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.