Induction of memory in rat pancreatic islets by tolbutamide. Dependence on ambient glucose level, calcium, and phosphoinositide hydrolysis

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Abstract
The ability of the sulfonylurea tolbutamide to induce insulin output, increase phosphoinositide (PI) hydrolysis, and modulate the insulin response to other agonists was assessed. At 200 μM, tolbutamide increased both insulin release and the efflux of 3H from [3H]inositol-prelabeled islets only in the presence of 5.5 or 7 mM glucose. When the glucose level was maintained at 2.75 mM, tolbutamide (200 μM) had no positive impact on either parameter. The calcium-influx inhibitor nitrendipine (200 nM) blocked the effects of 200 μM tolbutamide (with 7 mM glucose) on 3H efflux and insulin output. Prior exposure of islets to tolbutamide (200 μM) in the presence of 7 mM glucose amplified their subsequent insulin response to 10 mM glucose and 5 mM glyceraldehyde. The effect of 200 μM tolbutamide (with 7 mM glucose) was blocked by nitrendipine. Furthermore, the effect of 200 μM tolbutamide was not observed with 2.75 mM glucose; however, if the level of tolbutamide was increased to 1 mM, both PI hydrolysis and potentiated release to subsequent stimulation with 10 mM glucose were observed. Tolbutamide (200 μM with 7 mM glucose) stimulation for 20 min resulted in an increase in 3H efflux from [3H]inositol-prelabeled islets. Despite the rapid fall in insulin secretion, elevated rates of 3H efflux persisted long after the removal of the sulfonylurea from the medium. The duration of the 3H-efflux response paralleled the duration of potentiation. Furthermore, nitrendipine (200 nM) blocked the sustained increase in 3H efflux usually noted after tolbutamide, indicating that this efflux represented the continued hydrolysis of PI and was not simply the result of the slow efflux and/or degradation of preformed labeled inositol phosphates. Direct measurements of labeled inositol phosphate accumulation substantiate all the 3H-efflux data. These results support the following conclusions: 1 ) tolbutamide increases PI hydrolysis in islets, an effect dependent on the level of tolbutamide, the ambient glucose concentration, and calcium influx; 2 ) once initiated, the increase in PI hydrolysis is sustained even after the removal of tolbutamide; and 3 ) biochemical events in the inositol cycle appear at least partly responsible for time-dependent potentiation (memory) to subsequent stimulation induced by prior exposure to tolbutamide.