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

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

doi:10.1007/s00125-021-05461-z

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

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

Steno Diabetes Center Copenhagen

10 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Diabetologia
Vol/bind	64
Udgave nummer	8
Sider (fra-til)	1795-1804
Antal sider	10
ISSN	0012-186X
DOI	https://doi.org/10.1007/s00125-021-05461-z
Status	Udgivet - aug. 2021

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10.1007/s00125-021-05461-z

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Schnurr, T. M., Jørsboe, E., Chadt, A., Dahl-Petersen, I. K., Kristensen, J. M., Wojtaszewski, J. F. P., Springer, C., Bjerregaard, P., Brage, S., Pedersen, O., Moltke, I., Grarup, N., Al-Hasani, H., Albrechtsen, A., Jørgensen, M. E., & Hansen, T. (2021). Physical activity attenuates postprandial hyperglycaemia in homozygous TBC1D4 loss-of-function mutation carriers. Diabetologia, 64(8), 1795-1804. https://doi.org/10.1007/s00125-021-05461-z

Schnurr, TM, Jørsboe, E, Chadt, A, Dahl-Petersen, IK, Kristensen, JM, Wojtaszewski, JFP, Springer, C, Bjerregaard, P, Brage, S, Pedersen, O, Moltke, I, Grarup, N, Al-Hasani, H, Albrechtsen, A, Jørgensen, ME & Hansen, T 2021, 'Physical activity attenuates postprandial hyperglycaemia in homozygous TBC1D4 loss-of-function mutation carriers', Diabetologia, bind 64, nr. 8, s. 1795-1804. https://doi.org/10.1007/s00125-021-05461-z

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title = "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",

author = "Schnurr, {Theresia M} and Emil J{\o}rsboe and Alexandra Chadt and Dahl-Petersen, {Inger K} and Kristensen, {Jonas M} and Wojtaszewski, {J{\o}rgen F P} and Christian Springer and Peter Bjerregaard and S{\o}ren Brage and Oluf Pedersen and Ida Moltke and Niels Grarup and Hadi Al-Hasani and Anders Albrechtsen and J{\o}rgensen, {Marit E} and Torben Hansen",

year = "2021",

month = aug,

doi = "10.1007/s00125-021-05461-z",

language = "English",

volume = "64",

pages = "1795--1804",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer",

number = "8",

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T1 - Physical activity attenuates postprandial hyperglycaemia in homozygous TBC1D4 loss-of-function mutation carriers

AU - Schnurr, Theresia M

AU - Jørsboe, Emil

AU - Chadt, Alexandra

AU - Dahl-Petersen, Inger K

AU - Kristensen, Jonas M

AU - Wojtaszewski, Jørgen F P

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 E

AU - Hansen, Torben

PY - 2021/8

Y1 - 2021/8

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.

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KW - Gene-environment interaction

KW - Lifestyle therapy

KW - Physical activity

KW - Postprandial hyperglycaemia

KW - TBC1D4 loss-of-function

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U2 - 10.1007/s00125-021-05461-z

DO - 10.1007/s00125-021-05461-z

M3 - Journal article

C2 - 33912980

SN - 0012-186X

VL - 64

SP - 1795

EP - 1804

JO - Diabetologia

JF - Diabetologia

IS - 8

ER -

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

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