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Antidiabetic sulfonylurea stimulates insulin secretion independently of plasma membrane K_ATP channels

¹Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh; ²Department of Pediatrics, University of Pittsburgh School of Medicine, Division of Immunogenetics, Diabetes Institute, Rangos Research Center, Children's Hospital of Pittsburgh, Pittsburgh; ³Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Submitted 8 January 2007 ; accepted in final form 2 April 2007

Understanding mechanisms by which glibenclamide stimulates insulin release is important, particularly given recent promising treatment by glibenclamide of permanent neonatal diabetic subjects. Antidiabetic sulfonylureas are thought to stimulate insulin secretion solely by inhibiting their high-affinity ATP-sensitive potassium (K_ATP) channel receptors at the plasma membrane of -cells. This normally occurs during glucose stimulation, where ATP inhibition of plasmalemmal K_ATP 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 K_ATP channel receptors within -cells at insulin granules. We tested nonpermeabilized -cells in mouse islets for glibenclamide-stimulated insulin secretion mediated by granule-localized K_ATP channels by using conditions that bypass glibenclamide action on plasmalemmal K_ATP channels. High-potassium stimulation evoked a sustained rise in -cell calcium level 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 K_ATP channels that functionally contribute to sustained second-phase insulin secretion.

-cells; glibenclamide; permanent neonatal diabetes; exocytosis; endocytosis; adenosine 5'-triphosphate-sensitive potassium channels

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