The role of splanchnic glucose uptake (SGU) after oral glucose administration as a potential factor contributing to postprandial hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM) has not been established conclusively. Therefore, we investigated SGU in six patients with NIDDM and six weight-matched control subjects by means of the hepatic vein catheterization (HVC) technique. In a second part, we examined the applicability of the recently developed OG-CLAMP technique in NIDDM by comparing SGU and first-pass SGU during HVC with SGU during the OG-CLAMP experiment. The OG-CLAMP method combines a euglycemic, hyperinsulinemic clamp and an oral glucose tolerance test (75 g) during steady state glucose infusion (GINF). During HVC, SGU equals the splanchnic fractional extraction times the total (oral and arterial) glucose load presented to the liver. For OG-CLAMP, SGU was calculated as first-pass SGU by subtracting the integrated decrease in GINF over 180 min from 75 g. Cumulative splanchnic glucose output after oral glucose correlated significantly between both methods and was increased significantly in NIDDM patients (73.1+/-5.1 g for HVC, 76.5+/-5.5 for OG-CLAMP) compared with nondiabetic patients (46.7+/-4.4 g for HVC, 57.5+/-1.9 for OG-CLAMP). Thus, in NIDDM patients, SGU (7.4+/-2.1 vs. 37.8+/-5.9% in nondiabetic patients, P < 0.001) and first-pass SGU (4.7+/-1.7 vs. 26.5+/-5.1% in nondiabetic patients, P < 0.01) were decreased significantly during HVC, as was SGU during OG-CLAMP (3.9+/-1.7 vs. 23.4+/-2.5% in nondiabetic patients, P < 0.0001). SGU measured during OG-CLAMP correlated significantly with SGU (r = 0.87, P < 0.05 for NIDDM patients; r = 0.94, P < 0.01 for nondiabetic patients) and first-pass SGU (r = 0.87, P < 0.05 for NIDDM patients; r = 0.84, P < 0.05 for nondiabetic patients) during HVC. In conclusion, (a) SGU after oral glucose administration is decreased in NIDDM as measured by both methods, and (b) SGU during the OG-CLAMP is well-correlated to SGU and first-pass SGU during HVC in NIDDM. The decrease in SGU in NIDDM might contribute to postprandial hyperglycemia in diabetic subjects.