We tested the hypothesis that due to greater hepatic free fatty acid (FFA) load, portal delivery of FFA, as in visceral obesity, induces hyperinsulinemia and increases endogenous glucose production to a greater extent than peripheral FFA delivery. 10 µEq/kg.min portal oleate (n=6), equidose peripheral oleate (n=5) or saline (n=6) was given i.v. for 5h to conscious dogs infused with a combination of portal and peripheral insulin to enable calculation of hepatic insulin clearance during a pancreatic euglycemic clamp. Peripheral FFA were similar with both oleate treatments and were 3-fold greater than in controls. Portal FFA were 1.5 to 2-fold greater with portal than peripheral oleate. Peripheral insulin concentrations were greatest with portal oleate, intermediate with peripheral oleate (P<0.001 vs. portal oleate or controls) and lowest in controls, consistent with corresponding reductions in plasma insulin clearance and hepatic insulin clearance. Although endogenous glucose production did not differ between the two routes of oleate delivery, total glucose output (endogenous glucose production + glucose cycling) was greater with portal than peripheral oleate (P<0.001), despite the higher insulin levels. In conclusion, during euglycemic clamps in dogs, the main effect of short-term elevation in portal FFA is to generate peripheral hyperinsulinemia. This may in the long term contribute to the metabolic and cardiovascular risk of visceral obesity.