Insulin secretion in response to glucose stimulation is reduced in endurance-trained humans. In this study, a modified hyperglycemic clamp, with a superimposed arginine infusion and fat meal, was performed on eight endurance-trained and nine untrained men to determine whether insulin secretory capacity is reduced by exercise training. Raising the plasma glucose concentration to approximately 450 mg/dl resulted in a plasma insulin response in the trained men that was approximately 64% lower than that of the untrained (peak values: 54 +/- 8 vs. 149 +/- 35 microU/ml; P less than 0.001). When a primed continuous infusion of arginine was superimposed on the hyperglycemia, the plasma insulin response was also markedly lower (66%) in the trained subjects, reaching peak values of 333 +/- 68 and 974 +/- 188 microU/ml for trained and untrained subjects, respectively (P less than 0.005). When insulin secretion was further stimulated during the arginine-infused hyperglycemia by the ingestion of a high-fat meal, peak insulin concentrations averaged 989 +/- 205 microU/ml in the trained compared with 2,232 +/- 455 microU/ml in the untrained subjects (P less than 0.01). The response of gastric inhibitory polypeptide (GIP) to the fat meal was delayed and blunted, suggesting that some enteric factor(s) other than GIP mediated the insulinotropic effect of the fat meal. The reduced plasma insulin response in trained people to the stimuli investigated suggests that regular exercise produces either several adaptations within the beta-cell or a single alteration of the beta-cell that results in an attenuation of the insulin secretory response to glucose, arginine, and fat ingestion.