The effects of various hexoses upon immunoreactive insulin (IRI) secretion, glucose disposal, and gastric inhibitory polypeptide (GIP) release have been compared in 10 normal nonobese men. Rapid iv infusion (0.5 g/kg in 3 min) of Dmannose resulted in significant IRI release, the peak levels approaching those after D-glucose infusion. D-Galactose, however, was ineffective. The 60-min urine excretions of mannose, galactose, and glucose were 35 ± 7%, 16 ± 4%, and 5.5 ± 0.7% (mean ± SEM) of the administered dose, respectively. All subjects also received 50 g oral glucose, mannose, galactose, and fructose on different days, each followed by an iv glucose infusion 30 min later. The ingestion of glucose or galactose resulted in a similar increment of GIP (P < 0.01), followed by a similar increment in the IRI response to iv glucose. Furthermore, the glucose disposal rate increased 2.5-fold compared to that after iv glucose alone (P < 0.001). However, oral mannose or oral fructose caused no significant GIP release, yet the IRI response to a subsequent iv glucose load was moderately augmented after oral mannose or oral fructose when compared to iv glucose alone. In addition, there was a similar enhancement of glucose disposal of the iv glucose load after both oral mannose and oral fructose (JP < 0.01). From these studies we conclude that 1) galactose does not elicit IRI secretion per se, yet, like glucose, potentiates GIP and IRI secretion; 2) mannose, despite weak transport across gut or kidney, evokes significant betacytotropic effects; and 3) mannose- and fructose-induced enhancement of glucose disposal might be mediated by a factor(s) other than GIP. © 1979 by The Endocrine Society.