We employed the hyperglycemic clamp technique to investigate the effects of short-term inactivity on insulin secretion in nine (8 men, 1 woman) well-trained subjects. A 3-h hyperglycemic clamp (plasma glucose approximately 180 mg/100 ml) was performed approximately 16 h after a usual training bout and again 14 days after stopping exercise training. There was no significant change in body composition during this short period of inactivity. The mean plasma insulin response to an identical glycemic stimulus was 67% higher after 14 days without exercise (45 +/- 7 after vs. 27 +/- 4 microU/ml before stopping exercise training). Marked increases in the early (0-10 min, 150 +/- 28 vs. 101 +/- 15 microU.ml-1.min) and late (10-180 min, 6,051 +/- 1,257 vs. 3,521 +/- 749 microU.ml-1.min) incremental insulin areas were observed as a result of the physical inactivity. Incremental areas for C-peptide were also elevated significantly in the inactive state for early (12 +/- 2.0 vs. 7 +/- 1 ng.ml-1.min) and late (567 +/- 90 vs. 467 +/- 85 ng.ml-1.min) phases. Urinary excretion of C-peptide increased from 12.1 +/- 1.5 ng/240 min in the exercising state to 21.8 +/- 3.6 ng/240 min in the inactive state. Rates of whole body glucose disposal were not different between exercising and inactive states, indicating a large increase in resistance to the action of insulin. These findings indicate that the decreased insulin secretory response to a glucose stimulus in people who exercise regularly is a relatively short-term effect of exercise.