STIMULATING ACTIVITY OF A-4166 ON INSULIN RELEASE IN IN-SITU HAMSTER PANCREATIC PERFUSION

Using the in situ hamster pancreatic perfusion system, the stimulating action of A-4166 on insulin release was examined in comparison with that of glibenclamide. Both antidiabetic agents stimulated insulin release, but its onset by A-4166 was faster than that by glibenclamide. In the presence of a basal glucose concentration (3 mmol/l), insulin releases induced by A-4166 and glibenclamide were inhibited by preexisting diazoxide. At higher glucose concentrations (5-16.7 mmol/l), however, A-4166 was able to reverse the inhibitory effect of diazoxide on the first and second phases of insulin release, while glibenclamide did not reverse the first-phase release. On the other hand, in the presence of 16.7 mmol/l of glucose A-4166 completely reversed the inhibitory action of diazoxide added simultaneously, but glibenclamide reversed it only partially. In the presence of 8 mmol/l of glucose, the stimulating action of A-4166 and glibenclamide on insulin release was hardly affected by inhibitors of ATP production. These results indicate that the stimulating action of A-4166 on insulin release is different from glibenclamide in response to the inhibitory action of diazoxide. These results also suggest that A-4166 is an effective agent for release of insulin by acting on the K-ATP channel, especially under an impaired function of pancreatic B cells.