I n order to assess the combined and separate effects of pancreas and kidney transplant on whole-body protein metabolism, 9 insulin-dependent diabetic-uremic patients (IDDUP), 14 patients after combined kidney-pancreas transplantation (KP-Tx), and 6 insulin-dependent diabetic patients with isolated kidney transplant (K-Tx), were studied in the basal postabsorptive state and during euglycemic hyperinsulinemia (study 1). [1-14C]Leucine infusion and indirect calorimetry were utilized to assess leucine metabolism. The subjects were studied again with a combined infusion of insulin and amino acids, given to mimic postprandial amino acid levels (study 2). In the basal state, IDDUP demonstrated with respect to normal subjects (CON): (a) higher free-insulin concentration (17.8 +/- 2.8 vs. 6.8 +/- 1.1 microU/ml, P < 0.01) (107 +/- 17 vs. 41 +/- 7 pM); (b) reduced plasma leucine (92 +/- 9 vs. 124 +/- 2 microM, P < 0.05), branched chain amino acids (BCAA) (297 +/- 34 vs. 416 +/- 10 microM, P < 0.05), endogenous leucine flux (ELF) (28.7 +/- 0.8 vs. 39.5 +/- 0.7 mumol.m-2.min-1, P < 0.01) and nonoxidative leucine disposal (NOLD) (20.7 +/- 0.2 vs. 32.0 +/- 0.7 mumol.m-2. min-1, P < 0.01); (c) similar leucine oxidation (LO) (8.0 +/- 0.1 vs. 7.5 +/- 0.1 mumol.m-2.min-1; P = NS). Both KP-Tx and K-Tx patients showed a complete normalization of plasma leucine (116 +/- 5 and 107 +/- 9 microM), ELF (38.1 +/- 0.1 and 38.5 +/- 0.9 mumol.m-2.min-1), and NOLD (28.3 +/- 0.6 and 31.0 +/- 1.3 mumol.m-2.min-1) (P = NS vs, CON). During hyperinsulinemia (study 1), IDDUP showed a defective decrease of leucine (42% vs. 53%; P < 0.05), BCAA (38% vs. 47%, P < 0.05), ELF (28% vs. 33%, P < 0.05), and LO (0% vs. 32%, P < 0.05) with respect to CON. Isolated kidney transplant reverted the defective inhibition of ELF (34%, P = NS vs. CON) of IDDUP, but not the inhibition of LO (18%, P < 0.05 vs. CON) by insulin. Combined kidney and pancreas transplanation normalized all kinetic parameters of insulin-mediated protein turnover. During combined hyperinsulinemia and hyperaminoacidemia (study 2), IDDUP showed a defective stimulation of NOLD (27.9 +/- 0.7 vs. 36.1 +/- 0.8 mumol.m-2.min-1, P < 0.01 compared to CON), which was normalized by transplantation (44.3 +/- 0.8 mumol.m-2.min-1).