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D-(-)-beta-Hydroxybutyrate and acetoacetate cause a rapid, sustained, and rapidly reversible stimulation of insulin release from rat pancreatic islets incubated in the presence, but not absence, of D-glucose. This coincides with stimulation of both proinsulin biosynthesis and 45Ca net uptake. The ketone bodies also decrease 45Ca outflow from prelabeled islets perifused in the absence of Ca2+ and, in contrast, enhance effluent radioactivity in the presence of Ca2+. In the presence of D-glucose, the secretory response to D-(-)-beta-hydroxybutyrate is concentration related in the 2.5-20 mM range, abolished in the absence of Ca2+ or presence of KCN, and enhanced by theophylline and forskolin. It corresponds grossly to a shift to the left of the sigmoidal curve relating insulin output to the ambient concentration of D-glucose. The secretory, biosynthetic, and cationic response to acetoacetate is less marked than that evoked by an equimolar concentration of D-(-)-beta-hydroxybutyrate. These features are compatible with the view that the insulinotropic action of ketone bodies would be causally linked to their metabolism in islet cells.

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