ADAPTATION TO HYPERGLYCEMIA ENHANCES INSULIN-SECRETION IN GLUCOKINASEMUTANT MICE

The present study was undertaken to test the hypothesis that exposure to high glucose concentrations enhances insulin secretion in pancreati c islets from glucokinase-deficient mice. Insulin secretion and intrac ellular calcium ([Ca2+](i)) were measured as the glucose concentration was increased from 2 to 26 mmol/l in islets from heterozygous glucoki nase (GK)-deficient mice (GK(+/-)) and their wild-type littermates (GK (+/+)). Results obtained in islets incubated in 11.6 or 30 mmol/l gluc ose for 48-96 h were compared. GK(+/-) islets that had been incubated in 30 mmol/l glucose showed improved although not normal insulin secre tory and [Ca2+], responses to the standard glucose challenge as well a s an enhanced ability to sense small amplitude glucose oscillations. T hese effects were associated with increased glucokinase activity and p rotein. In contrast exposure of GK+/+ islets to 30 mmol/l glucose incr eased their basal insulin secretion but reduced their incremental secr etory responses to glucose and their ability to detect small amplitude glucose oscillations. Thus exposure of GK+/- islets to 30 mmol/l gluc ose for 48-96 h enhanced their ability to sense and respond to a gluco se stimulus, whereas similar exposure of GK(+/+) islets induced eviden ce of beta-cell. dysfunction, These findings provide a mechanistic fra mework for understanding why glucokinase diabetes results in mild hype rglycemia that tends not to increase over time. In addition, the absen ce of one allele of the glucokinase gene appears to protect against gl ucose-induced p-cell dysfunction (glucose toxicity).