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Published on: August 14, 2013
Modulation of glycogen phosphorylase activity and fructose 2,6-bisphosphate levels by glibenclamide and meglitinide
L López-Alarcón1, M J Muñoz-Alonso, C Guijarro
1Servicio de Bioquímica Experimental, Hospital Puerta de Hierro, Madrid, Spain.
Abstract:
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.
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