title: Glucose regulation of insulin secretion independent of the opening or closure of adenosine triphosphate-sensitive K+ channels in beta cells.
abstract: Two major pathways are implicated in the stimulation of insulin secretion by glucose. The K+-ATP channel-dependent pathway involves closure of these channels, depolarization of the beta-cell membrane, acceleration of Ca2+ influx, and a rise in cytosolic free Ca2+ ([Ca2+]i). The K+-ATP channel-independent pathway potentiates the stimulation of exocytosis by high [Ca2+]i. To determine whether this second pathway is influenced by the configuration of the channel, we compared the effects of glucose on [Ca2+]i and insulin secretion in mouse islets under three conditions. First, in the presence of 20, 25, and 30 mM K+, i.e. without pharmacological action on K+-ATP channels, [Ca2+]i and insulin secretion were already elevated at 3 mM glucose. High glucose (20 mM) caused a transient decrease in [Ca2+]i followed by an ascent to slightly above control levels, and rapidly stimulated insulin secretion. Second, opening of K+-ATP channels with diazoxide did not influence [Ca2+]i and insulin secretion at 3 mM glucose and high K+. However, high glucose now caused a sustained lowering of [Ca2+]i accompanied by a slow increase in secretion that augmented with the K+ concentration. Third, when K+-ATP channels were blocked and beta-cells depolarized by high concentrations of tolbutamide or glibenclamide, [Ca2+]i and insulin secretion were elevated even in low glucose. High glucose transiently lowered [Ca2+]i, which then increased to or slightly above control levels, while insulin secretion was rapidly stimulated. Under all conditions the correlation between [Ca2+]i and insulin secretion was excellent at low and high glucose levels, and high glucose increased release at all [Ca2+]i. The potentiation of Ca2+-induced exocytosis by glucose is thus independent of the closed or open state of K+-ATP channels. It is only when the channels are opened by diazoxide that the increase in release is a strict amplification of the action of Ca2+. When the channels are closed (sulfonylureas) or still closable (high K+ alone), the effect of glucose on secretion also comprises a slight increase in [Ca2+]i and, in the latter case, is not strictly K+-ATP channel independent.
authors.affiliation: Unité d'Endocrinologie et Métabolisme, University of Louvain Faculty of Medicine, Brussels, Belgium.
authors.forename: Y
authors.initials: Y
authors.lastname: Sato
authors.forename: M
authors.initials: M
authors.lastname: Anello
authors.forename: J C
authors.initials: JC
authors.lastname: Henquin
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D005089:Exocytosis; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D015640:Ion Channel Gating / Q000502:physiology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D015221:Potassium Channels / Q000502:physiology*; D013453:Sulfonylurea Compounds / Q000494:pharmacology; D014044:Tolbutamide / Q000494:pharmacology
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D015221:Potassium Channels; D013453:Sulfonylurea Compounds; D000255:Adenosine Triphosphate; D014044:Tolbutamide; D005947:Glucose; D003981:Diazoxide; D005905:Glyburide; D002118:Calcium