Carvalho-Martini Mirian, de Oliveira Denise S, Suzuki-Kemmelmeier Fumie, Bracht Adelar
Laboratory of Liver Metabolism, Department of Biochemistry, University of Maringá, Maringá, Brazil 87020-900.
Res Commun Mol Pathol Pharmacol. 2006;119(1-6):115-26.
Inhibitory effects on glycogenolysis have been reported for glibenclamide in the presence of insulin after stimulation of glycogenolysis by glucagon. Inhibition of oxidative phosphorylation, which has been equally reported for this drug, however, should stimulate glycogenolysis. The present work aimed to find an answer to the question of how glibenclamide affects glycogen catabolism in the liver of fed rats undergoing substrate- and hormone-free perfusion. The experimental system was the isolated perfused liver of ad libitum fed rats. Metabolites in the outflowing perfusate were assayed enzymatically. Oxygen uptake was measured polarographically. Glibenclamide (25-500 microM) stimulated glucose production and lactate release, with a clear correlation between concentrations and effects. Maximal stimulations were 132 and 127% for lactate production and glucose release, respectively. At low glibenclamide concentrations (up to 100 microM) both oxygen uptake and pyruvate production were stimulated, but at higher concentrations inhibition took place. Uric acid production was stimulated by glibenclamide. All effects of glibenclamide are probably due to decreases in oxidative phosphorylation. Stimulation of glucose release is the opposite of what should be expected for a hypoglycemic drug and it also contrasts with some reports of diminishing effects in the presence of glucagon plus insulin. This means that the stimulatory action on glycogenolysis that was seen as a net effect under the specific conditions of the present work could be counterbalancing inhibitory effects in vivo. This combination of events could eventually diminish the effectiveness of the drug as a hypoglycemic agent in the fed state.
据报道，在胰高血糖素刺激糖原分解后，格列本脲在胰岛素存在的情况下对糖原分解有抑制作用。然而，同样有报道称该药物会抑制氧化磷酸化，而这应该会刺激糖原分解。目前的研究旨在回答格列本脲如何影响在无底物和无激素灌注的进食大鼠肝脏中糖原分解代谢的问题。实验系统是随意进食大鼠的离体灌注肝脏。流出的灌注液中的代谢产物通过酶法进行测定。氧摄取通过极谱法进行测量。格列本脲（25 - 500微摩尔）刺激葡萄糖生成和乳酸释放，浓度与效应之间存在明显的相关性。乳酸生成和葡萄糖释放的最大刺激分别为132%和127%。在低格列本脲浓度（高达100微摩尔）时，氧摄取和丙酮酸生成均受到刺激，但在较高浓度时则出现抑制。格列本脲刺激尿酸生成。格列本脲的所有效应可能是由于氧化磷酸化的降低。葡萄糖释放的刺激与降糖药物预期的作用相反，也与一些关于在胰高血糖素加胰岛素存在时作用减弱的报道形成对比。这意味着在本研究的特定条件下被视为净效应的对糖原分解的刺激作用可能会抵消体内的抑制作用。这些事件的综合最终可能会降低该药物在进食状态下作为降糖剂的有效性。
