Chronic total parenteral nutrition (TPN) markedly augments net hepatic glucose uptake (NHGU). This adaptive increase is impaired by an infection despite accompanying hyperinsulinemia. In the non-adapted state NHGU is dependent upon the prevailing glucose levels. Our aims were to determine if the adaptation to TPN alters the glucose dependency of NHGU, if infection impairs this dependency and if insulin modulates the glucose dependency of NHGU during infection. Chronically catheterized dogs received TPN for 5 days. On day 3 of TPN dogs received either a bacterial fibrin clot to induce a non-lethal infection (INF, n=9) or a sterile fibrin clot (SHAM, n=6). Forty-two hours after clot implantation somatostatin was infused. In SHAM insulin and glucagon were infused to match the level seen in sham (9±1 µU/ml and 23±4 pg/ml). In infected animals insulin and glucagon were either infused to match the levels seen in infection (25±2 µU/ml and 101±15 pg/ml; INF-HI; n=5) or insulin was replaced to match the lower levels seen in SHAM (13±2 µU/ml), while glucagon was kept elevated (97±9 pg/ml; INF-LO; n=4). Then a 4-step (90 min each) hyperglycemic (120,150,200, 250 mg/dl) clamp was performed. NHGU (mg/kg/min) increased at each glucose step in SHAM (3.6±0.6 to 5.4±0.7 to 8.9±0.9 to 12.1±1.1); the slope of the relationship between glucose levels and NHGU (i.e. glucose dependency) was higher than that seen in non-adapted animals. Infection impaired glucose-dependent NHGU (mg/kg/min) in both INF-HI (1.3±0.4 to 2.9±0.5 to 5.5±1.0 to 7.7±1.6) and INF-LO (0.5±0.7 to 2.2±0.6 to 4.2±1.0 to 5.8±0.8). In summary: TPN augments glucose dependent NHGU, the presence of infection decreases glucose-dependent NHGU and the accompanying hyperinsulinemia associated with infection does not sustain the glucose dependency of NHGU.