Do oscillations of insulin secretion occur in the absence of cytoplasmic Ca2+ oscillations in β-cells?

Abstract

That oscillations of the cytoplasmic free Ca2+ concentration ([Ca2+]i) in β-cells induce oscillations of insulin secretion is not disputed, but whether metabolism-driven oscillations of secretion can occur in the absence of [Ca2+]i oscillations is still debated. Because this possibility is based partly on the results of experiments using islets from aged, hyperglycemic, hyperinsulinemic ob/ob mice, we compared [Ca2+]i and insulin secretion patterns of single islets from 4- and 10-month-old, normal NMRI mice to those of islets from 7- and 10-month-old ob/ob mice (Swedish colony) and their lean littermates. The responses were subjected to cluster analysis to identify significant peaks. Control experiments without islets and with a constant insulin concentration were run to detect false peaks. Both ob/ob and NMRI islets displayed large synchronous oscillations of [Ca2+]i and insulin secretion in response to repetitive depolarizations with 30 mmol/l K+ in the presence of 0.1 mmol/l diazoxide and 12 mmol/l glucose. Continuous depolarization with high K+ steadily elevated [Ca2+]i in all types of islets, with no significant oscillation, and caused a biphasic insulin response. In islets from young (4-month-old) NMRI mice and 7-month-old lean mice, the insulin profile did not show significant peaks when [Ca2+]i was stable. In contrast, two or more peaks were detected over 20 min in the response of most ob/ob islets. Similar insulin peaks appeared in the insulin response of 10-month-old lean and NMRI mice. However, the size of the insulin peaks detected in the presence of stable [Ca2+]i was small, so that no more than 10-13% of total insulin secretion occurred in a pulsatile manner. In conclusion, insulin secretion does not oscillate when [Ca2+]i is stably elevated in β-cells from young normal mice. Some oscillations are observed in aged mice and are seen more often in ob/ob islets. These fluctuations of the insulin secretion rate at stably elevated [Ca2+]i, however, are small compared with the large oscillations induced by [Ca2+]i oscillations in β-cells.