Exercise superimposed on insulin stimulation is shown to increase muscle glucose metabolism and these two stimuli have synergistic effects. The objective of this study was to investigate glucose infusion rates (GIR) in groups with a wide variation in terms of insulin sensitivity during insulin stimulation alone and with superimposed exercise. Patients with type 2 diabetes, subjects with impaired glucose tolerance (IGT), healthy controls, and endurance-trained subjects were studied. The groups were matched for age and lean body mass (LBM), and differed in peak oxygen uptake (VO2 peak), body fat percentage, body mass index (BMI), fasting plasma glucose concentration, and oral glucose-tolerance test (OGTT). Each subject underwent a two-step sequential hyperinsulinemic, euglycemic clamp. During the last 30 min of the 2nd clamp step, subjects exercised on a bicycle at 43% +/- 2% of VO2 peak. In agreement with the OGTT data, the presence of different GIR during insulin stimulation alone demonstrated varying levels of insulin sensitivity between groups. However, the impairment of GIR in IGT observed during insulin stimulation alone was abolished compared to controls when exercise was superimposed on insulin stimulation. Humans with IGT are resistant to insulin-stimulated but not to exercise-induced glucose uptake.