Inhibition of gluconeogenesis by tolbutamide in isolated rat hepatocytes: modulation of glucose-6-phosphate substrate cycle.
In hepatocytes isolated from 24-hour fasted rats, the oral hypoglycemic agent tolbutamide (1 mmol/L) inhibited glucose formation from different concentrations (1 to 20 mmol/L) of galactose, dihydroxyacetone, glycerol, and a mixture of L-lactate:pyruvate (molar ratio, 10:1). Parallel to the reduction of gluconeogenesis, tolbutamide stimulated L-lactate formation when cells were incubated with either galactose, dihydroxyacetone, or glycerol. All these tolbutamide effects occurred without significant modification of hepatocyte fructose-2,6-bisphosphate (F-2,6-P2) levels. Only when glucose was included in the incubation medium was the inhibition of gluconeogenesis caused by the sulfonylurea accompanied by a significant increment of the cellular F-2,6-P2 concentration. Under these conditions, tolbutamide potentiated the effect of glucose in promoting the increase of this regulatory metabolite, as well as the stimulation of glycolysis; in addition, tolbutamide increased the cellular pool of hexose-6-phosphates and the rate of tritium release from (2-3H)glucose. These results support the hypothesis that tolbutamide regulates hepatic glucose metabolism, at least, by modulating the glucose-6-phosphate substrate cycle.
Cabello
M A
MA
Servicio de Endocrinología Experimental, Hospital Puerta de Hierro, Universidad Autónoma de Madrid, Spain.
Rodríguez-Tarduchy
G
G
Ortega
J L
JL
Samper
B
B
Felíu
J E
JE
D000818:Animals; D002469:Cell Separation; D005635:Fructosediphosphates / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects*; D019298:Glucose-6-Phosphate; D005958:Glucosephosphates / Q000378:metabolism*; D006019:Glycolysis; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014044:Tolbutamide / Q000494:pharmacology*
D005635:Fructosediphosphates; D005958:Glucosephosphates; D019298:Glucose-6-Phosphate; C027652:fructose 2,6-diphosphate; D014044:Tolbutamide