Comparison of the effects of perchlorate and Bay K 8644 on the dynamics of cytoplasmic Ca2+ concentration and insulin secretion in mouse beta-cells

Non-inbred ob/ob mice were used to study the dynamics of cytoplasmic Ca2+ concentration ([Ca2+](i)) in isolated pancreatic beta-cells using microfluorimetry with fura 2/AM as probe, and the dynamics of insulin secretion in isolated pancreatic islets. D-Glucose (20 mM) caused a transient peak increase in [Ca2+](i) which changed to either an oscillating or a flat, elevated phase. The lag-time before the first peak increase in [Ca2+](i) was markedly shortened by 12 mM ClO4- and the glucose-stimulated level of [Ca2+](i) after the first peak was clearly elevated by the anion. ClO4- also amplified K+-stimulated (20 mM) [Ca2+](i). ClO4- did not change the basal [Ca2+](i) at 3 mM glucose. Extracellular Ca2+ deficiency abolished the effect of high glucose and ClO4- on [Ca2+](i). This suggests that ClO4- acts as an amplifier of transmembrane Ca2+ inflow. The L-type Ca2+ channel agonist, Bay K 8644 (0.01-1.0 mu M), strictly reproduced all the effects of perchlorate on the glucose-stimulated beta-cell [Ca2+](i). Both phases of insulin release (20 mM glucose) were markedly enhanced by ClO4- (12 mM) or Bay K 8644 (1.0 mu M). The lag-time for glucose-stimulated insulin release was shortened by both agents. Taken together, these data strengthen the idea that perchlorate amplifies the glucose-stimulation of [Ca2+](i) and insulin release by directly modifying the function of the L-type Ca2+ channel. This effect can induce both a more prompt onset of and an amplified level of beta-cell secretory activity.