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

• Published in: Diabetologia 2021-08, Vol.64 (8), p.1795-1804
• Main Authors: Schnurr, Theresia M., Jørsboe, Emil, Chadt, Alexandra, Dahl-Petersen, Inger K., Kristensen, Jonas M., Wojtaszewski, Jørgen F. P., Springer, Christian, Bjerregaard, Peter, Brage, Søren, Pedersen, Oluf, Moltke, Ida, Grarup, Niels, Al-Hasani, Hadi, Albrechtsen, Anders, Jørgensen, Marit E., Hansen, Torben
• Format: Article
• Language: English
• Subjects: Adult; Autoimmune diseases; Blood Glucose - metabolism; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - physiopathology; Energy expenditure; Exercise; Exercise - physiology; Female; Gene-Environment Interaction; Genetic Predisposition to Disease; Genomes; Genotypes; Genotyping Techniques; Glucose; Glucose Tolerance Test; Greenland - epidemiology; GTPase-Activating Proteins - genetics; Homeostasis; Human Physiology; Humans; Hyperglycemia; Hyperglycemia - genetics; Hyperglycemia - prevention & control; Insulin; Insulin - blood; Internal Medicine; Inuit - genetics; Life Style; Loss of Function Mutation - genetics; Male; Medicine; Medicine & Public Health; Metabolic Diseases; Middle Aged; Physical activity; Plasma; Postprandial Period - physiology; Precision medicine; Skeletal muscle
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-021-05461-z

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. Graphical abstract