Adenosine triphosphate-sensitive K+ channels may not be the sole regulators of glucose-induced electrical activity in pancreatic B-cells.
Stimulation of insulin release by glucose requires Ca2+ influx in pancreatic B-cells. This influx occurs during phases of electrical activity (slow waves of membrane potential with superimposed spikes) that can be monitored with intracellular microelectrodes. It has been suggested that closure of ATP-sensitive K+ channels contributes to the increase in electrical activity (and, hence, in Ca2+ influx and insulin release) produced by suprathreshold (greater than 7 mM) concentrations of glucose. If this is the sole mechanism of control, the decrease in electrical activity that follows a decrease in glucose concentration should be mimicked by opening these ATP-sensitive K+ channels. This was achieved by diazoxide, which selectively and directly acts at the channel level (without decreasing B-cell metabolism), and azide, which indirectly opens the channels by inhibiting mitochondrial ATP production. Stepwise lowering of the glucose concentration from 15 to 8 mM progressively decreased electrical activity in B-cells. This decrease was characterized by a shortening of the slow waves and a lengthening of the intervals between the slow waves, with little change in slow wave frequency. Similar changes followed the addition of azide (250-750 microM) to a medium containing 15 mM glucose. In contrast, in the presence of 15 mM glucose, diazoxide (5-20 microM) considerably increased the interval duration, but did not shorten the slow waves, thus causing a marked fall in slow wave frequency. In B-cells persistently depolarized by 30 mM glucose, diazoxide restored slow waves and intervals that were much longer than those recorded when the same cells were stimulated by 15 mM glucose. In conclusion, decreasing mitochondrial ATP production with azide is more able to reproduce the effects of a decrease in glucose concentration on electrical activity in B-cells than a direct pharmacological opening of ATP-sensitive K+ channels with diazoxide. This suggests that ionic channels other than ATP-sensitive K+ channels are under metabolic control and may contribute to the regulation of electrical activity by glucose.
Henquin
J C
JC
I. Physiologisches Institut, University of Saarland, Homburg/Saar, Germany.
D000255:Adenosine Triphosphate / Q000096:biosynthesis / Q000494:pharmacology*; D000818:Animals; D003981:Diazoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005260:Female; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*
D015221:Potassium Channels; D000255:Adenosine Triphosphate; D005947:Glucose; D003981:Diazoxide