Pulsatile Insulin Release from Single Islets of Langerhans

Westerlund, J. 2000. Pulsatile insulin release from single islets of Langerhans. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 945. 49 pp. Uppsala. ISBN 91-554-4782-1 Insulin release from single islets of Langerhans is pulsatile. The secretory activities of the islets in the pancreas are coordinated resulting in plasma insulin oscillations. Nutrients amplitude-regulate the insulin pulses without influencing their frequency. Diabetic patients show an abnormal plasma insulin pattern, but the cause of the disturbance remains to be elucidated. In the present thesis the influence of the cytoplasmic calcium concentration ([Ca]i) and cell metabolism on pulsatile insulin release was examined in single islets of Langerhans from ob/ob-mice. Glucose stimulation of insulin release involves closure of ATP-sensitive K channels (KATP channels), depolarization, and Ca 2+ influx in ß-cells. In the presence of 11 mM glucose, pulsatile insulin secretion occurs in synchrony with oscillations in [Ca]i. When [Ca]i is low and stable, e.g. under basal conditions, low amplitude insulin pulses are still observed. When [Ca]i is elevated and non-oscillating, e.g. when the ß-cells are depolarized by potassium, high amplitude insulin pulses are observed. The frequency of the insulin pulses under these conditions is similar to that observed when [Ca]i oscillations are present. By permanently opening or closing the KATP channels with diazoxide or tolbutamide, respectively, it was investigated if glucose can modulate pulsatile insulin secretion when it does not influence the channel activity. Under these conditions, [Ca]i remained stable whereas the amplitude of the insulin pulses increased with sugar stimulation without change in the frequency. Metabolic inhibition blunted but did not prevent the insulin pulses. The results indicate that oscillations in metabolism can generate pulsatile insulin release when [Ca]i is stable. However, under physiological conditions, pulsatile secretion is driven by oscillations in metabolism and [Ca]i, acting in synergy.