Relationships between the Na(+)/K(+) pump and ATP and ADP content in mouse pancreatic islets: effects of meglitinide and glibenclamide.

Abstract

We have previously demonstrated that both D-glucose and glibenclamide stimulate the Na(+)/K(+) pump and suggested that this may be part of the membrane repolarization process, following the primary depolarization by these agents. The aim of this study was to investigate whether the non-sulphonylurea meglitinide (HB 699) exerts similar effects as glibenclamide or glucose on the islet Na(+)/K(+) pump and if effects of meglitinide or glibenclamide on this pump activity is paralleled by changes in islet ATP content and/or ATP/ADP ratio. The acyl-amino-alkyl benzoic acid derivative, meglitinide, stimulated the islet ouabain-sensitive portion of (86)Rb(+) influx (Na(+)/K(+) pump) by 53%, while the ouabain-resistant portion was inhibited by 70%. The stimulatory effect was not additive to that caused by D-glucose, suggesting that both agents may activate the Na(+)/K(+) pump via the same mechanism. Glibenclamide (10 microM) decreased the islet ATP and ADP content as well as the ATP/ADP ratio at 0 mM glucose. These effects were no longer observed at 10 mM glucose. Meglitinide (10 or 50 microM) lowered the islet ATP and ADP content at 0 mM glucose without affecting the ATP/ADP ratio. At 10 mM glucose, however, 10 microM of the drug reduced the islet ATP content but not the ATP/ADP ratio, while 50 microM of the drug, besides lowering the ATP content, also reduced the ATP/ADP ratio. Diazoxide (0.5 mM) increased the islet ATP content in the absence of glucose, an effect not seen in the presence of 10 mM glucose. The rate of glucose oxidation at 1, 10 or 20 mM of the sugar was not affected by glibenclamide (0.1 - 10 microM) and at 10 or 20 mM of the sugar not affected by meglitinide (1 - 100 microM). These results suggest that glibenclamide and meglitinide lower the islet ATP level by indirectly activating the beta-cell Na(+)/K(+) pump, which is a major consumer of ATP in the islets, while diazoxide increases the ATP level due to inhibition of the pump.