Regulation of 86Rb outflow from pancreatic islets: the dual effect of nutrient secretagogues.

1. An increase in the concentration of extracellular D-glucose from zero to 1.7 mM or more (up to 16.7 mM) causes a rapid and sustained decrease in 86Rb fractional outflow rate (FOR) from prelabelled and perifused pancreatic rat islets. The 86Rb FOR also decreases when the concentration of D-glucose is raised from 1.7 mM or more (up to 5.6 mM) to higher values not exceeding 8.3 mM. 2. However, when the glucose concentration is raised from 8.3 mM (or 11.1 mM) to higher values, no decrease in 86Rb FOR is observed and, instead, a transient increase in 86Rb FOR now takes place. 3. Such a dual effect on 86Rb FOR is also observed when alpha-ketoisocaproic acid is used as the nutrient secretagogue or when the latter keto acid is used in combination with D-glucose. 4. The transient increase in 86Rb FOR evoked by D-glucose in islets already exposed to alpha-ketoisocaproate is abolished by mannoheptulose, suggesting that it depends on the integrity of glucose metabolism. 5. The transient increase in 86Rb FOR evoked, under suitable experimental conditions, by D-glucose of alpha-ketoisocaproate is abolished in the absence of extracellular Ca2+ and mimicked by theophylline and tolbutamide, suggesting that it is attributable to an increase in cytosolic Ca2+ concentration. The latter view is supported by the fact that the increase in 86Rb FOR coincides with an increase in 45Ca FOR, provided that Ca2+ is not removed from the extracellular medium. 6. It is concluded that, in contrast to the situation found when the concentration of the nutrient secretagogue is increased from a non-insulinotropic to a higher value, the stimulation of Ca2+ entry into islet cells and the subsequent increase in insulin secretion evoked by D-glucose or alpha-ketoisocaproate when the concentration of these nutrients is increased from intermediate (8.3-10.0 mM) to higher values is not attributable to a decrease in K+ conductance.