Prehepatic insulin production can be determined from analysis of connecting-peptide behavior in the plasma. In the present study, we have determined prehepatic insulin production in six normal men throughout a day that included three typical 750-cal meals. Total insulin secretion for the 24 h was 45.4 U, secreted as 10.6 U with breakfast, 13.4 U with lunch, and 13.8 U with dinner. The remaining 7.6 U was secreted during the 9 h night at a rate of 0.85 U/h. At least 50% of the newly secreted insulin is known to be extracted by the liver during the initial transhepatic passage, so that total peripheral delivery can be estimated as approximately 22 U/day. Consequently, portal vein insulin levels are in excess of those seen in peripheral blood by at least 20 +/- 8 microU/ml in the fasted state, and by as much as 115 +/- 15 microU/ml in the 2-h postabsorptive state. The data suggest that insulinization of the liver, without peripheral hyperinsulinemia, may be a goal of artificial insulin delivery.