-The effect of small amounts of fructose on net hepatic glucose uptake (NHGU) during hyperglycemia was examined in the presence of insulinopenia in conscious 42-h fasted dogs. During the study, somatostatin (0.8 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) was given along with basal insulin (1.8 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) and glucagon (0.5 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ). After a control period, glucose (36.1 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) was continuously given intraportally for 4 h with (2.2 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) or without fructose. In the fructose group, the sinusoidal blood fructose level (nmol/ml) rose from Ͻ16 to 176 Ϯ 11. The infusion of glucose alone (the control group) elevated arterial blood glucose (mol/ml) from 4.3 Ϯ 0.3 to 11.2 Ϯ 0.6 during the first 2 h after which it remained at 11.6 Ϯ 0.8. In the presence of fructose, glucose infusion elevated arterial blood glucose (mol/ml) from 4.3 Ϯ 0.2 to 7.4 Ϯ 0.6 during the first 1 h after which it decreased to 6.1 Ϯ 0.4 by 180 min. With glucose infusion, net hepatic glucose balance (mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) switched from output (8.9 Ϯ 1.7 and 13.3 Ϯ 2.8) to uptake (12.2 Ϯ 4.4 and 29.4 Ϯ 6.7) in the control and fructose groups, respectively. Average NHGU (mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) and fractional glucose extraction (%) during last 3 h of the test period were higher in the fructose group (30.6 Ϯ 3.3 and 14.5 Ϯ 1.4) than in the control group (15.0 Ϯ 4.4 and 5.9 Ϯ 1.8). Glucose 6-phosphate and glycogen content (mol glucose/g) in the liver and glucose incorporation into hepatic glycogen (mol glucose/g) were higher in the fructose (218 Ϯ 2, 283 Ϯ 25, and 109 Ϯ 26, respectively) than in the control group (80 Ϯ 8, 220 Ϯ 31, and 41 Ϯ 5, respectively). In conclusion, small amounts of fructose can markedly reduce hyperglycemia during intraportal glucose infusion by increasing NHGU even when insulin secretion is compromised. diabetes mellitus; hyperglycemia; hyperinsulinemia INDIVIDUALS WITH TYPE 2 DIABETES MELLITUS exhibit excessive postprandial hyperglycemia with a defect in meal-or glucoseinduced suppression of endogenous glucose production (18,21,28,34). Several studies (21,28,34) have demonstrated that the greater net splanchnic glucose release in diabetic compared with nondiabetic subjects after glucose injection was due to excessive endogenous glucose production rather than lower initial splanchnic extraction of the ingested glucose. However, the insulin and glucose concentrations differed in the diabetic and nondiabetic subjects in all of those studies, precluding direct comparison of the efficiency of splanchnic glucose uptake. DeFronzo et al. (15) (15), found decreased splanchnic glucose uptake in diabetic subjects. It is known, however, that in the presence of euglycemia and hyperinsulinemia, there is minimal splanchnic glucose uptake (14,15,23,42). Thus the size of the signal in the above studies was very small. Hyperglycemia combined with hyperinsulinemia, on the other hand, substantially increases glucose uptake by the liver (14,23,42). Recently, Basu et al. (5) carried out a hyperglycemic and hyperins...