Modulation of epinephrine-stimulated gluconeogenesis by insulin in hepatocytes isolated from genetically obese (fa/fa) Zucker rats.
Genetically obese (fa/fa) Zucker rats present an impaired response of hepatic glucose production to the inhibition by insulin. In this work, we have investigated the modulation by this hormone of epinephrine-stimulated gluconeogenesis, in hepatocytes isolated from obese (fa/fa) rats and their lean (Fa/-) littermates. Epinephrine (1 microM) caused a maximal stimulation of [14C]lactate conversion to [14C]glucose in hepatocytes isolated from either obese or lean animals. The stimulation of gluconeogenesis by epinephrine was accompanied by a significant reduction of fructose 2,6-bisphosphate levels, an inactivation of both pyruvate kinase and 6-phosphofructo 2-kinase, and by a 2-fold increase in the cellular concentrations of cAMP. The presence of insulin in the incubation medium antagonized, in a concentration-dependent manner, the effects of epinephrine. In hepatocytes isolated from lean rats, the reversion caused by insulin was complete, the concentration required for half-maximal insulin action ranging from 0.22 to 0.56 nM. In contrast, in obese rat hepatocytes, insulin only partially blocked epinephrine-mediated effects, and the sensitivity to insulin was 2- to 4-fold lower, as indicated by the corresponding half-maximal insulin action values. Furthermore, insulin (10 nM) almost completely blocked the increase in cAMP levels induced by epinephrine in lean rat hepatocytes, whereas it only provoked a small and nonsignificant reduction of epinephrine-stimulated levels of the cyclic nucleotide in hepatocytes obtained from obese rats.
Sánchez-Gutierrez
J C
JC
Hospital Puerta de Hierro, Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
Sánchez-Arias
J A
JA
Samper
B
B
Felíu
J E
JE
D000818:Animals; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology*; D005635:Fructosediphosphates / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects*; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007700:Kinetics; D007773:Lactates / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D025481:Phosphofructokinase-2; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011770:Pyruvate Kinase / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D013851:Thinness / Q000378:metabolism
D002250:Carbon Radioisotopes; D005635:Fructosediphosphates; D007328:Insulin; D007773:Lactates; C027652:fructose 2,6-diphosphate; D000242:Cyclic AMP; D017853:Phosphotransferases (Alcohol Group Acceptor); D025481:Phosphofructokinase-2; D011770:Pyruvate Kinase; D004837:Epinephrine