Rosiglitazone (BRL 49653) enhances insulin secretory response via phosphatidylinositol 3-kinase pathway

To elucidate the direct effect of rosiglitazone (RSG), a new thiazolidinedi one antihyperglycemic agent, on pancreatic insulin secretion, an in situ in vestigation by rat pancreatic perfusion was performed. At a basal glucose c oncentration of 6 mmol/l, RSG (0.045-4.5 mu mol/l) stimulated insulin relea se in a dose-dependent manner. In addition, 4.5 mu mol/l RSG potentiated th e glucose (10 mmol/l)-induced insulin secretion. Both the first and second phases of glucose-induced insulin secretion were significantly enhanced by RSG, by 80.7 and 52.4%, respectively. The effects of RSG on insulin secreti on were inhibited by a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY29 4002. In contrast, the glucose-stimulated insulin secretion was not affecte d by LY294002. The potentiation effect of RSG on glucose-stimulated insulin secretion, in both the first and second phases, was significantly blocked by LY294002. These results suggest that RSG has a direct potentiation effec t on insulin secretion in the presence of 10 mmol/l glucose, mediated throu gh PI3K activity. The inability of LY294002 to inhibit glucose-induced insu lin secretion suggests that different pathways are responsible for glucose and RSG signaling.