The difference in absorption of insulin and its glucose lowering-effect after the administration of crystalline insulin by the intravenous, intramuscular, and subcutaneous routes was compared in 14 lean normal subjects. Insulin in a dose of 0.1 U/kg body weight was given by the three different routes. Blood was drawn from the opposite arm at regular intervals for the determination of insulin, glucose, glucagon, cortisol, and potassium. Intravenous insulin produced the highest pharmacological level of insulin in 2 minutes (2099 +/- 414 muU/ml) with marked hypoglycemia at 30 minutes (a 68% drop). Intravenous insulin injection produced an increase in plasma glucagon and cortisol reaching a 2-fold increase above the fasting level 30 minutes after the glucose nadir. An equivalent amount of intramuscular insulin produced a maximal increase in plasma insulin at 50 minutes (45 +/- 4 muU/ml) and caused a 35% drop in plasma glucose at 60 minutes, which effects were greater than those caused by subcutaneous injection (highest IRI = 36 +/- 3.5 muU/ml and 23% glucose drop at 180 minutes). No significant increase in glucagon or cortisol was noted with equivalent amounts of subcutaneous or intramuscular insulin injection. Our studies suggest that, in normal lean subjects, insulin injection by the intramuscular route provides a faster absorption of insulin with a concomitant greater drop in plasma glucose than does injection by the subcutaneous route.