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A Minimum of Fuel Is Necessary for Tolbutamide to Mimic the Effects of Glucose on Electrical Activity in Pancreatic ß-Cells¹

Unité d’Endocrinologie et Métabolisme, University of Louvain Faculty of Medicine, UCL 55.30, B 1200 Brussels, Belgium

Address all correspondence and requests for reprints to: Dr. J. C. Henquin, Unité d’Endocrinologie et Métabolisme, UCL 55.30, avenue Hippocrate 55, B-1200 Brussels, Belgium.

Glucose stimulation of pancreatic ß-cells triggers electrical activity (slow waves of membrane potential with superimposed spikes) that is best monitored with intracellular microelectrodes. Closure of ATP-sensitive K⁺ channels underlies the depolarization to the threshold potential and participates in the increase in electrical activity produced by suprathreshold (>7 mM) concentrations of glucose, but it is still unclear whether this is the sole mechanism of control. This was investigated by testing whether blockade of ATP-sensitive K⁺ channels by low concentrations of tolbutamide is able to mimic the effects of glucose on mouse ß-cell electrical activity even in the absence of the sugar. The response to tolbutamide was influenced by the duration of the perifusion with the low glucose medium. Tolbutamide (25 µM) caused a rapid and sustained depolarization with continuous activity after 6 min of perifusion of the islet with 3 mM glucose, and a progressive depolarization with slow waves of the membrane potential after 20 min. In the absence of glucose, the ß-cell response to tolbutamide was a transient phase of depolarization with rare slow waves (6 min) or a silent, small, but sustained, depolarization (20 min). Readministration of 3 mM glucose was sufficient to restore slow waves, whereas an increase in the glucose concentration to 5 and 7 mM was followed by a lengthening of the slow waves and a shortening of the intervals. In contrast, induction of slow waves by tolbutamide proved very difficult in the absence of glucose, because the ß-cell membrane tended to depolarize from a silent level to the plateau level, at which electrical activity is continuous. Azide, a mitochondrial poison, abrogated the electrical activity induced by tolbutamide in the absence of glucose, which demonstrates the influence of the metabolism of endogenous fuels on the response to the sulfonylurea. The partial repolarization that azide also produced was reversed by increasing the concentration of tolbutamide, but reappearance of the spikes required the addition of glucose. It is concluded that inhibition of ATP-sensitive K⁺ channels is not the only mechanism by which glucose controls electrical activity in ß-cells.

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