Intraportal infusion of small amounts of fructose markedly augmented net hepatic glucose uptake (NHGU) during hyperglycemic hyperinsulinemia in conscious dogs. In this study, we examined whether the inclusion of catalytic amounts of fructose with a glucose load reduces postprandial hyperglycemia and the pancreatic -cell response to a glucose load in conscious 42-hfasted dogs. Each study consisted of an equilibration (؊140 to ؊40 min), control (؊40 to 0 min), and test period (0 -240 min). During the latter period, glucose (44.4 mol ⅐ kg ؊1 ⅐ min ؊1 ) was continuously given intraduodenally with (2.22 mol ⅐ kg ؊1 ⅐ min ؊1 ) or without fructose. The glucose appearance rate in portal vein blood was not significantly different with or without the inclusion of fructose (41.3 ؎ 2.7 vs. 37.3 ؎ 8.3 mol ⅐ kg ؊1 ⅐ min ؊1 , respectively). In response to glucose infusion without the inclusion of fructose, the net hepatic glucose balance switched from output to uptake (from 10 ؎ 2 to 11 ؎ 4 mol ⅐ kg ؊1 ⅐ min ؊1 ) by 30 min and averaged 17 ؎ 6 mol ⅐ kg ؊1 ⅐ min ؊1 . The fractional extraction of glucose by the liver during the infusion period was 7 ؎ 2%. Net glycogen deposition was 2.44 mmol glucose equivalent/kg body wt; 49% of deposited glycogen was synthesized via the direct pathway. Net hepatic lactate production was 1.4 mmol/kg body wt. Arterial blood glucose rose from 4.1 ؎ 0.2 to 7.3 ؎ 0.4 mmol/l, and arterial plasma insulin rose from 42 ؎ 6 to 258 ؎ 66 pmol/l at 30 min, after which they decreased to 7.0 ؎ 0.5 mmol/l and 198 ؎ 66 pmol/l, respectively. Arterial plasma glucagon decreased from 54 ؎ 7 to 32 ؎ 3 ng/l. In response to intraduodenal glucose infusion in the presence of fructose, net hepatic glucose balance switched from 9 ؎ 1 mol ⅐ kg G lucose uptake by the liver contributes in a major way to the disposal of alimentary glucose (1). In healthy humans, 20 -30% of absorbed glucose is taken up by the liver, and hepatic glycogen synthesis accounts for the disposal of about 70% of that amount. Liver glycogen is synthesized by both direct (glucose 3 glucose-6-phosphate [G6P] 3 glucose-1-phosphate 3 uridine 5Ј-diphosphate [UDP] glucose 3 glycogen) and indirect (three carbon unit 3 phosphoenolpyruvate 3 G6P 3 glucose-1-phosphate 3 UDP glucose 3 glycogen) pathways (2). After oral glucose ingestion in the healthy human, 50 -77% of the liver glycogen synthesized is derived via the direct pathway (3-6). The response of the conscious dog is similar to that of humans, with 25-40% of a gastrointestinal glucose load being taken up by the liver and 50 -62% of accumulated hepatic glycogen being synthesized via the direct pathway (7-9).Individuals with diabetes exhibit excessive postprandial hyperglycemia, with a defect in meal-or glucose-induced suppression of endogenous glucose production (10 -15). Only a few studies have examined the effect of type 2 diabetes on splanchnic glucose uptake, and the results from these data are not concordant. Several studies (12,13,15,16) have demonstrated that the greater net splanchnic glucose rel...