We have shown, previously, that the pulmonary delivery of nebulized insulin effectively lowers plasma glucose level to within the normal range in fasting patients with non-insulin dependent diabetes mellitus (JAMA 269:2106-2109, 1993). In this study, we investigated whether pulmonary administration of nebulized insulin lowers plasma glucose after a meal. On two randomized visits, seven NIDDM patients inhaled an average of approximately 1.5 U/kg body weight regular port insulin (Eli Lilly) or placebo aerosol 5 minutes before ingesting a 681 calorie meal. Aerosol was generated by a jet nebulizer delivery system (Health Line Medical) and was inhaled continuously for 3.94 plus or minus 1.18 min. Plasma samples were collected before and one hour after the meal and analyzed for glucose, insulin and c-peptide (an indicator of endogenous secretion of insulin) levels. After the meal, plasma glucose levels were significantly lower on the insulin visit (140 plus or minus 34 mg/dl) than with placebo (250 plus or minus 79 mg/dl) (p less than 0.01). Mean insulin levels were significantly higher one hour after inhaling insulin (89.8 plus or minus 34.9 uU/ml) compared to placebo (40.4 plus or minus 22.0 uU/ml) (p less than 0.05). It is likely that this increase in insulin levels was due predominantly to nebulized insulin, since c-peptide levels after the meal on the insulin visit were significantly less (1.53 plus or minus 0.70 ng/ml) than with placebo (2.96 plus or minus 1.13 ng/ml) (p less than 0.01). No side effects were reported after inhalation of insulin or placebo aerosols. These results suggest that nebulized insulin, delivered through the lungs, may be an effective alternative route of administration for controlling plasma glucose levels after a meal in patients with NIDDM.