Physical training affects insulin secretion and action, but there is a paucity of data on the direct effects in skeletal muscle and adipose tissue and on the effect of training in first-degree relatives (FDR) of patients with type 2 diabetes. We studied insulin action at the whole body level and peripherally in skeletal muscle and adipose tissue as well as insulin-secretory capacity in seven FDR and eight control (CON) subjects before and after 12 wk of endurance training. Training improved physical fitness. Insulin-mediated glucose uptake (GU) increased (whole body and leg; P < 0.05) after training in CON but not in FDR, whereas glucose-mediated GU increased (P < 0.05) in both groups. Adipose tissue GU was not affected by training, but it was higher (abdominal, P < 0.05; femoral, P = 0.09) in FDR compared with CON. Training increased skeletal muscle lipolysis (P < 0.05), and it was markedly higher (P < 0.05) in subcutaneous abdominal than in femoral adipose tissue and quadriceps muscle with no difference between FDR and CON. Glucose-stimulated insulin secretion was lower in FDR compared with CON, but no effect of training was seen. Glucagon-like peptide-1 stimulated insulin secretion five- to sevenfold. We conclude that insulin-secretory capacity is lower in FDR than in CON and that there is dissociation between training-induced changes in insulin secretion and insulin-mediated GU. Maximal GU rates are similar between groups and increases with physical training.