To evaluate the pharmacodynamic and pharmacokinetic properties and the dose-ranging effects of an oral insulin spray in comparison with subcutaneous regular insulin. In this randomized, five-way, cross-over study, seven healthy volunteers were assessed under euglycemic clamp and received four different doses of oral spray and one dose of subcutaneous regular insulin. The time to maximum insulin concentration was shorter for oral insulin than for subcutaneous insulin (25.9 +/- 9 vs. 145.7 +/- 49.5 min, P < 0.05). Maximum serum insulin levels (C(max)) were comparable between the subcutaneous and 20 puffs of oral insulin (39.1 +/- 19.6 vs. 34.0 +/- 7.4 microU/ml, NS). The Ins-AUC(0-120) (area under the curve from 0 to 120 min for serum insulin) (339.8 +/- 218, 681.3 +/- 407, and 1,586.7 +/- 8 microU/ml, P < 0.05) and C(max) (7.6 +/- 2.8, 16.4 +/- 9.3, and 39.1 +/- 19.6 microU/ml, P < 0.005) proved a dose-response relationship for the three doses of oral insulin (5, 10, and 20 puffs, respectively). Oral insulin had an earlier onset of action (31.7 +/- 12 vs. 77.8 +/- 3 min, P < 0.05), earlier peak (44.2 +/- 10 vs. 159.2 +/- 68 min, P < 0.05), and a shorter duration of action (85.1 +/- 25 vs. 319.2 +/- 45 min, P < 0.05) compared with subcutaneous insulin. The maximum metabolic effect (1.7 +/- 1.0, 3.09 +/- 1.7, and 4.6 +/- 1.5 mg . kg(-1) . min(-1), P < 0.05) and the GIR-AUC(0-120) (amount of glucose infused from 0 to 120 min) (106.7 +/- 74.3, 162.9 +/- 116.1, and 254 +/- 123 mg/kg) increased in a dose-dependent relationship for the three doses. Oral insulin was absorbed in direct relation to the amount given and had a faster onset and a shorter duration of action compared with subcutaneous regular insulin. A dose-response relationship in the absorption and metabolic effect of the oral insulin was noted.