Age-dependent differences in insulin secretion and intracellular handling of insulin in isolated pancreatic islets of the rat.

Abstract

Insulin secretory response to glucose changes with age. To elucidate age-dependent differences in pancreatic islet responsiveness to glucose, isolated islets from rats one week, three months and 14 months old were investigated in vitro. At three months of age, islet insulin secretion was increased five-fold by an acute glucose challenge. There was a significantly lower insulin response in both younger and older age groups. Islet insulin biosynthesis, as determined by the rate of incorporation of radioactive leucine into immunoprecipitable insulin, was lower at three months of age than at one week or 14 months. Insulin content was lowest in islets from the youngest rats and increased with age. The capacity for islet intracellular degradation of insulin was estimated according to the disappearance of tritiated leucine-labelled insulin during a 24-hour chase incubation. At a high glucose concentration, virtually no insulin was degraded intracellularly in islets from three-month-old rats, whereas islets from both younger and older animals showed a significant degradative capacity. High activities of a number of lysosomal enzymes in islets from one-week-old rats could account for the high degradative capacity and relatively low insulin content of these islets. Thus, low insulin response to glucose during early development may depend primarily on low insulin stores. However, during ageing, when islets are characterised by high insulin content, low response may depend primarily on impairment of beta-cell stimulus-secretion coupling, with high intracellular degradation of insulin resulting secondarily from an accumulation of insulin in the islets.