First-degree relatives of type 2 diabetic patients (offspring) are often characterized by insulin resistance and reduced physical fitness (VO₂max). We hypothesized that offspring may differ in their ability to respond to exercise training in terms of improvement in aerobic capacity and insulin sensitivity compared to subjects without diabetic predisposition. We determined the response of healthy first-degree relatives to a standardized 10-week exercise program and compared to an age, gender and BMI matched control group. Improvements in VO₂max (14.1±11.3 and 16.1±14.2% both p<0.001) and insulin sensitivity (ISGU) (0.6±1.4 and 1.0±2.1 mg/kg/min; both p<0.05) were comparable in offspring and control subjects. However, VO₂max and insulin sensitivity in offspring were not related at baseline as in the controls (r=0.009; p=0.96 vs. r=0.67; p=0.002). Likewise, in offspring exercise induced changes in VO₂max did not correlate with changes in insulin sensitivity as opposed to controls (r=0.06; p=0.76 vs. r=0.57; p=0.01). Skeletal muscle oxidative capacity tended to be lower in offspring at baseline but improved equally in both groups in response to exercise training (CS enzyme activity 26% vs. 20%, and COX enzyme activity 25% vs. 23%; p=NS (both)). Skeletal muscle fiber morphology and capillary density were comparable between groups at baseline and did not change significantly with exercise training. In conclusion, this study shows that first-degree relatives of type 2 diabetic patients respond normally to endurance exercise in terms of changes in VO₂max and insulin sensitivity. However, the lack of a correlation between the VO₂max and insulin sensitivity in the first degree relatives of type 2 diabetic patients indicates that skeletal muscle adaptations is dissociated from the improvement in VO₂max. The results indicate that in the first degree relatives of type 2 diabetic patients improvement of insulin sensitivity is dissociated from muscle mitochondrial functions.