A family history of type 2 diabetes (e.g. first degree relatives, FDR) and low birth weight (LBW) are risk factors of type 2 diabetes and predisposes to type 2 diabetes via genetically and environmental susceptibility, respectively. Severe physical inactivity could purposely unmask their predisposal and reveal a larger vulnerability to physical inactivity than those without preexisting risk factors. Furthermore, comparisons between FDR and LBW in the response to alterations in the daily physical activity level may exemplify the relative influence of genes and environmental factors. We have studied such groups before and after a ten-day bed rest intervention study, which was followed by a four wk re-training program. Thirteen FDR (age: 26 ± 1 yr; body weight 80 ± 3 kg; BMI: 25 ± 1; VO2max: 39 ± 1 ml/min/kg), twenty LBW (age: 26 ± 1 yr; body weight 72 ± 3 kg; BMI: 23 ± 1; VO2max: 44 ± 3 ml/min/kg) and twenty healthy controls (CON) (age: 25 ± 1 yr; body weight 78 ± 2 kg; BMI: 24 ± 1; VO2max: 44 ± 1 ml/min/kg) was included in the study (Sonne et al., 2010). Insulin secretion and action, endothelial function, inflammation, and muscle transcriptional and translational changes was studied in a comprehensive experimental program. Aging per se does not lead to skeletal muscle insulin resistance (Dela et al., 1996b;Dela et al., 1996a), but with age physical inactivity may develop. Data from a study on how one-legged immobilization for 2 wks with subsequent 6 wks rehabilitation may change markers on insulin sensitivity in young and old men will be reported.