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 mumol of lactate/g of cells X 20 min; N = 5, P less than 0.05) and to the inhibition of gluconeogenesis (0.57 +/- 0.1 versus 0.94 +/- 0.09 mumol of [U-14C]pyruvate converted to glucose/g of cells X 20 min; N = 5, P less than 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-P2 provoked 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.
D000818:Animals; D002747:Chlorpropamide / Q000494:pharmacology*; D000242:Cyclic AMP / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005635:Fructosediphosphates / Q000032:analysis / Q000096:biosynthesis*; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D006598:Hexosediphosphates / Q000096:biosynthesis*; D006801:Humans; D007773:Lactates / Q000096:biosynthesis; D019344:Lactic Acid; D008099:Liver / Q000032:analysis / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D025481:Phosphofructokinase-2; D010770:Phosphotransferases / Q000378:metabolism; D011770:Pyruvate Kinase / Q000378:metabolism; D011773:Pyruvates / Q000378:metabolism; D019289:Pyruvic Acid; D051381:Rats; D011919:Rats, Inbred Strains
D005635:Fructosediphosphates; D006598:Hexosediphosphates; D007773:Lactates; D011773:Pyruvates; D019344:Lactic Acid; C027652:fructose 2,6-diphosphate; D019289:Pyruvic Acid; D000242:Cyclic AMP; D010770:Phosphotransferases; D025481:Phosphofructokinase-2; D011770:Pyruvate Kinase; D005947:Glucose; D002747:Chlorpropamide