In the Greenlandic Inuit population, 4% are homozygous carriers of a genetic nonsense TBC1D4 p.Arg684Ter variant leading to loss of the muscle-specific isoform of TBC1D4 and an approximately tenfold increased risk of type 2 diabetes¹. Here we show the metabolic consequences of this variant in four female and four male homozygous carriers and matched controls. An extended glucose tolerance test reveals prolonged hyperglycaemia followed by reactive hypoglycaemia in the carriers. Whole-body glucose disposal is impaired during euglycaemic-hyperinsulinaemic clamp conditions and associates with severe insulin resistance in skeletal muscle only. Notably, a marked reduction in muscle glucose transporter GLUT4 and associated proteins is observed. While metabolic regulation during exercise remains normal, the insulin-sensitizing effect of a single exercise bout is compromised. Thus, loss of the muscle-specific isoform of TBC1D4 causes severe skeletal muscle insulin resistance without baseline hyperinsulinaemia. However, physical activity can ameliorate this condition. These observations offer avenues for personalized interventions and targeted preventive strategies.

在格陵兰因纽特人中，4% 是遗传无义 TBC1D4 p.Arg684Ter 变体的纯合子携带者，导致 TBC1D4 的肌肉特异性亚型丢失，患 2 型糖尿病的风险增加约 10 倍¹。在这里，我们展示了这种变异在 4 名女性和 4 名男性纯合子携带者和匹配对照中的代谢后果。扩展葡萄糖耐量试验显示携带者出现长期高血糖，随后出现反应性低血糖。在正常血糖-高胰岛素钳夹条件下，全身葡萄糖处理受损，并且仅与骨骼肌的严重胰岛素抵抗有关。值得注意的是，观察到肌葡萄糖转运蛋白 GLUT4 和相关蛋白的显着降低。虽然运动期间的代谢调节保持正常，但单次运动的胰岛素增敏作用会受到影响。因此，TBC1D4 的肌肉特异性亚型的缺失会导致严重的骨骼肌胰岛素抵抗，而没有基线高胰岛素血症。然而，身体活动可以改善这种情况。这些观察结果为个性化干预和有针对性的预防策略提供了途径。