Monolayer cultures of neonatal rat pancreatic islets were superfused to examine phasic insulin secretion. When stimulated with a constant glucose concentration of 300 mg/dl, insulin secretion promptly rose to a peak more than eightfold higher than the basal levels observed with glucose 30 mg/dl. This first-phase peak was followed by a quick decline in insulin to a level about four- to fivefold higher than basal, representing second-phase insulin secretion. Addition of sodium salicylate 20 mg/dl enhanced glucose-stimulated insulin secretion. Addition of salicylate concurrently with glucose greatly enhanced second-phase insulin secretion, but did not affect the first-phase peak, thereby converting the biphasic pattern to one that appeared to be monophasic. However, when cultures were super-fused with salicylate both before and concurrent with stimulation by glucose, both the first-phase peak and the second phase of insulin secretion were increased, resulting in not only preservation but enhancement of the biphasic pattern. Salicylate had no effect on basal insulin secretion at glucose 30 mg/dl. During the transition from glucose 300 mg/dl to 30 mg/dl, immediately as glucose concentration began to fall in the superfusate, insulin secretion showed a transient increase (”off response”). Conclusions: (1) Cultures of neonatal rat pancreatic islet cells respond with a biphasic pattern of insulin secretion when exposed to a continuous and constant glucose stimulus. (2) When endogenous prostaglandin synthesis is inhibited by sodium salicylate, the biphasic pattern not only remains but is enhanced, indicating that endogenous prostaglandin synthesis exerts a tonic restraint throughout the entire period of glucose-stimulated phasic insulin release. (3) The biphasic pattern of glucose-stimulated insulin release is unlikely to be solely the consequence of an inhibitory action of prostaglandins. (4) Insulin responsiveness of neonatal rat islet B-cells to glucose is greater than previously reported. (5) A brief “off response” in insulin secretion is observed immediately upon removal of the glucose stimulus.

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