The Restoring Effect of Caffeine on the Decreased Sensitivity of the Insulin Secretory Mechanism in Mouse Pancreatic Islets during Starvation

Abstract

It has been shown previously that isolated pancreatic islets display a decreased sensitivity of the insulin secretory mechanism to glucose during starvation. In the present study the insulinotropic actions of the primary stimuli glucose, mannose, leucine, tolbutamide, ouabain, and a high extracellular potassium concentration have been compared in isolated islets from fed and 48 h starved mice - in the presence and absence of caffeine. Also the effect of β-hydroxybutyrate and an increase of the extracellular concentration of calcium have been tested but both in the presence of glucose. The decreased sensitivity of the secretory mechanism was not restricted to glucose stimulation. Rates of insulin release in the presence of 16.7 mM mannose, 15 mM leucine, 20 mM potassium, (30 mM potassium + 2.5 mM glucose) and (20 mM β-hydroxybutyrate + 5 mM glucose) were also decreased by starvation as was the stimulatory response on raising the extracellular concentration of calcium in the presence of 16.7 mM glucose. The response to tolbutamide was unaffected. The diminished response to all the other stimulatory conditions was restored or greatly improved by the presence of 5 mM caffeine in the incubation medium. The results may suggest that the mechanism underlying the decrease sensitivity to a series of stimulatory conditions during starvation is an inability of the islets to increase the concentration of cyclic AMP on stimulation and/or disturbance of the distribution of calcium in the β-cells of starved mice. These disturbances may both be caused by the decreased islet glucose metabolism seen during starvation.