Regular U-500 insulin is being used with increasing frequency in individuals with type 2 diabetes mellitus, but the onset, peak, and duration of its effect are unclear. The objective of this study was to evaluate the pharmacokinetic and pharmacodynamic properties of regular U-500 insulin in healthy subjects. Three subjects (ages 25-35 yrs) were studied using the euglycemic clamp technique. Regular U-500 insulin (0.2 units/kg body weight) was injected subcutaneously in the abdomen. A 20% dextrose infusion was initiated and titrated to maintain the serum glucose level between 90-110 mg/dl. Pharmacokinetic and pharmacodynamic measurements were derived from blood sample measurements of glucose, insulin, and C-peptide levels. Subjects A and B were females weighing 50 kg (BMI 18 kg/m²) and 60 kg (BMI 23 kg/m²) respectively and subject C was male weighing 81 kg (BMI 26 kg/m²). Time to onset was within 30 minutes in all subjects. In subject A, maximum insulin concentration (C[sub max]) was 609 picomoles/liter, time to reach maximum insulin concentration (T[sub max]) was 105 minutes, insulin residence time (total duration of insulin action) was 390 minutes with area under the curve (AUC) of 125000 picomnles.min.1[sup -1]. In subject B, C[sub max], was 136 picomoles/liter, T[sub max] was 210 minutes and AUC was 46000 pieomoles.min.1[sup -1] In subject C, C[sub max], was 151 picomoles/liter, T[sub max] was 240 minutes and AUC was 58000 picomoles.min.1[sup -1]. The insulin residence time in subjects B and C was > 480 and > 570 minutes respectively and the corresponding insulin concentration at those times was 33% and 37% of the peak insulin concentration respectively. The pharmacodynamic data showed that time of maximal glucose infusion rate occurred at 240, 285 and 210 minutes in subjects A, B and C respectively. The maximal glucose infusion rate was 460, 120, and 510 mg/min in subjects A, B and C respectively. The duration of glucose infusion was 420, 420 and 540 minutes in subjects A, B and C respectively. In conclusion, in healthy volunteers, regular U-500 insulin had an onset of action of within 30 minutes, a variable time to peak action of between 1 3/4 and 4 hours and a duration of action of 6 hrs to greater than 10 hours. Further studies in overweight and obese individuals are planned. [ABSTRACT FROM AUTHOR]