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Skeletal muscle proteome analysis of Inuit homozygous carriers of the common Greenlandic TBC1D4 p.Arg684Ter variant

ABSTRACT: In the Greenlandic Inuit population, 17% are carriers of a nonsense TBC1D4 p.Arg684Ter variant. Homozygous variant carriers have impaired glucose tolerance and a 10-fold increased risk of type 2 diabetes. Here, we illuminate the consequences of lacking this muscle-specific long isoform of TBC1D4 during metabolic challenges in humans.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skeletal Muscle

SUBMITTER: Sean Humphrey

LAB HEAD: Sean Humphrey

PROVIDER: PXD045301 | Pride | 2024-10-26

REPOSITORIES: Pride

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			Action	DRS
	20220711_EXP1_SeHu_Inuit_muscleProteome_1a_1.raw	Raw
	20220711_EXP1_SeHu_Inuit_muscleProteome_1a_10.raw	Raw
	20220711_EXP1_SeHu_Inuit_muscleProteome_1a_11.raw	Raw
	20220711_EXP1_SeHu_Inuit_muscleProteome_1a_12.raw	Raw
	20220711_EXP1_SeHu_Inuit_muscleProteome_1a_13.raw	Raw

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Project description: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.

Dataset Information

Skeletal muscle proteome analysis of Inuit homozygous carriers of the common Greenlandic TBC1D4 p.Arg684Ter variant

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