Following glucose ingestion, tissue glucose uptake is enhanced and endogenous glucose production is inhibited, thus contributing to the maintenance of normal glucose tolerance. To examine whether these responses are disturbed in diabetes, glucose kinetics after oral glucose administration were studied in 12 non-insulin-dependent diabetic and 10 age- and weight-matched control subjects. A double tracer approach was used, whereby the endogenous glucose pool was labeled with 3-³H-glucose and the oral load with 1-¹⁴C-glucose. The two glucose tracers were separated in plasma by a two-step chromatographic procedure, and the two sets of isotopic data were analyzed according to a two-compartment model for the glucose system. Basally, glucose production was slightly higher in diabetics than in controls (2.51 ± 0.24 v 2.28 ± 0.11 mg/kg · min, NS) even though the former had higher plasma glucose (189 ± 19 v 93 ± 2 mg/dL, P < .001) and insulin (23 ± 4 v 12 ± 1 μU/mL, P < .05) concentrations. Following the ingestion of 1 g/kg of glucose, oral glucose appeared in the peripheral circulation in similar time-course and amount in the two groups (75 ± 2% of the load over 3.5 hours in the diabetics v 76 ± 3% in controls). Endogenous glucose production was promptly inhibited in diabetic and normal subjects alike, but the mean residual hepatic glucose production after glucose ingestion was significantly greater in the diabetic group (17 ± 2 v 10 ± 3 g/3.5 h, P < .05). At the end of the 3.5-hour study period, hepatic glucose production was still partially suppressed in both groups (by about 50%). This impairment in suppression of hepatic glucose production in the diabetics occurred despite the presence of marked hyperglycemia (mean plasma glucose following glucose ingestion = 298 ± 23 v 147 ± 7 mg/dL in controls, P < .001) and similar plasma insulin concentrations (46 ± 10 v 60 ± 7 μU/mL, NS). In the diabetics, endogenous glucose production was directly correlated with plasma glucose concentration both basally (r = .92, P < .001) and after glucose (r = .63, P < .05). At the end of 3.5 hours the healthy subjects had disposed of 60 ± 4 g by tissue uptake; this amount represented nearly 100% of the glucose (both oral and endogenous) that had appeared in the peripheral circulation. In contrast, in the diabetics tissue glucose disposal was only 44 ± 4 g over 3.5 hours (P < .05 v controls); 11 ± 3 g were lost into the urine and 16 ± 3 g had accumulated in the glucose space. In the diabetic group the mean plasma glucose concentration postload was inversely correlated with tissue glucose disposal (r = −.70, P < .01). We conclude that, in non-insulin-dependent diabetic patients: (1) the peripheral appearance of an ingested glucose load follows a normal pattern; (2) suppression of endogenous glucose production after oral glucose ingestion is impaired when compared with controls despite a twofold higher plasma glucose concentration and comparable plasma insulin levels; (3) tissue uptake of oral and endogenous glucose is markedly impaired; and (4) reduced tissue glucose uptake and relative overproduction of glucose by the liver both contribute to postprandial hyperglycemia.