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F Ishihara, T Aizawa, N Taguchi, Y Sato and K Hashizume

Abstract

Insulin release, glucose utilization (3H2O formation from [5-3H]glucose), and glucose oxidation (14CO2 formation from [4C(U)] glucose) were determined in pancreatic islets from 96-h fasted rats at 37 ° C and those from fed rats at 22 ° C, using the islets from fed rats incubated at 37 ° C as controls. In the islets from 96-h fasted rats and those from fed rats incubated at 22 ° C, we could not demonstrate significant insulin release in response to high glucose concentrations of up to 16·7 mmol/l. However, 16·7 mmol/l glucose clearly augmented insulin release caused by a depolarizing concentration (50 mmol/l) of K+ in these islets: i.e. 16·7 mmol/l glucose plus 50 mmol/l K+ produced significantly greater insulin release than 50 mmol/l K alone. Glucose utilization and oxidation by the islet cells were suppressed by 96-h fasting of the rats or by lowering the incubation temperature to 22 ° C, and depolarization with K at 50 mmol/l did not at all augment glucose utilization and oxidation by the islets. Thus we conclude that reduction of glucose metabohsm in islets from fasted rats and in those incubated at low temperature eliminated initiation, but not augmentation, of insulin release by 16·7 mmol/l glucose. The data indicate that the metabolic threshold for the initiation of insulin release is significantly higher than it is for the augmentation of release by glucose.

Journal of Endocrinology (1994) 143, 497–503

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S Yamada, M Komatsu, T Aizawa, Y Sato, H Yajima, T Yada, S Hashiguchi, K Yamauchi and K Hashizume

When isolated rat pancreatic islets are treated with 16.7 mM glucose, a time-dependent potentiation (TDP) of insulin release occurs that can be detected by subsequent treatment with 50 mM KCl. It has been thought that TDP by glucose is a Ca2+-dependent phenomenon and only occurs when exposure to glucose is carried out in the presence of Ca2+. In contrast to this, we now demonstrate TDP under stringent Ca2+-free conditions (Ca2+-free buffer containing 1 mM EGTA). In fact, under these Ca2+-free conditions glucose caused an even stronger TDP than in the presence of Ca2+. TDP induced by glucose in the absence of extracellular Ca2+ was unaffected by inhibitors of protein kinase C (PKC). However, cerulenin or tunicamycin, two inhibitors of protein acylation, eradicated TDP without affecting glucose metabolism. The TDP by glucose was not associated with an increase in the cytosolic free Ca2+ concentration ([Ca2+]i) during subsequent treatment with high K+. Exposure of islets to forskolin under Ca(2+)-free conditions did not cause TDP despite a large increase in the cellular cAMP levels. In conclusion, glucose alone induces TDP under stringent Ca2+-free conditions when [Ca2+]i was significantly lowered. Protein acylation is implicated in the underlying mechanism of TDP.

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T Aizawa, T Kaneko, H Yajima, S Yamada, Y Sato, Y Kanda, S Kanda, M Noda, T Kadowaki, M Nagai, K Yamauchi, M Komatsu and K Hashizume

Oscillation of insulin release by the pancreatic islets was evaluated under stringent Ca(2+)-free conditions for the first time. Isolated single rat islets were exposed to 16.7 mM glucose in the presence of 1.9 mM Ca(2+), or under the stringent Ca(2+)-free conditions (Ca(2+) omission with 1 mM EGTA, 6 microM forskolin and 100 nM phorbol 12-myristate 13-acetate). Fifteen minutes after the initiation of glucose stimulation, effluent was collected at a 6-s interval, insulin was determined in duplicate by a highly sensitive insulin radioimmunoassay, and oscillation and pulsatility of release statistically analyzed. Significant oscillation of insulin release was observed in all islets irrespective of presence and absence of Ca(2+). Significant pulsatility of release was detected in 7 of 11 islets in the presence of Ca(2+) and three of six isl! ets in the absence of Ca(2+). In conclusion, high glucose elicits oscillatory insulin release both in the presence and absence of extracellular Ca(2+).