The plasma glucose excursion may influence the metabolic responses after oral glucose ingestion. Although previous studies adressed the effects of hyperglycemia in conditions of hyperinsulinemia, it has not been evaluated whether the route of glucose administration (oral vs I.V.) plays a role. Our aim was to determine the effects of moderate controlled hyperglycemia on glucose metabolism, before and after oral glucose ingestion. Eight normal men underwent two Oral Glucose Clamps, at 6 and 10 mmol/L plasma glucose. Glucose Turnover and cycling rates were measured by infusion of [2H7] glucose. The oral glucose load was labelled by D-[6,6-2H2] glucose to monitor exogenous glucose appearance, and respiratory exchanges were measured by indirect calorimetry. 60% of the oral glucose load appeared in the systemic circulation, during both the 6 and 10 mmol/L plasma glucose tests, although less endogenous glucose appeared during the 10 mmol/L tests before glucose ingestion (p<0.05). This inhibitory effect of hyperglycemia was not detectable after oral glucose ingestion, although glucose utilization was increased (+28%, p<0.05) due to increased non-oxidative glucose disposal (10 vs 6 mmol/L: +20%, NS before oral glucose ingestion; +40%, p<0.05 after oral glucose ingestion). Glucose cycling rates were increased by hyperglycemia (+13% before oral glucose ingestion, p<0.001; +31% after oral glucose ingestion, p<0.05), and by oral glucose ingestion both during the 6 mmol/L (+10%, p<0.05) and 10 mmol/L tests (+26%, p<0.005). A moderate hyperglycemia inhibits endogenous glucose production, and contributes to glucose tolerance by enhancing non-oxidative glucose disposal. Hyperglycemia and oral glucose ingestion both stimulate glucose cycling.