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 the rat. After a hyperinsulinemic euglycemic clamp in postabsorptive (PA) anesthetized rats, the 70% inhibition of HGP could be explained by a dramatic decrease in the glucose 6-phosphate (G-6-P) concentration, whereas the glucose-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. Under similar conditions in fasted rats, the GK flux was very low. The suppression of G-6-Pase and HGP did not occur, despite plasma insulin and glucose concentrations similar to those in PA rats. Therefore, 1) insulin suppresses HGP in euglycemia by solely decreasing the G-6-P concentration; 2) when combining both hyperinsulinemia and hyperglycemia, the suppression of HGP involves the inhibition of the G-6-Pase activity; and 3) a sustained glucose-phosphorylation flux might be a crucial determinant in the inhibition of G-6-Pase and of HGP.
Guignot
L
L
Institut National de la Santé et de la Recherche Médicale U.449, Faculté de Médecine René Theóphile Hyacinthe Laennec, F-69372 Lyon Cedex 08, France.
Mithieux
G
G
D000818:Animals; D001786:Blood Glucose; D005215:Fasting / Q000502:physiology; D005941:Glucokinase / Q000378:metabolism; D005947:Glucose / Q000096:biosynthesis* / Q000494:pharmacology*; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism; D006946:Hyperinsulinism / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D019518:Postprandial Period; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D005941:Glucokinase; D005952:Glucose-6-Phosphatase; D005947:Glucose