Anti-Diabetic Sulfonylurea Stimulates Insulin Secretion Independent of Plasma Membrane KATP Channels

Understanding mechanisms by which glibenclamide stimulates insulin release is important particularly given recent promising treatment by glibenclamide of permanent neonatal diabetic subjects. Anti-diabetic sulfonylureas are thought to stimulate insulin secretion solely by inhibiting their high affinity KATP channel receptors at the plasma membrane of β cells. This normally occurs during glucose stimulation where ATP inhibition of plasmalemmal KATP channels leads to voltage-activation of L-type calcium channels for rapidly switching on and off calcium influx governing the duration of insulin secretion. However, growing evidence indicates that sulfonylureas including glibenclamide have additional KATP channel receptors within β cells at insulin granules. We tested non-permeabilized β cells in mouse islets for glibenclamide stimulated insulin secretion mediated by granule localized KATP channels by using conditions that bypass glibenclamide action on plasmalemmal KATP channels. High potassium stimulation evoked a sustained rise in β cell calcium but a transient rise in insulin secretion. With continued high potassium depolarization, addition of glibenclamide dramatically enhanced insulin secretion without affecting calcium. These findings support the hypothesis that glibenclamide, or an increased ATP/ADP ratio, stimulates insulin secretion in part by binding at granule localized KATP channels that functionally contribute to sustained second phase insulin secretion.