Diphenylhydantoin (DPH) is known to inhibit insulin secretion in vitro and can cause hyperglycemia in man. To determine if there were selective effects of this drug in diabetes, insulin responses to intravenous stimuli were measured before and after ingesting the drug for several days in seven nonobese subjects with mild oral glucose intolerance. These were compared with responses of eight nonobese control subjects with normal oral glucose tolerance.

Before DPH, early insulin release after intravenous glucose was similar in both groups, though glucose clearance was subnormal in the glucose-intolerant group. Arginine, given thirty minutes after glucose (postglucose arginine) was followed by prominent insulin release in both groups. After DPH, there was no significant alteration in glucoseinduced earlyinsulin release or clearance of glucose, though downward trends were noted in both groups. However, after DPH, the glucose-intolerant group showed significant reduction of insulin responses to postglucose arginine.

These differences in drug effect occurred despite similar serum drug levels and per cent binding of DPH in the normal and in the glucose-intolerant group. Drug levels attained were in the effective range seen in patients taking DPH for epilepsy.

In the isolated, perfused rat pancreas, effects of DPH in the presence of a high arginine stimulus were differentiated from those of a glucose stimulus. Whereas DPH eliminated both early and late arginine-induced insulin secretion, only late glucose-induced secretion was abolished by the drug.

These data suggest that DPH will unmask early defects of insulin secretion in patients with mild oral glucose intolerance. The major early effect of the drug on insulin secretion in these patients is thus seen after a nonglycemic stimulus, postglucose arginine, which may have an insulinotropic mechanism distinctive from that of glucose.

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