Mechanisms by which insulin, associated or not with glucose, may inhibit hepatic glucose production in the rat

We investigated the intrahepatic mechanisms by which insulin, associated or not with hyperglycemia, may inhibit hepatic glucose production (HGP) in th e rat. After a hyperinsulinemic euglycemic clamp in postabsorptive (PA) ane sthetized rats, the 70% inhibition of HGP could be explained by a dramatic decrease in the glucose 6-phosphate (G-6-P) concentration, whereas the gluc ose-6-phosphatase (G-6-Pase) and glucokinase (GK) activities were unchanged . Under hyperinsulinemic hyperglycemic condition, the GK flux was increased . The G-6-P concentration was not or only weakly decreased. The inhibition of HGP involved a significant 25% inhibition of the G-6-Pase activity. Unde r similar conditions in fasted rats, the GK flux was very low. The suppress ion of G-6-Pase and HGP did not occur, despite plasma insulin and glucose c oncentrations similar to those in PA rats. Therefore, 1) insulin suppresses HGP in euglycemia by solely decreasing the G-6-P concentration; 2) when co mbining both hyperinsulinemia and hyperglycemia, the suppression of HGP inv olves the inhibition of the G-6-Pase activity; and 3) a sustained glucose-p hosphorylation flux might be a crucial determinant in the inhibition of G-6 -Pase and of HGP.