Onset and reversibility of changes in secretory function and composition of isolated rat pancreatic islets following long-term administrationof high or low tolbutamide doses.

Chronic administration of a high tolbutamide dose to rats induces islet hypertrophy associated with a decreased insulin content per islet and with a diminished insulin release in response to a glucose or leucine stimulus. These changes are reversible after discontinuation of tolbutamide. Chronic administration of a low tolbutamide dose (effective on islet size, on insulin content per islet, or on leucine-induced insulin release is normal in the presence of glucagon (5 mug/ml) or theophylline (5 mM). Since islet hypertrophy occurs following administration of high tolbutamide doses only and is associated with hypofunction rather than with hyperfunction, it seems hardly conceivable that the therapeutic principle of tolbutamide is based on a beta-cytotrophic effect. B-cell hypofunction seems to be due to at least three factors: the decrease in the insulin content per islet, an impairement in secretory signal recognition, and an interference with the process of signal transmission.