Modulation of glycogen phosphorylase activity and fructose 2,6-bisphosphate levels by glibenclamide and meglitinide in isolated rat hepatocytes: a comparative study.
The influence of glibenclamide and meglitinide, or 4-[2-(5-chloro-2-methoxybenzamide)ethyl]-benzoic acid, a compound similar to the nonsulfonylurea moiety of glibenclamide, on glycogen phosphorylase a activity, fructose 2,6-bisphosphate (F-2,6-P2) level, and cytoplasmic free-Ca2+ concentration has been studied in isolated rat hepatocytes. Both glibenclamide and meglitinide caused a transient and dose-dependent activation of glycogen phosphorylase, with half-maximal effects corresponding to 3.7 +/- 1.6 and 9.6 +/- 3.3 mumol/L, respectively. This enzyme activation occurred without significant changes in hepatocyte cyclic adenosine monophosphate (cAMP) levels and was accompanied by an increase in cytoplasmic concentration of free Ca2+. Parallel to these effects, glibenclamide increased the cellular content of F-2,6-P2, with this effect being associated with a reduction in the rate of glucose formation from a mixture of [14C]lactate/pyruvate. Under similar conditions, meglitinide caused a significant reduction of F-2,6-P2 levels and accelerated the gluconeogenic flux. The mechanism by which meglitinide decreases hepatocyte F-2,6-P2 levels seems to be mediated by stimulation of fructose-2,6-bisphosphatase. This comparative study may help to elucidate which among the hepatic effects of glibenclamide are exerted specifically by the sulfonylurea moiety.
López-Alarcón
L
L
Servicio de Bioquímica Experimental, Hospital Puerta de Hierro, Madrid, Spain.
Muñoz-Alonso
M J
MJ
Guijarro
C
C
Felíu
J E
JE
D000227:Adenine Nucleotides / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000032:analysis / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005635:Fructosediphosphates / Q000032:analysis* / Q000378:metabolism; D005905:Glyburide / Q000737:chemistry / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D010656:Phenylephrine / Q000494:pharmacology; D006005:Phosphorylases / Q000032:analysis* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000227:Adenine Nucleotides; D001549:Benzamides; D005635:Fructosediphosphates; D007004:Hypoglycemic Agents; D010656:Phenylephrine; C027652:fructose 2,6-diphosphate; C030516:meglitinide; D006005:Phosphorylases; D005905:Glyburide; D002118:Calcium