function mutation carriers
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Physical activity attenuates postprandial hyperglycaemia in homozygous TBC1D4 loss-of-function mutation carriers. / Schnurr, Theresia Maria; Jørsboe, Emil; Chadt, Alexandra; Dahl-Petersen, Inger Katrine; Kristensen, Jonas Møller; Wojtaszewski, Jørgen; Springer, Christian; Bjerregaard, Peter; Brage, Søren; Pedersen, Oluf; Moltke, Ida; Grarup, Niels; Al-Hasani, Hadi; Albrechtsen, Anders; Jørgensen, Marit Eika; Hansen, Torben.
I: Diabetologia, Bind 64, 2021, s. 1795-1804.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Physical activity attenuates postprandial hyperglycaemia in homozygous TBC1D4 loss-of-function mutation carriers
AU - Schnurr, Theresia Maria
AU - Jørsboe, Emil
AU - Chadt, Alexandra
AU - Dahl-Petersen, Inger Katrine
AU - Kristensen, Jonas Møller
AU - Wojtaszewski, Jørgen
AU - Springer, Christian
AU - Bjerregaard, Peter
AU - Brage, Søren
AU - Pedersen, Oluf
AU - Moltke, Ida
AU - Grarup, Niels
AU - Al-Hasani, Hadi
AU - Albrechtsen, Anders
AU - Jørgensen, Marit Eika
AU - Hansen, Torben
N1 - CURIS 2021 NEXS 156 (Open Access --> upload pdf-fil)
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Faculty of Science
KW - Arctic
KW - Gene-environment interaction
KW - Lifestyle therapy
KW - Physical activity
KW - Postprandial hyperglycaemia
KW - TBC1D4
KW - Loss-of-function
U2 - 10.1007/s00125-021-05461-z
DO - 10.1007/s00125-021-05461-z
M3 - Journal article
C2 - 33912980
VL - 64
SP - 1795
EP - 1804
JO - Diabetologia
JF - Diabetologia
SN - 0012-186X
ER -
ID: 260994635