Somatostatin and insulin secretion due to common mechanisms by a new hypoglycemic agent, A-4166, in perfused rat pancreas

Abstract

N-[(trans-4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine (A-4166) is a nonsulfonylurea hypoglycemic agent that decreases blood glucose levels in nondiabetic and diabetic animals. In the present study, we attempted to determine the effect of A-4166 on hormone secretion from the in vitro-perfused rat pancreas and to examine the underlying secretory mechanisms. In the presence of basal glucose (3 mmol/L), A-4166 markedly stimulated insulin and somatostatin release in a concentration-dependent manner over 0.03 to 3 mmol/L. A sulfonylurea, tolbutamide, also stimulated insulin and somatostatin release. A-4166 and tolbutamide elevated the level of glucagon release; however, the change lacked a clear concentration-dependent property. A-4166 at 0.3 mmol/L and tolbutamide at 3 mmol/L exhibited maximal stimulation of insulin release to a similar extent, indicating that A-4166 is one log-order more potent than and as effective as tolbutamide. By contrast, A-4166 stimulated somatostatin release to a threefold greater extent than tolbutamide. A-4166 evoked an increase in the cytosolic free-Ca2+ concentration ([Ca2+]i) in rat pancreatic beta cells. [Ca2+]i and insulin secretory responses to A-4166 were inhibited by nitrendipine (NTD), a blocker of the L-type Ca2+ channel, and by diazoxide (DAZ), an opener of the adenosine triphosphate (ATP)-sensitive K+ channel. Furthermore, A-4166-stimulated somatostatin release was also inhibited by NTD and by DAZ. The results indicate that A-4166 and tolbutamide stimulate the release of insulin and somatostatin, and that A-4166 is much more effective than tolbutamide in releasing somatostatin, a hormone that attenuates hyperglycemia under certain circumstances. It is concluded that A-4166-induced insulin release is mediated by an increase in [Ca2+]i in beta cells. An inhibition of ATP-sensitive K+ channels and a consequent activation of L-type Ca2+ channels appear to play a key role not only in insulin secretion from beta cells, but also in somatostatin secretion from delta cells in response to A-4166.