It is known that alterations in insulin metabolism following injury and infection result in depression of insulin levels and the development of insulin resistance. In order to further study insulin during septic and traumatic stress, we estimated insulin production in control (Group 1,n= 6), postoperative (Group 2,n= 5), and postoperative-septic (Group 3,n= 8) human subjects by measuring the 24-hour urinary C-peptide excretion. In addition, basal and peak glucose and insulin levels in response to a standard (0.5 gm/kg) intravenous glucose stimulus were measured immediately thereafter to determine if insulin levels reflected insulin production. Basal insulin for Groups 1, 2, and 3 (16 ± 8.4, 10 ± 3.4, 9.5 ± 4.4 μU/ml ± SD, respectively) were not substantially different. Peak insulin response to glucose infusion declined from Groups 1 to 3 (51 ± 14, 42.4 ± 31, 20.4 ± 6.8 μU/ml, respectively) with Group 3 exhibiting a significantly decreased mean peak level compared to the other groups. Corresponding C-peptide excretion rates increased from Groups 1 to 3 (28.3 ± 15.3, 63.7 ± 27.6, 121.3 ± 95.2 μg/day, respectively) with Group 3 exhibiting a significantly (p< 0.05) higher level than Group 1. These data suggest that low insulin levels which may be evident in injured or septic patients not in shock reflect increased clearance and not decreased production. We postulate that increased insulin turnover under these circumstances may contribute to the insulin resistance of post-traumatic or septic stress.