Abstract We measured splanchnic and leg glucose uptake during prolonged (i.e., 15 hours), moderate hyperglycemia–hyperinsulinemia (clamp). Plasma free fatty acid (FFA) concentration was maintained at basal concentration during the clamp via infusion of exogenous lipids and heparin in healthy volunteers to create a metabolic profile similar to glucose intolerance (i.e., hyperglycemia–hyperinsulinemia with elevated FFA concentration). During the clamp, glucose was infused at an average rate of 49 ± 4 μmol/kg/min, which resulted in a plasma glucose concentration of 8.8 ± 0.5 mmol/L compared with a concentration of 4.4 ± 0.2 mmol/L in the basal state ( P < 0.05). Insulin concentration increased from 5.5 ± 1.1 μU/mL (basal) to 31.3 ± 12.7 μU/mL (clamp; P < 0.05), whereas plasma FFA concentration was similar in the two conditions (3.9 ± 0.5 mmol/L and 4.1 ± 0.5 mmol/L, basal and clamp, respectively). Glucose balance across the splanchnic region switched from net release (−5.8 ± 0.7 μmol/kg/min) in the basal state to net uptake in the clamp (19.8 ± 3.7 μmol/kg/min; P < 0.05) and accounted for approximately 40% of the infused glucose. Glucose uptake across the leg was 0.7 ± 0.2 μmol/kg/min (basal) and 5.5 ± 2.2 μmol/kg/min (clamp; P < 0.05). In summary, tissues in the splanchnic region (i.e., liver) are important for disposal of intravenously infused glucose during prolonged, moderate hyperglycemia–hyperinsulinemia. Accelerated hepatic glucose uptake may disrupt normal liver metabolism, with potentially dangerous consequences for the patient. Measures to control systemic glucose concentration may be necessary to prevent excessive glucose disposal in the liver.