Somatostatin and insulin secretion due to common mechanisms by a new hypoglycemic agent, A-4166, in perfused rat pancreas.
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.
Fujitani
S
S
Life Science Laboratories, Central Research Laboratories, Yokohama, Japan.
Ikenoue
T
T
Akiyoshi
M
M
Maki
T
T
Yada
T
T
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects; D003510:Cyclohexanes / Q000008:administration & dosage / Q000494:pharmacology*; D005934:Glucagon / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D000077715:Nateglinide; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism*; D010477:Perfusion; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013004:Somatostatin / Q000378:metabolism*; D013997:Time Factors
D015220:Calcium Channels; D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D007328:Insulin; D015221:Potassium Channels; D000077715:Nateglinide; D010649:Phenylalanine; D013004:Somatostatin; D000255:Adenosine Triphosphate; D005934:Glucagon; D002118:Calcium