Nakayama K, Murakami N, Ohta M, Kato K, Notsu T, Mizota M, Miwa I, Okuda J
Department of Pharmacology, Fuji Central Research Laboratory, Mochida Pharmaceutical Co., Ltd., Tokyo, Japan.
Eur J Pharmacol. 1995 Mar 24;276(1-2):85-91. doi: 10.1016/0014-2999(95)00016-e.
We investigated the stimulatory effect of M16209 (1-(3-bromobenzo[b]furan-2-yl-sulfonyl)hydantoin), a novel aldose reductase inhibitor, on insulin secretion using isolated, perfused pancreases of rats. In the pancreases from normal rats, M16209 (100 microM) greatly augmented glucose-stimulated insulin secretion, but showed no effect on unstimulated insulin secretion at 2.8 mM glucose. In contrast, gliclazide (10 microM), a sulfonylurea, strongly enhanced both glucose-stimulated and unstimulated insulin secretion. Sorbinil and epalrestat, potent aldose reductase inhibitors, had no stimulatory effect on insulin secretion. M16209 (100 microM) improved appreciably the decreased insulin response to 22.2 mM glucose and enhanced slightly unstimulated insulin secretion in the pancreases of rats with neonatally streptozotocin-induced, non-insulin-dependent diabetes mellitus (NIDDM). Gliclazide (10 microM), however, failed to affect the pancreases of NIDDM rats. Furthermore, M16209 showed no appreciable effect on ATP-sensitive K(+)-channels in pancreatic beta-cells. These results suggest that M16209, unlike sulfonylureas, selectively enhances glucose-stimulated insulin secretion in both normal and NIDDM rats through a direct action on the pancreas. The site of action remains unknown, but the inhibition of aldose reductase or the ATP-sensitive K+ channels is unlikely to be involved.
我们使用大鼠分离的灌注胰腺研究了新型醛糖还原酶抑制剂M16209（1-(3-溴苯并[b]呋喃-2-基-磺酰基)乙内酰脲）对胰岛素分泌的刺激作用。在正常大鼠的胰腺中，M16209（100微摩尔）极大地增强了葡萄糖刺激的胰岛素分泌，但在2.8毫摩尔葡萄糖浓度下对基础胰岛素分泌无影响。相比之下，磺脲类药物格列齐特（10微摩尔）强烈增强了葡萄糖刺激的和基础胰岛素分泌。强效醛糖还原酶抑制剂索比尼尔和依帕司他对胰岛素分泌无刺激作用。M16209（100微摩尔）显著改善了新生链脲佐菌素诱导的非胰岛素依赖型糖尿病（NIDDM）大鼠胰腺对22.2毫摩尔葡萄糖降低的胰岛素反应，并轻微增强了基础胰岛素分泌。然而，格列齐特（10微摩尔）对NIDDM大鼠的胰腺无影响。此外，M16209对胰腺β细胞中的ATP敏感性钾通道无明显作用。这些结果表明，与磺脲类药物不同，M16209通过对胰腺的直接作用，在正常和NIDDM大鼠中选择性增强葡萄糖刺激的胰岛素分泌。作用位点尚不清楚，但醛糖还原酶或ATP敏感性钾通道的抑制不太可能参与其中。
