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-me thoxybenzamide)ethyl]-benzoic acid, a compound similar to the nonsulfo nylurea moiety of glibenclamide, on glycogen phosphorylase a activity, fructose 2,6-bisphosphate (F-2,6-P-2) level, and cytoplasmic free-Ca2 + concentration has been studied in isolated rat hepatocytes. Both gli benclamide and meglitinide caused a transient and dose-dependent activ ation of glycogen phosphorylase, with half-maximal effects correspondi ng to 3.7 +/- 1.6 and 9.6 +/- 3.3 mu mol/L, respectively. This enzyme activation occurred without significant changes in hepatocyte cyclic a denosine monophosphate (cAMP) levels and was accompanied by an increas e in cytoplasmic concentration of free Ca2+. Parallel to these effects , glibenclamide increased the cellular content of F-2,6-P-2, with this effect being associated with a reduction in the rate of glucose forma tion from a mixture of [C-14]lactate/pyruvate. Under similar condition s, meglitinide caused a significant reduction of F-2,6-P-2 levels and accelerated the gluconeogenic flux. The mechanism by which meglitinide decreases hepatocyte F-2,6-P-2 levels seems to be mediated by stimula tion of fructose-2,6-bisphosphatase. This comparative study may help t o elucidate which among the hepatic effects of glibenclamide are exert ed specifically by the sulfonylurea moiety. Copyright (C) 1995 by W.B. Saunders Company