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Inhibition of Protein Synthesis Sequentially Impairs Distinct Steps of Stimulus-secretion Coupling in Pancreatic ß Cells¹

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

Address all correspondence and requests for reprints to: J. C. Henquin, Unité d’Endocrinologie et Metabolisme, UCL 55.30, avenue Hippocrate 55, B-1200 Brussels, Belgium. E-mail: henquin{at}endo.ucl.ac.be

Proteins with a short half-life are potential sites of pancreatic ß cell dysfunction under pathophysiological conditions. In this study, mouse islets were used to establish which step in the regulation of insulin secretion is most sensitive to inhibition of protein synthesis by 10 µM cycloheximide (CHX). Although islet protein synthesis was inhibited approximately 95% after 1 h, the inhibition of insulin secretion was delayed and progressive. After long (18–20 h) CHX-treatment, the strong (80%) inhibition of glucose-, tolbutamide-, and K⁺-induced insulin secretion was not due to lower insulin stores, to any marked impairment of glucose metabolism or to altered function of K⁺-ATP channels (total K⁺-ATP currents were however decreased). It was partly caused by a decreased Ca²⁺ influx (whole-cell Ca²⁺ current) resulting in a smaller rise in cytosolic Ca²⁺ ([Ca²⁺]_i). The situation was very different after short (2–5 h) CHX-treatment. Insulin secretion was 50–60% inhibited although islet glucose metabolism was unaffected and stimulus-induced [Ca²⁺]_i rise was not (2 h) or only marginally (5 h) decreased. The efficiency of Ca²⁺ on secretion was thus impaired. The inhibition of insulin secretion by 15 h of CHX treatment was more slowly reversible (>4 h) than that of protein synthesis. This reversibility of secretion was largely attributable to recovery of a normal Ca²⁺ efficiency. In conclusion, inhibition of protein synthesis in islets inhibits insulin secretion in two stages: a rapid decrease in the efficiency of Ca²⁺ on exocytosis, followed by a decrease in the Ca²⁺ signal mediated by a slower loss of functional Ca²⁺ channels. Glucose metabolism and the regulation of K⁺-ATP channels are more resistant. Proteins with a short half-life appear to be important to ensure optimal Ca²⁺ effects on exocytosis, and are the potential Achille’s heel of stimulus-secretion coupling.

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