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

被引:32
作者
Fujitani, S [1 ]
Ikenoue, T [1 ]
Akiyoshi, M [1 ]
Maki, T [1 ]
Yada, T [1 ]
机构
[1] KAGOSHIMA UNIV,SCH MED,DEPT PHYSIOL,KAGOSHIMA 890,JAPAN
来源
METABOLISM-CLINICAL AND EXPERIMENTAL | 1996年 / 45卷 / 02期
关键词
D O I
10.1016/S0026-0495(96)90051-7
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 6 cells, but also in somatostatin secretion from 6 cells in response to A-4166. (C) 1996 by W.B. Saunders Company
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页码:184 / 189
页数:6
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