P revious studies suggest that insulin can inhibit hepatic glucose production (HGP) by both direct and indirect actions. The indirect effects include inhibition of glucagon secretion, reduction in plasma nonesterified fatty acid levels, reduction of the amount of gluconeogenic precursor supplied to the liver, and change in neural input to the liver. A study in this issue of the JCI demonstrates that, in overnight-fasted dogs, an acute, selective increase of portal insulin induces a rapid inhibition of HGP, and a 4-fold rise in head insulin level does not enhance the inhibition of HGP in response to portal insulin infusion. This study demonstrates that insulin’s direct effects on the liver dominate the control of HGP. These data balance previous studies in mice that suggested that indirect effects of insulin via the hypothalamus are the primary determinant of HGP.