Pancreatic islet responsiveness to D-glucose after repeated administration of repaglinide.

The influence of three daily oral doses of repaglinide (1.0 microg/g body wt.) on plasma insulin and glucose concentrations, pancreatic islet insulin content and both protein biosynthesis and insulin release in isolated islets incubated for 90 min in the presence of either 2.8 or 16.7 mM D-glucose was examined in both control and hereditary diabetic Goto-Kakizaki (GK) rats. In the control rats, repaglinide lowered the plasma glucose concentration, whilst failing to affect significantly the plasma insulin concentration or insulin/glucose ratio, 24 h after the last administration of the antidiabetic agent. Despite a severe decrease of islet insulin content, the ratio between insulin release and content was not altered in islets obtained from repaglinide-treated control rats and incubated in the presence of 16.7 mM D-glucose. Also the biosynthesis of islet peptides was increased at both low and high hexose concentrations. In GK rats, repaglinide administration affected neither plasma glucose nor insulin concentration, restored a normal value for the otherwise abnormally high basal insulin output, increased the 16.7 mM/2.8 mM ratio for insulin release, and again augmented protein biosynthesis at both low and high hexose concentrations. In both control and GK rats, the stress induced by bleeding and decapitation augmented plasma glucose concentration. This effect was more pronounced in GK than in control rats and, in the diabetic animals, coincided with a severe lowering of the plasma insulin/glucose ratio, suggesting a higher adrenergic sensitivity of islet cells in the GK than in control rats. The increased secretory responsiveness to glucose and increased biosynthetic activity found in islets from GK rats after repaglinide administration, are considered favourable attributes of this meglitinide analogue in the perspective of its use as an insulinotropic agent in noninsulin-dependent diabetes.