A late rise in serum GH occurs 3-5 h following oral glucose in man. In order to investigate the mechanisms through which this occurs we have studied the late GH rise after oral glucose during administration of a supramaximal dose of GHRH. In eight normal subjects, oral glucose (100 g) greatly enhanced the GH responses to a supramaximal dose of GHRH (50 micrograms bolus, followed immediately by 100 micrograms/h infusion for 3 h) given 3.5 h after the glucose. GH peak (mean +/- SEM) elicited by GHRH (bolus + infusion) rose from 55.2 +/- 20.4 to 133.4 +/- 29.6 mU/l (P less than 0.02) after glucose pretreatment. In conclusion, it is likely that the late rise in GH secretion induced by oral glucose occurs via a non-GHRH-dependent mechanism. These data are consistent with the hypothesis that the delayed GH response to glucose is a consequence of reduced release of somatostatin from the hypothalamus.