Effect of a non-sulphonylurea hypoglycaemic agent, KAD-1229 on hormone secretion in the isolated perfused pancreas of the rat

1 We examined the cooperative effect of a newly synthesized oral hypoglycaemic agent, KAD-1229 with glucose on insulin, glucagon and somatostatin secretion in the isolated perfused pancreas of the rat. 2 KAD-1229 stimulated concentration-dependently the first phase of insulin secretion without the second phase in the presence of 2.8 mM glucose, while it stimulated both the first and the second phase of insulin release in the presence of 5.6 mM glucose. It was confirmed that the first phase of insulin release is depolarization-induced release with no other additional signal transduction. 3 KAD-1229 also enhanced insulin release evoked by 16.7 mM glucose, a concentration known to inhibit the ATP-sensitive K+ current completely. 4 A low concentration (2.8 mM) of glucose stimulated somatostatin release transiently, while a higher concentration (16.7 mM) of glucose exerted a sustained stimulation. KAD-1229 stimulated somatostatin secretion in a concentration-dependent manner irrespective of glucose concentrations. 5 When glucagon release was stimulated with 2.8 mM glucose, KAD-1229 inhibited this hypoglycaemia-induced glucagon secretion. 6 When pancreata from rats pretreated with streptozotocin (STZ) 60 mg kg(-1) were perfused, the basal secretion of glucagon was markedly elevated, and the glucagon response to the low glucose was abolished. Further, the insulin and somatostatin responses to KAD-1229 were largely attenuated. KAD-1229 showed transient enhancement followed by inhibition of the glucagon release from the STZ-pretreated rat pancreas. 7 We conclude that KAD-1229 stimulates insulin and somatostatin release, while it inhibits glucagon release following transient stimulation.