Noninsulin dependent diabetics have insulin responses to nonglucose secretagogues that are subnormal for their plasma glucose levels. Since endogenous prostaglandins have been implicated in the abnormal insulin responses to glucose in diabetics, the present study was performed to explore whether prostaglandins might also play a role in the defective insulin responses to nonglucose stimuli. We examined the effects of infusions of either prostaglandin E2 (PGE2) or sodium salicylate (SS), a PG synthesis inhibitor, on the acute insulin responses (AIR's) to arginine and isoproterenol and on the glucose potentiation of the insulin response to arginine in both normal and diabetic subjects. The AIR to arginine was augmented by SS in diabetics (SS = 61 ± 12 μU/ml, control = 37 ± 5 μU/ml, n = 11, p < .01). SS, however, had no effect on the AIR to arginine in normal subjects (SS = 39 ± 4 μU/ml, control = 34 ± 4 μU/ml, n = 6, p = ns). Similarly, SS augmented the AIR to an isoproterenol pulse in diabetics (SS = 38 ± 9 μU/ml, control = 18 ± 3, n = 9, p < .05) but not in normal subjects (SS = 19 ± 4 μU/ml, control = 21 ± 4 μU/ml, n = 8, p = ns), suggesting a SS-sensitive defect in the insulin response to these nonglucose stimuli in diabetics. Conversely, PGE2 inhibited the AIR to arginine in diabetics (PGE = 28 ± 5 μU/ml, control = 39 ± 7 μU/ml, n = 7, p < .05), but not in normal subjects (PGE = 74 ± 7 μU/ml, control = 80 ± 14 μU/ml, n = 5, p = ns). The effect of SS on glucose potentiation of the AIR to arginine was studied by measuring the AIR to arginine at two different levels of plasma glucose, one before and one after an insulin infusion, with glucose potentiation defined as the ratio ΔAIR/Δprestimulus glucose. Glucose potentiation was significantly less in diabetics than in normals and SS significantly improved glucose potentiation toward normal values in diabetics but did not change glucose potentiation in normals. These findings suggest that endogenous PG's may play a role in the defective glucose potentiation of the AIR to nonglucose secretagogues in diabetics resulting in impaired insulin responses to these stimuli. This defect is partially reversible by an inhibitor of PG synthesis.