Greenlandic Inuit carrying the TBC1D4 loss-of-function variant are at a 10-fold increased risk of type 2 diabetes (T2D). Findings presented at EASD 2025 examined whether high-intensity interval training (HIIT) could improve glucose homeostasis in homozygous carriers (HO carriers) versus matched non-carriers.

Six HO carriers and six non-carriers completed a 6-week HIIT program (3 sessions/week). Glucose tolerance was assessed via extended oral glucose tolerance test and 14-day continuous glucose monitoring, while skeletal muscle biopsies evaluated molecular adaptations.

HIIT enhanced VO₂ₘₐₓ and key muscle enzymes in both groups. However, muscle GLUT4 protein—a critical mediator of glucose uptake—significantly increased in non-carriers (p=0.0009) but remained unchanged in HO carriers (p=0.3764). Correspondingly, nighttime glucose levels decreased only in non-carriers, and overall glucose tolerance was unaffected by HIIT in HO carriers.

These findings indicate that HO carriers exhibit partial skeletal muscle adaptations to exercise, limiting the glucose-lowering effects of standard HIIT. Personalized exercise strategies or complementary therapies may be necessary to reduce T2D risk in genetically susceptible populations.