Contrasting effects of sulfonylurea and K+ depolarization on insulin and glucagon secretion by perifused mouse islets

Background and aims: In pancreatic beta cells K_ATP channels couple changes in glucose metabolism to changes in insulin secretion via depolarization of the plasma membrane. In alpha cells, in contrast, where increased glucose levels inhibit hormone secretion, their role is in dispute.

Methods: Batches of 50 freshly isolated NMRI mouse islets were perifused with a HEPES-buffered Krebs-Ringer medium (2 mg/ml BSA) saturated with 95% O₂ and 5% CO₂, which contained the respective secretagogue. The contents of insulin and of glucagon were determined by ELISA from the same samples of the fractionated efflux.

Results: In the presence of 5 mM glucose steady state secretion levels of both hormones were reached after 60 min. Addition of the K_ATP channel blocker tolbutamide at a maximally effective concentration (500µM) led to an immediate increase in insulin secretion which reached a steady state after an initial overshoot. During this time there was no increase in glucagon secretion. Raising the potassium concentration to 40 mM resulted in a massive but only transient further increase in insulin secretion. Now the glucagon secretion increased too, with a biphasic characteristic: simultaneously with insulin a peak of secretion was reached which was followed by a nadir and a second peak when insulin levels decreased.

Conclusion: Block of K_ATP channels does not appear to be sufficient to elicit glucagon secretion, in contrast to the effect of a high extracellular K⁺ concentration. This is remarkable since the latter is widely believed to mimic depolarization by K_ATP channel closure.