Antidiabetic sulfonylurea stimulates insulin secretion independently 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. 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 beta-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 beta-cells at insulin granules. We tested nonpermeabilized beta-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 beta-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.
Geng
Xuehui
X
Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, 3500 Terrace St., Pittsburgh, PA 15261, USA.
Li
Lehong
L
Bottino
Rita
R
Balamurugan
A N
AN
Bertera
Suzanne
S
Densmore
Erik
E
Su
Anjey
A
Chang
Yigang
Y
Trucco
Massimo
M
Drain
Peter
P
D000251:Adenosine Triphosphatases / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D027682:Cation Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D005905:Glyburide / Q000008:administration & dosage; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D011189:Potassium Chloride / Q000494:pharmacology; D013453:Sulfonylurea Compounds / Q000494:pharmacology*
D027682:Cation Transport Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D013453:Sulfonylurea Compounds; D011189:Potassium Chloride; D000251:Adenosine Triphosphatases; C022761:potassium transporting ATPase; D005905:Glyburide; D002118:Calcium