Chlorpropamide Raises Fructose-2,6-Bisphosphate Concentration and Inhibits Gluconeogenesis in Isolated Rat Hepatocytes

The addition of chlorpropamide to hepatocytes isolated from fed rats raised the cellular concentration of fructose-2,6-bisphosphate (F-2,6-P₂), a regulatory metabolite that plays a relevant role in the control of hepatic glucose metabolism. The effect of chlorpropamide was dose dependent; a statistically significant increase was already seen at 0.2 mM of the sulfonylurea. The accumulation of F-2,6-P₂ caused by chlorpropamide (1 mM) was parallel to the stimulation of L-lactate production (36.6 ± 4.8 versus 26.1 ± 2.6 μmol of lactate/g of cells × 20 min; N = 5, P < 0.05) and to the inhibition of gluconeogenesis (0.57 ± 0.1 versus 0.94 ± 0.09 μmol of [U-¹⁴C]pyruvate converted to glucose/g of cells × 20 min; N = 5, P < 0.05). In addition, chlorpropamide enhanced the inhibitory action evoked by insulin on glucagon-stimulated gluconeogenesis. This combined effect of chlorpropamide and insulin seems to be correlated with the synergistic accumulation of F-2,6-P₂provoked by the simultaneous action of these two agents on glucagon-treated hepatocytes. Finally, neither 6-phosphofructo-2-kinase activity nor hepatocyte cyclic AMP levels were significantly changed by the presence of the sulfonylurea in the incubation medium. Our results support the concept that chlorpropamide, by a cyclic AMP-independent mechanism, increases the hepatic content of F-2,6-P₂ and, in this way, enhances the glycolytic flux and inhibits glucose output by the liver.