To assess the effect of pancreas transplantation on free fatty acid (FFA) and glucose metabolism, we studied seven uremic IDDM patients (HbA1c 9.1%), nine IDDM patients after combined kidney-pancreas transplantation (HbA1c 5.8%), seven patients with chronic uveitis (HbA1c 5.6%), and nine normal control subjects (HbA1c 5.5%) by means of the [3(- 3)H]glucose and [1(-14)C]palmitate infusion techniques combined with indirect calorimetry and euglycemic insulin clamp. In the postabsorptive state, pancreas-transplant patients had similar plasma glucose and FFA concentrations and non-statistically different rates of hepatic glucose production (HGP) and FFA turnover, while demonstrating a reduced rate of FFA oxidation (42 +/- 5 vs. 73 +/- 10 micromol x m-2 x min-1; P < 0.05) compared with control subjects. After 180 min of tracer equilibration, all subjects underwent a low-dose (100 min, 8 mU x m-2 x min-1) followed by a high-dose (100 min, 40 mU x m-2 x min-1) euglycemic insulin infusion. During insulin infusion, pancreas-transplant patients showed a greater inhibition of FFA concentration (609 +/- 76 to 58 +/- 15 micromol/l) compared with healthy subjects (681 +/- 90 to 187 +/- 25 micromol/l; P < 0.01 vs. pancreas-transplant patients). FFA turnover and oxidation rates during both low-dose and high-dose insulin infusions were lower in pancreas-transplant patients compared with healthy subjects (P < 0.03 and P < 0.01, for turnover and oxidation, respectively). Uremic IDDM patients demonstration altered basal and insulin-mediated glucose metabolism. Pancreas transplantation normalized only insulin-mediated glucose oxidation, leaving the stimulation of non-oxidative glucose disposal still markedly defective. In conclusion, patients after pancreas transplantation have normal basal FFA turnover and reduced basal FFA oxidation rates. During hyperinsulinemia, pancreas-transplant patients show a normal inhibition of FFA turnover and FFA oxidation. Insulin-mediated glucose metabolism remained abnormal after pancreas transplantation. Our findings may be related to the effect of chronic immunosuppressive therapy on glucose and FFA metabolism.