A B S T R A C T To assess the effect of age on 18-cell insulin release, collagenase-isolated islets of Langerhans were obtained from rats aged 2-18 mo and incubated with increasing concentrations of glucose. Similar islets were analyzed for insulin content or subjected to morphometric measurements to identify both the number of 13-cells and the volume of 8-granules per islet. In parallel studies, the islet content of intact pancreata was also determined. The results showed thatf1-cell number increased from 2,300 to 5,000 cells as rats aged from 2 to 18 mo and islet insulin content doubled. However, glucose-stimulated insulin release decreased progressively with age, and this was especially striking when considered in terms of the increase in number of,1-cells/islet; e.g., mean (±SEM) insulin secretion (nanounits per minute per ,8-cell) of islets incubated with 450 mg/dl of glucose was 1.3 (±0.2), 1.0 (±0.1), 0.4 (±0.05), and 0.3 (±0.01), respectively for 2-, 6-, 12-, and 18-mo-old rats. Thus, insulin secretion per 13-cell was decreased, despite increased stores of insulin per cell. These findings demonstrate that the aging process leads to a profound defect in glucose-stimulated insulin release from the ,8-cell. Whether this is a global secretory defect, or solely a failure ofthe ,3-cell to respond to glucose, remains to be defined.

Studies of isolated islets labeled with radioactive leucine show that glucose at a critical time "marks" islets in such a way as to cause preferential release of newly synthesized insulin. The preferential release of insulin from marked islets is relatively independent of subsequent secretagogues or rates of insulin secretion. Previous kinetic studies have indicated that the critical time at which marking occurs is after proinsulin biosynthesis but before the secretory event. Thus, secretory cells may regulate the diversion of newly synthesized material for immediate release as it is approaching or transiting the Golgi apparatus.

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A novel imidazoline compound, RX871024, was used to investigate the mechanisms by which imidazoline derivatives promote insulin secretion in rat pancreatic beta-cells and HIT T15 cells. RX871024 stimulated insulin release from rat pancreatic beta-cells and HIT T15 cells in a glucose-dependent way. This effect was not related to alpha2-adrenergic, I1-, and I2-imidazoline receptors. RX871024 promoted insulin release by at least two modes of action. One included an increase in cytoplasmic free Ca2+ concentration ([Ca2+]i), subsequent to blocking of ATP-dependent K+ channels, membrane depolarization, and activation of voltage-dependent Ca2+ channels. The other, a more distal effect of imidazoline, affected the exocytotic machinery and was unrelated to changes in membrane potential and [Ca2+]i. The mechanism of RX871024-induced insulin release was dependent on protein kinases A and C. The sensitizing effect of a low dose of RX871024 on glucose-induced insulin secretion suggests that imidazoline compounds of this kind may constitute the basis for development of a new class of oral hypoglycemic agents.