In the present study we compared the hepatic effects of a selective increase in hepatic sinusoidal insulin brought about by insulin infusion into the hepatic artery with those resulting from insulin infusion into the portal vein. A pancreatic clamp was used to control the endocrine pancreas in conscious overnight-fasted dogs. In the control period, insulin was infused via peripheral vein and the portal vein. After the 40-min basal period, there was a 180-min test period during which the peripheral insulin infusion was stopped and an additional 1.2 pmol. kg-1. min-1 of insulin was infused into the hepatic artery (HART, n = 5) or the portal vein (PORT, n = 5, data published previously). In the HART group, the calculated hepatic sinusoidal insulin level increased from 99 +/- 20 (basal) to 165 +/- 21 pmol/l (last 30 min). The calculated hepatic artery insulin concentration rose from 50 +/- 8 (basal) to 289 +/- 19 pmol/l (last 30 min). However, the overall arterial (50 +/- 8 pmol/l) and portal vein insulin levels (118 +/- 24 pmol/l) did not change over the course of the experiment. In the PORT group, the calculated hepatic sinusoidal insulin level increased from 94 +/- 30 (basal) to 156 +/- 33 pmol/l (last 30 min). The portal insulin rose from 108 +/- 42 (basal) to 192 +/- 42 pmol/l (last 30 min), whereas the overall arterial insulin (54 +/- 6 pmol/l) was unaltered during the study. In both groups hepatic sinusoidal glucagon levels remained unchanged, and euglycemia was maintained by peripheral glucose infusion. In the HART group, net hepatic glucose output (NHGO) was suppressed from 9.6 +/- 2.1 micromol. kg-1. min-1 (basal) to 4.6 +/- 1.0 micromol. kg-1. min-1 (15 min) and eventually fell to 3.5 +/- 0.8 micromol. kg-1. min-1 (last 30 min, P < 0.05). In the PORT group, NHGO dropped quickly (P < 0.05) from 10.0 +/- 0.9 (basal) to 7.8 +/- 1.6 (15 min) and eventually reached 3.1 +/- 1.1 micromol. kg-1. min-1 (last 30 min). Thus NHGO decreases in response to a selective increase in hepatic sinusoidal insulin, regardless of whether it comes about because of hyperinsulinemia in the hepatic artery or portal vein.