Tolbutamide potentiates the volume-regulated anion channel current in rat pancreatic beta cells

Abstract

Aims/hypothesis. Hypoglycaemic sulphonylureas are thought to stimulate insulin release by binding to a sulphonylurea receptor, closing K ATP channels and inducing electrical activity. However, the fact that these drugs stimulate insulin release at high glucose concentrations where K ATP channels are closed suggests additional ionic actions. The aim of this study was to test the hypothesis that sulphonylureas influence the current of the glucose-and volume-regulated anion channel. Methods. Electrical and ion-channel activity were recorded in isolated rat beta cells using the patchclamp technique. 86 Rb + efflux was measured using intact islets. Beta cell volume was measured using a video-imaging technique. Results. In the absence of glucose, tolbutamide (100 µmol/l) transiently depolarised the cells. In the presence of glucose (5 mmol/l), tolbutamide evoked a sustained period of electrical activity, whilst at 10 mmol/l glucose, the drug evoked a pronounced 'silent' depolarisation. In the absence of glucose, tolbutamide inhibited 86 Rb + efflux. However, at 10 mmol/l glucose, tolbutamide induced a transient stimulation of efflux. Tolbutamide potentiated the whole-cell volume-regulated anion conductance in a glucose-dependent manner with an EC 50 of 85 µmol/l. In single channel recordings, tolbutamide increased the channel-open probability. Tolbutamide caused beta cell swelling in the presence of glucose, but not in its absence. Conclusions/interpretation. Tolbutamide can induce beta cell electrical activity by potentiating the glucose-and volume-regulated anion channel current. This effect is probably not due to a direct effect of the drug on the channel, but could be secondary to a metabolic action in the beta cell.

Glucose Induces Anion Conductance and Cytosol-To-Membrane Transposition of ICln in INS-1E Rat Insulinoma Cells

“…This does by no means exclude that metabolic effects are involved in glucose-induced cell swelling and Cl -current activation in INS-1E cells. In isolated pancreatic beta cells the sulfonylurea tolbutamide has been reported both to be without an effect [10,11] as well as to augment the glucose-induced anion current in a glucose concentration-dependent manner [40]. Therefore we tested for a possible inhibitory effect of tolbutamide on the Cl -currents in INS-1E cells.…”

Electrical activity in pancreatic islet cells: The VRAC hypothesis

“…84,85 Consistent with this suggestion, tolbutamide has been reported to increase lactate output from islets. 83,86 It is also conceivable that SUR1 could play a role in regulating activity of the VRAC. Whatever the coupling mechanism, this K ATP channel-independent action of sulphonylureas could account, at least in part, for the insulinotropic effect of sulphonylureas in the presence of raised blood glucose levels and might therefore be of therapeutic relevance in treating hyperglycaemia in diabetes mellitus.…”

Functional identification of islet cell types by electrophysiological fingerprinting

“…In contrast, there is evidence that non-β-cells express an A-type transient K + current [29,31,38,46–48], a Na + current with depolarized inactivation properties relative to the β-cell [11,29,39–41,44–47,49,50] and T-type Ca 2+ channels [3,38,46]. Several laboratories have used these different electrophysiological fingerprints to distinguish between α-, β- and δ-cells [11,13,31,34–36,39–44,46–48,50–53]. …”