title: Mechanisms by which insulin, associated or not with glucose, may inhibit hepatic glucose production in the rat.
abstract: 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.
authors.affiliation: 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.
authors.forename: L
authors.initials: L
authors.lastname: Guignot
authors.forename: G
authors.initials: G
authors.lastname: Mithieux
mesh_terms: 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
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D005941:Glucokinase; D005952:Glucose-6-Phosphatase; D005947:Glucose