Effect of sulfonylureas on hepatic glycogen metabolism: activation of glycogen phosphorylase.
In hepatocytes isolated from fed rats, both tolbutamide and glipizide caused a dose-dependent activation of glycogen phosphorylase, possibly by a Ca2+-mediated mechanism. Maximal effects (about twofold) were already obtained when drugs were used at 0.5 mmol/L, the calculated concentrations of tolbutamide and glipizide responsible for the half-maximal effects being 60 and 30 mumol/L, respectively. The activation of glycogen phosphorylase caused the mobilization of glycogen and increased the cellular concentration of hexose 6-phosphates (glucose 6-phosphate plus fructose 6-phosphate) and that of fructose 2,6-bisphosphate. Under the influence of sulfonylureas, glucose formation was slightly stimulated while the rate of L-lactate production was more markedly incremented, indicating that sulfonylureas canalize the metabolic flux coming from glycogen mainly to the glycolytic pathway. These results suggest that a glycogenolytic action of sulfonylureas could collaborate to raise hepatic fructose 2,6-bisphosphate concentration in the fed animal.
Mojena
M
M
Servicio de Endocrinología Experimental, Universidad Autónoma de Madrid, Spain.
Marcos
M L
ML
Monge
L
L
Felíu
J E
JE
D000818:Animals; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005913:Glipizide / Q000494:pharmacology*; D005947:Glucose / Q000096:biosynthesis; D006003:Glycogen / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D006005:Phosphorylases / Q000378:metabolism*; D051381:Rats; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D014044:Tolbutamide / Q000494:pharmacology*
D013453:Sulfonylurea Compounds; D006003:Glycogen; D014044:Tolbutamide; D006005:Phosphorylases; D005947:Glucose; D005913:Glipizide