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Glucose Controls Cytosolic Ca²⁺ and Insulin Secretion in Mouse Islets Lacking Adenosine Triphosphate-Sensitive K⁺ Channels Owing to a Knockout of the Pore-Forming Subunit Kir6.2

Unit of Endocrinology and Metabolism (M.A.R., M.N., J.-C.H.), University of Louvain Faculty of Medicine, B-1200 Brussels, Belgium; and Division of Cellular and Molecular Medicine (T.M., S.S.), Kobe University Graduate School of Medicine, Kobe 650-0017, Japan

Address all correspondence and requests for reprints to: J. C. Henquin, Unité d'Endocrinologie et Métabolisme, UCL 55.30, Avenue Hippocrate 55, B-1200 Brussels, Belgium. E-mail: jean-claude.henquin{at}uclouvain.be.

Glucose-induced insulin secretion is classically attributed to the cooperation of an ATP-sensitive potassium (K_ATP) channel-dependent Ca²⁺ influx with a subsequent increase of the cytosolic free Ca²⁺ concentration ([Ca²⁺]_c) (triggering pathway) and a K_ATP channel-independent augmentation of secretion without further increase of [Ca²⁺]_c (amplifying pathway). Here, we characterized the effects of glucose in β-cells lacking K_ATP channels because of a knockout (KO) of the pore-forming subunit Kir6.2. Islets from 1-yr and 2-wk-old Kir6.2KO mice were used freshly after isolation and after 18 h culture to measure glucose effects on [Ca²⁺]_c and insulin secretion. Kir6.2KO islets were insensitive to diazoxide and tolbutamide. In fresh adult Kir6.2KO islets, basal [Ca²⁺]_c and insulin secretion were marginally elevated, and high glucose increased [Ca²⁺]_c only transiently, so that the secretory response was minimal (10% of controls) despite a functioning amplifying pathway (evidenced in 30 mM KCl). Culture in 10 mM glucose increased basal secretion and considerably improved glucose-induced insulin secretion (200% of controls), unexpectedly because of an increase in [Ca²⁺]_c with modulation of [Ca²⁺]_c oscillations. Similar results were obtained in 2-wk-old Kir6.2KO islets. Under selected conditions, high glucose evoked biphasic increases in [Ca²⁺]_c and insulin secretion, by inducing K_ATP channel-independent depolarization and Ca²⁺ influx via voltage-dependent Ca²⁺ channels. In conclusion, Kir6.2KO β-cells down-regulate insulin secretion by maintaining low [Ca²⁺]_c, but culture reveals a glucose-responsive phenotype mainly by increasing [Ca²⁺]_c. The results support models implicating a K_ATP channel-independent amplifying pathway in glucose-induced insulin secretion, and show that K_ATP channels are not the only possible transducers of metabolic effects on the triggering Ca²⁺ signal.