Glucose metabolism and pulsatile insulin release from isolated islets.

The effects of metabolic inhibition on insulin release and the cytoplasmic Ca(2+) concentration (Ca(2+)) were studied in individually perifused pancreatic islets from ob/ob mice. The modest basal secretion in the presence of 3 mmol/l glucose was pulsatile with a frequency of approximately 0.2/min, although Ca(2+) was stable at approximately 100 nmol/l. Introduction of 11 mmol/l glucose resulted in large amplitude oscillations of Ca(2+) and almost 20-fold stimulation of average secretion manifested as increased amplitude of the insulin pulses without change in frequency. Inhibition of glycolysis with iodoacetamide or mitochondrial metabolism with dinitrophenol or antimycin A reduced glucose-stimulated secretion back to basal levels with maintained pulsatility. The Ca(2+) responses to the metabolic inhibitors were more complex, but in general there was an initial peak and eventually sustained elevation without oscillations. When introduced in the presence of 3 mmol/l glucose, the metabolic inhibitors tended to increase the amplitude of the insulin pulses, although the simultaneous elevation in Ca(2+) occurred without oscillations. The data indicate that pulsatile secretion is regulated by factors other than Ca(2+) under basal conditions and after metabolic inhibition. Although pulsatile secretion can be driven by oscillations in metabolism when Ca(2+) is stable, it was not possible from the present data to determine whether insulin pulses have a glycolytic or mitochondrial origin.