Patients with insulin-dependent diabetes mellitus (IDDM) who have undergone combined pancreas and kidney (P/K) transplantation, are hyperinsulinemic and have impaired insulin-stimulated whole body glucose uptake. We have investigated whether their reduced glucose uptake was due to insulin resistance at the tissue level or was caused by reduced muscle blood flow, previously reported to be present in patients with IDDM. Leg blood flow (LBF, determined with mercury strain-gauge plethysmography), glucose uptake (GRd, determined with 6,6 D2-glucose), and glucose oxidation (Gox, determined by indirect calorimetry) were obtained during euglycemic-hyperinsulinemic (approximately 500 pM) clamping in five P/K patients, five kidney transplant (K) patients, and six controls. Insulin-stimulated GRd was reduced in P/K patients compared to controls (23 +/- 4 vs. 44 +/- 6 mumol/kg/min, P < 0.05); Gox was comparable but glucose storage was reduced in P/K and K patients compared to controls (9 +/- 3 and 13 +/- 4 vs. 28 +/- 7 mumol/kg/min, P < 0.05). Basal LBF (3.9 +/- 0.3, 4.6 +/- 0.9, and 4.9 +/- 0.6 mL/dL leg tissue/min) and insulin-stimulated LBF (5.6 +/- 0.6, 6.1 +/- 1.1 and 6.1 +/- 0.9 mL/dL leg tissue/min) were similar in P/K, K patients, and controls. We concluded, that P/K patients had normal muscle blood flow but were insulin resistant at the tissue level, and that the insulin resistance was responsible, at least in part, for their hyperinsulinemia.