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We determined whether intraportal caffeine infusion, at rates designed to create concentrations similar to that seen with normal dietary intake, would enhance net hepatic glucose uptake (NHGU) during a glucose load. Dogs (n = 15) were implanted with sampling and infusion catheters as well as flow probes >16 d before the studies. After a basal sampling period, dogs were administered a somatostatin infusion (0-150 min) as well as intraportal infusions of glucose [18 micromol/(kg . min)], basal glucagon [0.5 ng/(kg . min)], and insulin [8.3 pmol/(kg . min)] to establish mild hyperinsulinemia. Arterial glucose was clamped at 10 mmol/L with a peripheral glucose infusion. At 80 min, either saline (Control; n = 7) or caffeine [1.5 micromol/(kg . min); n = 8] was infused into the portal vein. Arterial insulin, glucagon, norepinephrine, and glucose did not differ between groups. In dogs infused with caffeine, NHGU was significantly higher than in controls [21.2 +/- 4.3 vs. 11.2 +/- 1.6 micromol/(kg . min)]. Caffeine increased net hepatic lactate output compared with controls [12.5 +/- 3.8 vs. 5.5 +/- 1.5 micromol/(kg . min)]. These findings indicate that physiologic circulating levels of caffeine can enhance NHGU during a glucose load, and the added glucose consumed by the liver is in part converted to lactate.