Total parenteral nutrition (TPN) markedly augments net hepatic glucose uptake (NHGU) and hepatic glycolysis in the presence of mild hyperglycemia and hyperinsulinemia. This increase is impaired by an infection. Our aims were to determine if the adaptation to TPN alters the responsiveness of the liver to insulin and if infection impairs that response. 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 hypermetabolic infection (INF, n=5) or a sterile fibrin clot (SHAM, n=5). Forty-two hours after clot implantation, somatostatin and glucagon (34 ± 3 vs. 84 ± 11 pg/ml in artery, SHAM vs. INF) were infused and a 3-step (120 min each) isoglycemic (~120 mg/dl) hyperinsulinemic (~12, 25, and 50 µU/ml) clamp was performed to simulate levels seen in normal, infected, and exogenous insulin treatment states. In SHAM insulin only modestly increased NHGU(3.5 ± 0.2 to 4.2 ± 0.4, to 4.6 ± 0.5 mg^.kg^-1.min^-1), In INF NHGU was consistently lower at each insulin step(1.1 ± 0.5 to 2.6 ± 0.5 to 2.8 ± 0.7 mg^.kg^-1.min^-1). While NHGU increased from the first to the second step in INF, it did not increase further with the highest dose of insulin. Despite increases in NHGU in response to increases in insulin, net hepatic lactate release did not increase in SHAM and fell in INF (1.6 ± 0.2 to 1.4 ± 0.1, to 1.2 ± 0.2 vs. 1.3 ± 0.4 to 1.0 ± 0.3 to 0.6 ± 0.5 mg^.kg^-1.min^-1). In summary, in the TPN-adapted state liver glucose uptake is unresponsive to increases in insulin above the basal level. While the infection-induced increase in insulin helps to sustain NHGU, further increments in insulin neither enhance NHGU, nor glycolysis.